National Evidence Based Guidelines.pdf

National Evidence Based Guidelines for the

Management of Type 2 Diabetes Mellitus

Part 7

Lipid Control in Type 2 Diabetes

Prepared by the Australian Centre for Diabetes Strategies

Prince of Wales Hospital, Sydney for the Diabetes Australia Guideline Development Consortium

APPROVED BY THE NHMRC 16 SEPTEMBER 2004

Table of Contents PART 7 1.0 Lipids Expert Working Group ................................................................................3 2.0 Guideline for Lipid Control in Type 2 Diabetes ....................................................5 2.1 Introduction..............................................................................................................5 2.2 Issues for Lipid Control in Type 2 Diabetes ............................................................7 2.3 Summary of Recommendations ...............................................................................8 2.4 Recommendations....................................................................................................9 Section 1: Lipid abnormalities associated with Type 2 diabetes ............................9 Section 2: Effect of diet and exercise on lipids ..................................................42 Section 3: Effect of improved blood glucose control on lipids.............................78 Section 4: Effects of treatment with lipid-modifying agents on lipids .................94 Section 5: Effects of treatment on outcomes ......................................................124 References ............................................................................................................167 Evidence References...................................................................................167 General References.....................................................................................184 Other References Identified........................................................................188 2.5 Lipid Control Search Strategy and Yield Table...................................................223

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1.0 Lipid Control Guideline Expert Working Group Chairperson Professor James Best Department of Medicine University of Melbourne MELBOURNE VIC Content Experts Dr Harvey Newnham Department of Medicine Monash University MELBOURNE VIC A/Professor Richard O’Brien Diabetes Unit Monash Medical Centre MELBOURNE VIC A/Professor Gerald Watts Department of Medicine Royal Perth Hospital PERTH WA A/Professor Tony Dart Baker Medical Research Institute MELBOURNE VIC ADEA Ms Gloria Kilmartin Department of Diabetes & Endocrinology Royal Melbourne Hospital MELBOURNE VIC Consumer Dr Graham Giles Cancer Control Research Institute

Cancer Epidemiology Centre MELBOURNE VIC RACGP Dr Peter Harris School of Medical Education University of NSW SYDNEY NSW Content and Methods Adviser Professor Stephen Colagiuri Department of Endocrinology Prince of Wales Hospital SYDNEY NSW

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Research Officers Dr Nasseem Malouf Diabetes Centre Prince of Wales Hospital SYDNEY NSW Ms Robyn Barnes Public Health Unit South Eastern Sydney Area Health Service SYDNEY NSW

Ms Sarah Smith Human Nutrition Unit University of Sydney SYDNEY NSW Ms Caroline George Human Nutrition Unit University of Sydney SYDNEY NSW

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2.0 Guideline for Lipid Control 2.1 Introduction Aim of the Guideline This guideline addresses issues relating to the control of lipid levels in Type 2 diabetes. Lipid abnormalities in people with in Type 2 diabetes can be broadly categorised into 2 groups: • those common to the general population such as elevated total and LDL cholesterol and • additional diabetes related abnormalities such as elevated triglycerides and reduced HDL

cholesterol The aim of the guideline is to assist health practitioners, principally general practitioners, to effectively and efficiently detect and manage lipid abnormalities in those with Type 2 diabetes. Quality Assurance The methods used to identify and critically appraise the evidence in order to formulate the guideline recommendations are described in detail in Part 1 of the document. Additional steps were taken to assure the quality of the Lipid Control Guideline eg: • the Project Management Team reviewed and checked each step of the methods process • selected searches were repeated • the chairman of the Lipids Control EWG double reviewed the majority of the articles

used as evidence references • the Medical Advisor reviewed and revised the entire final draft • the Project Management Team checked all recommendations and evidence statements and

compiled and checked the evidence tables, reference lists, and search strategy and yield tables

Guideline Format Issues identified by the EWG and from the literature as critical to the control of lipids in Type 2 diabetes are shown in point 7.1.2 (next page). Each of these issues is addressed in a separate section in a format presenting: • Recommendation(s) • Evidence Statements – supporting the recommendations • Background – to issues for the guideline • Evidence – detailing and interpreting the key findings • Summary – of major evidence found • Evidence Tables – summarising the evidence ratings for the articles reviewed For all issues combined, supporting material appears at the end of the guideline topic and includes: • Evidence references • General references • Other references identified • Search Strategy and Yield Tables documenting the identification of the evidence sources.

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The prevention of macrovascular disease is a major goal in the care of the person with Type 2 diabetes.

Multifactorial intervention is the key to the prevention of macrovascular disease.

This document should be considered in association with the

Macrovascular Disease, Blood Pressure Control, and Blood Glucose Control Guidelines

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2.2 Issues for Lipid Control in Type 2 diabetes

What lipid abnormalities are associated with Type 2 diabetes and what are the consequences?

What are the effects of diet and exercise on lipids in people with Type 2 diabetes?

What is the effect of improved blood glucose control on lipids in Type 2 diabetes?

What are the effects on lipids of treatment with lipid-modifying agents and hormone replacement therapy in Type 2 diabetes?

Does treatment with lipid modifying agents or hormone replacement therapy improve outcomes in Type 2 diabetes?

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2.3 Summary of Recommendations

Recommendations • People with Type 2 diabetes should have measurement of total cholesterol, triglycerides

and HDL cholesterol levels and calculation of LDL cholesterol • If feasible, lipid levels should be measured after a 10 to 12 hour overnight fast • More than one lipid measurement should be used to make decisions to initiate or

intensify lipid modifying therapy • Specific dietary advice should be given to all people with Type 2 diabetes and elevated

lipids which emphasises weight reduction in the overweight

• In people with Type 2 diabetes whose lipid levels are above target and who have

unsatisfactory diabetes control, efforts should be made to improve their blood glucose control before considering lipid modifying medication

• Statins should be used to lower LDL cholesterol when triglycerides are normal or only

slightly elevated. For severe hypercholesterolaemia, a bile acid binding resin or low dose nicotinic acid may be added.

• Fibrates should be used as first line therapy in people with predominantly elevated

triglycerides and low HDL cholesterol with normal to slightly elevated LDL cholesterol levels. If treatment with a fibrate is not tolerated or if additional triglycerides lowering effect is required, fish oil can be used but the effect on diabetes control should be monitored.

• Treatment with a statin and fibrate should be considered in people with moderate to

marked elevation of both LDL cholesterol and triglycerides. Because of the increased risk of myositis, the person should be fully informed and carefully monitored.

• People with Type 2 diabetes who have an LDL cholesterol >2.5mmol/L after

interventions to modify lifestyle and improve blood glucose control, should be considered for statin therapy

• People with Type 2 diabetes who have triglycerides >2.0mmol/L after interventions to

modify lifestyle and improve blood glucose control, should be considered for fibrate therapy

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2.4 Recommendations

Section 1: Lipids Issue

What lipid abnormalities are associated with Type 2 diabetes and what are the consequences?

Recommendations

People with Type 2 diabetes should have measurement of total cholesterol, triglycerides and HDL cholesterol levels and calculation of LDL cholesterol If feasible, lipid levels should be measured after a 10 to 12 hour overnight fast More than one lipid measurement should be used to make decisions to initiate or intensify lipid modifying therapy

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Evidence Statements • Triglycerides levels are increased in Type 2 diabetes

Evidence Level III-2

• HDL cholesterol is decreased in Type 2 diabetes Evidence Level III-2

• LDL cholesterol is similar in Type 2 diabetes and the general population, but LDL particle size is smaller Evidence Level III-2

• Total cholesterol is similar in Type 2 diabetes and the general population Evidence Level III-2

• There are intra-individual variations over time in lipid and lipoprotein levels in Type 2 diabetes Evidence level III-2

• Apolipoprotein A1 is reduced, apolipoprotein B is increased, and lipoprotein(a) is not altered in Type 2 diabetes Evidence Level III-2

• Lipid abnormalities are accentuated by increased body weight, poor glycaemic control

and diabetic renal disease Evidence Level III-2

• There is insufficient evidence to draw any conclusion about the importance of

lipoprotein oxidation in Type 2 diabetes Evidence Level III-2

• Total cholesterol and LDL cholesterol predict cardiovascular disease in Type 2 diabetes

Evidence level III-2

• HDL cholesterol and triglycerides predict cardiovascular disease in Type 2 diabetes Evidence level III-2

• The contribution of increased lipoprotein (a) to risk of cardiovascular disease in Type 2 diabetes is uncertain

Evidence level III-2

• There is limited evidence linking lipid levels and diabetic nephropathy Evidence level III-2

• There is limited evidence that lipid levels predict the development of hard exudates in

diabetic retinopathy Evidence level III-2

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Background – Lipid levels and Type 2 diabetes Lipid abnormalities are common in people with Type 2 diabetes and are a major contributor to the increase in cardiovascular disease experienced by people with Type 2 diabetes. Lipid abnormalities in Type 2 diabetes can be broadly categorised into 2 groups: Those which are common to the general population eg elevated total and LDL cholesterol Additional diabetes related abnormalities eg elevated triglycerides and reduced HDL

cholesterol Insulin resistance and central obesity are two closely linked factors (Brunzell & Hokanson, 1999) that are important in determining the additional lipid abnormalities found in Type 2 diabetes. The role of insulin resistance in the pathogenesis of Type 2 diabetes was recognised by Himsworth (1936) over 60 years ago. Central obesity was recognised as a risk factor for the development of Type 2 diabetes over 40 years ago (Vague, 1956) and many subsequent studies have confirmed this association. However, it was not until quantitative tests for insulin resistance were available that the importance and prevalence of insulin resistance was fully appreciated (Reaven, 1988). Under the heading of “Syndrome X”, Reaven linked insulin resistance with increased very-low-density lipoprotein (VLDL) triglycerides, decreased high-density lipoprotein (HDL) cholesterol levels and hypertension. Subsequently, the presence of small, dense low density lipoprotein (LDL) particles has been added to the list of lipid abnormalities associated with insulin resistance (Reaven et al, 1993). The association of lipid abnormalities with insulin resistance has led to an appreciation that disordered lipid metabolism is a fundamental aspect of Type 2 diabetes (McGarry et al, 1992). There is also strong evidence linking central adiposity with insulin resistance (Carey et al, 1996; Karter et al, 1996) so that central obesity is now considered an integral part of the insulin resistance syndrome (Haffner, 1996). Insulin resistance and central obesity have the potential to cause lipid abnormalities by several mechanisms (Garg, 1996; Brunzell & Hokanson, 1999). Impaired insulin action allows greater free fatty acid release from an increased mass of intra-abdominal adipose tissue, promoting hepatic triglycerides synthesis and VLDL production. At the same time, lipoprotein lipase activity, and therefore triglycerides clearance, is reduced by insulin resistance. Reduction of HDL cholesterol levels has been attributed to triglycerides enrichment by cholesterol ester transfer protein (CETP) and also to an increase of hepatic triglycerides lipase activity, related to insulin resistance. The concept that these lipid abnormalities are linked with insulin resistance and central adiposity rather than with Type 2 diabetes per se has been supported by the finding of elevated triglycerides and reduced HDL cholesterol levels in individuals who subsequently develop diabetes (Haffner et al, 1990; McPhillips et al, 1990). Reduced HDL cholesterol levels in first-degree relatives of people with diabetes have also been found (Stewart et al, 1995; Shaw et al, 1999). There is abundant epidemiological and clinical trial evidence in people without diabetes that lipoproteins play a major role in the pathogenesis of atherosclerotic vascular disease. The Framingham study showed a strong, graded, continuous positive relationship between total cholesterol and all clinical manifestations of coronary heart disease (CHD) risk (Kannel et al, 1988). This study also showed a very similar direct relationship between LDL cholesterol and CHD risk, reporting that a 1% increase in LDL cholesterol is associated with slightly more than a 2% increase in CHD over 6 years (Wilson, 1990). Similarly the MRFIT (Multiple Risk

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Factor Intervention Trial) study showed a strong, graded, positive relationship between death from CHD and total cholesterol above levels of 4.65 mmol/L for 316,099 white men followed for an average of 12 years (Neaton & Wentworth, 1992). During the course of the study there were 6,327 deaths from CHD. Death rates for men in the three categories of total cholesterol levels below 4.65 mmol/L (3.1; 3.6; 4.1 mmol/L) were similar (ranging from 7.7 to 8.9 deaths per 10,000 person-years). For cholesterol levels above 4.65 mmol/L age-adjusted death rates due to CHD gradually increased to a peak of 54.5 deaths per 10,000 person-years for cholesterol levels of 8.28 mmol/L or above (Neaton & Wentworth, 1992). HDL cholesterol is inversely related to triglycerides levels and both parameters have been linked with CHD risk in large prospective studies, the data being more consistent for low HDL cholesterol level and increased risk of CHD than for high triglycerides. In 12 years of follow-up for 2,748 Framingham Heart Study participants the relative risk of death from CHD was increased 4.1-fold for men with HDL cholesterol <0.9 mmol/L (lowest quintile) compared with men with HDL cholesterol >1.4 mmol/L (highest quintile). For women, death from CHD was increased 3.1-fold when HDL cholesterol was <1.2 mmol/L compared with HDL cholesterol >1.8 mmol/L (Wilson et al, 1988). Over 6 years, a 1% lower HDL cholesterol level was associated with a 3-4% higher risk of CHD (Wilson, 1990). The importance of HDL cholesterol level as a predictor of CHD has also been shown in the MRFIT study (Multiple Risk Factor Intervention Trial Research Group, 1986), the placebo arm of the Helsinki Heart Study (Manninen et al, 1990) and the Prospective Cardiovascular Munster (PROCAM) study (Assmann & Funke, 1990). There has been divided opinion about the importance of plasma triglycerides levels as an independent risk factor for CHD. The evidence from three major prospective studies supports a role for triglycerides as a synergistic risk factor. The Framingham Heart Study showed that over a 14-year period, triglycerides >1.7 mmol/L predicted increased CHD risk in men and women with HDL cholesterol <1.03 mmol/L after adjustment for age, systolic blood pressure, body mass index (BMI), low HDL, and electrocardiographically determined left ventricular hypertrophy (Castelli, 1992). For the 2,045 men in the placebo arm of the Helsinki Heart Study, triglycerides >2.3 mmol/L in conjunction with LDL cholesterol to HDL cholesterol ratio (LDL/HDL) >5 were associated with increased risk of death from CHD, with a relative risk (RR) of 3.82 (CI 2.20-6.63), whereas in people with triglycerides ≤2.3 mmol/L and LDL/HDL >5, the increased risk was only 1.19 (CI 0.61-2.32) (Manninen et al, 1992). The PROCAM study found very similar results (Assmann et al, 1998). People who had major coronary events (n=258) over 8 years had higher triglycerides levels and a greater LDL/HDL compared with those without major coronary events (n=4,381) (1.98 v 1.5. mmol/L, p<0.001; 4.6±1.6 v 3.4±1.2, p<0.001, respectively). Therefore, the combined data support a role for triglycerides level above 2.0 mmol/L as a risk factor when the LDL/HDL is > 5. In Type 2 diabetes the risk of CHD is significantly increased compared with the non-diabetic population. The key question regarding lipids and the increased CHD risk in Type 2 diabetes is whether the lipid and lipoprotein predictors of CHD in the general population operate in the same way in Type 2 diabetes. Lipid levels are not a universally recognised risk factor for cerebrovascular disease. A recent meta-analysis failed to find hypercholesterolaemia to be a risk factor for stroke in the general population (Prospective Studies Collaboration, 1995). On the other hand recent evidence indicates a reduced risk of stroke after lipid-lowering interventions with statins in people with

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pre-existing CHD (Sacks et al, 1996; LIPID Study Group, 1998; White et al, 2000; Heart Protection Study Collaborative Group, 2002a). A link between lipid levels and diabetic retinopathy and progression of diabetic nephropathy has been suggested and this is also reviewed in this Section. Evidence – Lipid levels and Type 2 diabetes Triglycerides levels are increased in Type 2 diabetes Elevation of triglycerides levels in people with Type 2 diabetes compared with those without diabetes has been consistently reported by most population-based and clinic-based surveys (Table 1). In most of the studies summarised in Table 1, average triglycerides levels were similar in men and women, although some studies indicate that hypertriglyceridaemia may be more marked in women with Type 2 diabetes than in men (Siegel et al, 1996). In people with Type 2 diabetes, average triglycerides levels were approximately 2.2 mmol/L compared with 1.6 mmol/L in the non-diabetic population. The difference in prevalence of elevated triglycerides levels is illustrated by the following sample of studies. Data from the Second National Health and Nutrition Examination Survey (NHANES II) (Cowie et al, 1994) showed that the prevalence of hypertriglyceridaemia (>2.8 mmol/L) was 34% in men aged 40-69 years with diabetes, compared with 11% in controls and 30% in women with diabetes compared with 6% in controls, but significance values were not stated. Another US-based population study, the Framingham Offspring Study, (Siegel et al, 1996) found that the prevalence of hypertriglyceridaemia (>2.75 mmol/L) was 23% in 120 men with diabetes compared with 9% in 1,878 controls (p<0.001) and 29% in 54 women with diabetes compared with 3% in 1,879 controls (p<0.001). Marked hypertriglyceridaemia (>5.5 mmol/L) was not more prevalent in men with diabetes (1.1% v 1.5% in controls), but was more prevalent in women with diabetes (11% v 0.2% in controls, p<0.001). In a Finnish population-based study (Salomaa et al, 1992) triglycerides were elevated (>2.3 mmol/L) in 48% of 42 men with diabetes compared with 22% of 32 men with impaired glucose tolerance (IGT) and 15% of 136 controls (p=0.008). Elevated triglycerides were found in 52% of 54 women with diabetes compared with 26% of 70 women with IGT and 11% of 187 controls (p=0.0001). Overall studies show that the crude prevalence of elevated triglycerides levels in people with diabetes is approximately 30% which is some 3-fold higher than the prevalence in people without diabetes. Studies of triglycerides levels after a fatty meal show increased levels in Type 2 diabetes (Cavallero et al, 1994; Curtin et al, 1994). In the diabetic group (n=14), people with hypertriglyceridaemia (n=8) had higher postprandial triglycerides levels compared with those with normotriglyceridaemia (n=6) (3.28±0.70 v 1.20±0.46 mmol/L, p<0.001), whereas diabetic people with normotriglyceridaemia (n=6) and controls (n=12) had a similar triglycerides levels after the test meal which contained 45 to 55% fat (Cavallero et al, 1994). Curtin et al (1994) also reported a significantly different pattern for triglycerides (p<0.05) following a fat-rich meal in the diabetic group (n=6) compared with the control group (n=6). Triglycerides-rich lipoprotein fraction were significantly higher after the fat-rich meal at all time points in people with diabetes (p<0.01). This postprandial hyperlipidaemia has been interpreted as indicating reduced chylomicron clearance and accumulation of triglycerides-rich chylomicron remnants in Type 2 diabetes.

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Table 1: Lipid levels and Type 2 diabetes

Lipid levelsReference Population Studied Mean Total

Cholesterol (mmol/L)Mean LDL

Cholesterol (mmol/L)Mean HDL

Cholesterol (mmol/L)Mean Triglycerides

(mmol/L)

Billingham, 1989 (UK)

n=130 mean age 57yrs New Type 2 diabetes: 22 Established Diabetes Diet treated: 30 Sulphonylureas: 28 Insulin: 17 Control: 33

6.2

6.3† (v control)

6.0 5.0† (v control)

5.7

4.50†

4.70† 4.30 3.30† 4.00

1.03†

1.12† 1.07† 1.33 1.36

1.19†

1.29† 1.34† 1.60 1.55

1.8†

1.5† 1.6† 0.7 0.9

Burchfiel, 1990 (US)

n=856, 20-74yrs, Anglo (A) & Hispanic (H), Type 2 Diabetes: 121 M; 158 W Control: 219 M; 269 W

M A, H

5.42, 5.46 5.57, 5.60

W A, H

5.90, 5.93 5.79, 5.82

M A, H

3.48, 3.37 3.62, 3.51

W A, H

3.52, 3.52 3.61, 3.62

M A, H

0.96, 1.05†† 1.15, 1.23

W A, H

1.24, 1.20†† 1.48, 1.44

M A, H

2.51,2.53†††† 1.80, 1.81

W A, H

2.56, 2.77†††† 1.54, 1.75

Byrne, 1994 (UK)

n=1,156, age 40-64yrs Type 2: 23 M; 28 W Control: 129 M; 181 W

- - - - - -

1.69 1.35

1.94††††

1.04

Cowie, 1994 (US)

n= 751M; 1,987W NHANES II age 20-74 yrs Type 2 diabetes Control

5.53 5.33

5.66 5.51

3.75 3.59

3.65 3.49

1.09††† 1.16

1.29††† 1.37

1.72†††† 1.32

1.60†††† 1.23

Haffner, 1994 (US)

San Antonio Heart Study Type 2: 33 M 62 W Control: 155 M 216 W

M 5.70 5.78

W 5.72 5.70

M 3.65 3.81

W 3.50 3.70

M 0.95

1.04††††

W 1.05

1.20††††

M 2.97

1.86††††

W 2.38

1.71††††

Hughes, 1998 (Singapore: Chinese, Indians, Malays)

Singapore Heart Study; age 30-69yrs Type 2 diabetes 72M; 54W Control: 248 M; 282 W

M

5.6 5.7

W

6.0 5.8

M

4.0 4.0

W

4.3 4.2

M

0.78 0.81

W

0.93 0.93

M

2.3†††† 1.9

W

2.2††† 1.6

Laakso, 1985 (East Finland)

Age: 45-64; Type 2 Diabetes (diet): 48 M; 40 W Sulphonylurea: 56M; 49W SU/Metformin: 14M; 15W Insulin: 17 M; 38 W Control: 65 M; 59 W

6.45 6.95 6.63 6.69 6.71

7.07 6.96 8.23 7.39 7.26

4.15 4.23 4.14 4.34 4.46

4.60 4.49† 4.86 4.34† 4.92

(all v control)

1.15†† 1.10†††† 1.12†† 1.05†† 1.34

(all v control)

1.25† 1.16†

1.19†††† 1.10†† 1.42

(all v control)

2.17† 3.52††

2.53†††† 2.45†† 1.49

(all v control)

2.16†††† 2.51†

4.65†††† 4.11†† 1.49

Between groups comparison † p<0.05, †† p<0.01, ††† p<0.005, †††† p<0.001

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(mmol/L)

Laakso, 1990 (Finland)

age 45-64yrs Type 2: 152 M; 153 W BMI <25: BMI 25-27 BMI >27 Control: 65 M; 59 W BMI <25: BMI 25-27 BMI >27

M

6.53 6.06 6.86

6.86 6.61 6.47

W

7.43 7.40 7.34

7.08 7.36 7.36

M

4.16 3.99 4.26

4.54 4.42 4.31

W

4.90 4.32 4.44

4.65 4.93 5.15

M (v BMI <25)

1.33 1.02††††

1.06††††

1.35 1.38 1.27

W (v BMI <25)

1.48 1.24†

1.09††††

1.49 1.57 1.31

M (v BMI <25)

1.72 1.82

3.36††††

1.38 1.39 1.77

W (v BMI <25)

1.74 3.80†

3.63††††

1.47 1.41 1.54

Manzato, 1993 (Italy)

mean age 67yrs Type 2 Diet: 54 Sulphonylurea: 26 SU/Fenformin: 17 Insulin: 23 Control: 30

6.06† (v control)

5.62 5.69 5.69 5.43

3.64 3.41 3.30 3.33 3.22

1.38 1.38 1.35 1.51 1.40

1.74 1.50 1.48 1.45 1.33

Mattock, 1988 (UK)

Type 2 diabetes; 82M; 59W Age 35-64yrs

M 5.63

W 6.08†

M -

W -

M 0.98

W 1.16††††

M 2.00

W 1.79

Nielsen, 1993 (Denmark)

30M; 7W per gp age 61yrs Type 2+Normoalbuminuria +Microalbuminuria +Macroalbuminuria Control

5.6 5.6 6.5 6.1

3.56 3.63 3.83 4.06

1.23 1.12 1.18 1.46

1.30

1.82†† (v control) 2.01†† (v control)

1.09

Niskanen, 1990 (Finland)

Type 2; mean age 56yrs + microalbuminuria: n=12 - micoralbuminuria: n=101 Control

6.88 6.44 6.71

3.65 4.00 4.28

0.92† (v AU-)

1.07 1.28†† (v AU-)

4.24† (v AU-)

2.38 1.55†† (v AU-)

Salomaa, 1992 (Finland)

Age: 45-64yrs Type 2: 42M; 54 W IGT: 32 M; 70 W Control: 136 M; 187 W

M 6.2

(v control) 6.4 6.1

W 6.4†

(v control) 6.9 6.5

- -

M 1.1††††

(v control) 1.2 1.3

W 1.3††††

(v control) 1.4 1.6

M 2.7††††

(v control) 1.8 1.6

W 2.7††††

(v control) 1.8 1.4

Scheffer, 2003 (The Netherlands)

Age >65yrs Type 2 diabetes, n=58 Controls, n=58

5.8 6.0

3.7 3.9

1.29

1.54††††

1.5

1.2†††† Between groups comparison † p<0.05, †† p<0.01, ††† p<0.005, †††† p<0.001. AU: microalbuminuria

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(mmol/L)Siegal, 1996 (US)

Framingham offspring Diabetes (1+2): 120M; 54W Control: 1,878M; 1,879W

M 5.45 5.51

W 5.93††††

5.47

M 3.42† 3.55

W 3.46 3.42

M 1.00††††

1.15

W 1.09††††

1.48

M 2.04††††

1.61

W 3.33††††

1.15

Suranti, 1992 (France)

Type 2 diabetes; n=380 - normoalbuminuria - microalbuminuria

5.88 5.90

-

1.31

1.21††††

1.67 1.82

UKPDS 11, 1994 (UK)

Age 52yra, New Type 2 Diabetes: 297 M; 210 W Control: 52 M; 143 W

M 5.5 5.2

W 5.8† 5.5

M 3.6 3.3

W 3.9†††† 3.40

M 1.01† 1.09

W 1.15††††

1.38

M 1.79††††

1.22

W 1.66††††

1.10

Uusitupa, 1986 (East Finland)

Age: 45-64yrs Type 2: 70 M; 63 W Control: 62 M; 82 W

M 6.3 6.7

W 6.5 6.7

M 4.08† 4.45

W 4.26† 4.52

M 0.99††††

1.25

W 1.17††††

1.41

M 2.46† 1.90

W 2.37††††

1.38 Between groups comparison † p<0.05, †† p<0.01, ††† p<0.005, †††† p<0.001

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HDL cholesterol is decreased in Type 2 diabetes A reduced HDL cholesterol in people with Type 2 diabetes has been demonstrated in many population-based and clinic-based surveys. Of the studies summarised in Table 1, average HDL cholesterol levels were approximately 0.2-0.3 mmol/L higher in women than in men. In people with Type 2 diabetes, average HDL cholesterol levels were approximately 0.2 mmol/L lower than in the non-diabetic population. The difference in prevalence of decreased HDL cholesterol levels is illustrated by the following sample of studies. In the Framingham Offspring Study (Siegal et al, 1996) the prevalence of low HDL cholesterol (<0.9 mmol/L) was 44% in diabetic men compared with 20% in controls (p<0.001) and 38% in diabetic women compared with 9% in controls (p<0.001). NHANES II data (Cowie et al, 1994) showed HDL cholesterol was <0.9 mmol/L in 28% of diabetic men compared with 14% of controls and 10% in diabetic women compared with 6% in controls. In a Finnish population-based study (Salomaa et al, 1992), HDL cholesterol was <1.02 mmol/L in 55% of men with diabetes compared with 25% of men with IGT and 20% of controls. HDL cholesterol was <1.2 mmol/L in 52% of women with diabetes compared with 31% of women with IGT and 18% of controls. In general studies show that the crude prevalence of reduced HDL cholesterol levels in people with diabetes is approximately 2-fold higher than in people without diabetes. LDL cholesterol is similar in Type 2 diabetes and the general population, but LDL particle size is smaller LDL cholesterol concentration can be determined in the following ways: Calculated: • The approach most frequently used in the reviewed studies was to separate VLDL and

HDL particles by ultracentrifugation or by precipitation of non-HDL particles. Cholesterol content of the VLDL and HDL fractions was measured and LDL cholesterol concentration was calculated by subtracting VLDL cholesterol and HDL cholesterol from total cholesterol concentration (Laakso et al, 1985; Billingham et al, 1989; UKPDS 11, 1994; Siegel et al, 1996).

• The main alternative approach is to calculate LDL concentration using the Friedewald equation (Burchfiel et al, 1990; Hughes et al, 1998; Tsalamandris et al, 1998). This method estimates the cholesterol content of the triglycerides-rich lipoproteins as triglycerides concentration in mmol/L ÷ 2.2 (providing triglycerides ≤4.5 mmol/L) and calculates LDL cholesterol by subtracting this value and HDL cholesterol from total cholesterol (Friedewald et al, 1972).

Direct measurement: Less commonly, LDL particles are separated by ultracentrifugation and cholesterol concentration measured directly (Manzato et al, 1993). There is a good correlation between calculated and measured LDL cholesterol in people with Type 2 diabetes (Branchi et al, 1998), but the more direct measures are preferred for epidemiological studies. Most studies have found similar LDL cholesterol levels in people with Type 2 diabetes and people without diabetes (Table 1). Average LDL cholesterol levels in the Caucasian populations were 3.6 mmol/L for men with diabetes, 3.8 mmol/L for women with diabetes, 3.6 mmol/L for non-diabetic men and 3.7 mmol/L for non-diabetic women. Also the prevalence of elevated LDL cholesterol is similar. In the Framingham Offspring Study

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(Siegel et al, 1996), LDL cholesterol levels ≥4.2 mmol/L were present in 22% of men with diabetes compared with 27% of controls and in 35% of women with diabetes compared with 22% of controls (p=NS). NHANES II data (Cowie et al, 1994) showed LDL cholesterol was ≥4.2 mmol/L in 38% of diabetic men compared with 39% of controls and 52% in diabetic white compared with 35% in controls (the 95% CI were very wide for each of these figures). However, consistent with the strong inverse correlation between triglycerides level and LDL particle size, diabetes is associated with smaller LDL particle size. In the Framingham Offspring Study a weighted LDL particle score ≥3.5 (small, dense particles) was present in 49% of women with diabetes compared with 33% of controls (p<0.05) and in 40% of men with diabetes compared with 11% of controls (p<0.001). The presence of small dense LDL particles was significantly associated with diabetes and hypertriglyceridaemia in both sexes (OR 1.79, p=0.002 for men; OR 5.27, p<0.0001 for women) (Siegel et al, 1996). In the San Antonio Heart Study of mainly Mexican-American subjects (Haffner et al, 1994), LDL particle size was smaller in diabetic men and women, compared with non-diabetic men and women (252.2±1.8 v 256.1±0.8 Å, p=0.048 for men; 254.7±1.3 v 259.7±0.7 Å, p=0.005 for women). Also the percentage of small LDL particles was higher in people with diabetes (men 52%; 49% women) than in people without diabetes (38%; 33%, respectively). After adjustment for triglycerides and HDL cholesterol levels, LDL size was only significantly smaller in women with diabetes than in women without diabetes (p=0.043). In a case-control study, Scheffer et al (2003) examined the relationship of in vitro LDL oxidisability (ie lag time) and circulating in vivo oxidised LDL with LDL particle size in 58 elderly people (aged >65 years) with well-controlled Type 2 diabetes and 58 age-matched controls with normal glucose metabolism. Mean LDL cholesterol level was similar in people with and without diabetes (3.7±0.9 v 3.9±0.9 mmol/L, p=0.36), but the LDL particle size was significantly smaller in people with diabetes (21.3±0.5 v 21.7±0.3 nm, p<0.001). Although lag time did not differ between the diabetes and control group (71.5±9.6 v 71.7±7.7 min, p=0.94), the diabetes group had a non-significantly higher level of circulating in vivo oxidised LDL (87.2±26.9 v 81.0±22.1 U/L, p=0.18). The LDL particle size was found to be inversely associated with oxidised LDL in people with diabetes (r= -0.35, p=0.007). This relation remained strong after controlling for LDL cholesterol level (r= -0.52, p<0.001). Total cholesterol is similar in Type 2 diabetes and the general population Total cholesterol concentration represents the sum of LDL, HDL and VLDL cholesterol, with contributions usually ranking in that order. Lower HDL cholesterol levels in Type 2 diabetes reduce total cholesterol, while higher triglycerides levels are associated with more VLDL cholesterol and so increase total cholesterol. The balance of total cholesterol represents LDL cholesterol, the concentration of which is usually unaltered by diabetes. Because diabetes induced changes in HDL cholesterol and VLDL cholesterol are in opposite directions and LDL cholesterol is unaltered, total cholesterol levels in diabetic subjects are similar to non-diabetic populations in most studies (Table 1). Of the studies summarised in Table 1, average total cholesterol levels in the Caucasian populations were 6.2 mmol/L for men with diabetes, 6.6 mmol/L for women with diabetes, 6.2 mmol/L for non-diabetic men and 6.4 mmol/L for non-diabetic women. Overall the prevalence of elevated total cholesterol is similar in diabetic and non-diabetic people. For example, NHANES II data (Cowie et al, 1994) showed total cholesterol was ≥6.2 mmol/L in 46% of diabetic men compared with 35% of controls and 49% in diabetic women

19

compared with 40% in controls. In the Finnish survey by Salomaa and colleagues (1992), total cholesterol was >6.9 mmol/L in 33% of men with diabetes compared with 31% of men with IGT and 21% of controls. Total cholesterol >7.3 mmol/l was found in 11% of women with diabetes, 37% with IGT and 24% of controls (Salomaa et al, 1992). However some studies have noted some differences in total cholesterol levels in diabetes. The Framingham Offspring Study (Siegel et al, 1996) reported total cholesterol ≥6.2 mmol/l in 18% of men with diabetes compared with 23% of controls (p=NS) and in 41% of women with diabetes compared with 23% of controls (p<0.001). Implications for Clinical Practice People with Type 2 diabetes frequently have higher triglycerides levels and lower HDL cholesterol levels compared with the general population. Total and LDL cholesterol levels are similar in people with and without diabetes and the prevalence of elevated total and HDL cholesterol levels are also similar. As reviewed in other Sections of this Guideline, elevated total cholesterol, LDL cholesterol and triglycerides, and a low HDL cholesterol all predict an increased risk for coronary heart disease in Type 2 diabetes. Therefore, a complete assessment of lipid levels in people with Type 2 diabetes requires the measurement of total cholesterol, triglycerides and HDL cholesterol and calculation of LDL cholesterol. There are intra-individual variations over time in lipid and lipoprotein levels in Type 2 diabetes. Intra-individual variations of lipid and lipoprotein levels are observed in people with Type 2 diabetes. This intra-individual variability is derived from both analytical variability (measurement error) and biological variability with the latter accounting for most of the variability (Smith et al, 1993). A study of biological variability in 135 people with diabetes (both Type 1 and Type 2) (Tsalamandris et al, 1998) found that total variability expressed as a coefficient of variation was 8.8±0.4% for total cholesterol, 23.9±1.5% for triglycerides, 10.2±0.5% for HDL cholesterol and 12.0±0.5% for calculated LDL cholesterol over an average follow-up period of 5.1 years. Greater variability was observed in men compared with women for total cholesterol (9.5±0.5% v 7.9±0.5%, p<0.01) and for triglycerides (26.5±2.2% v 20.4±1.4%, p=0.03). Most of the variability in these parameters was related to biological factors, not measurement error (Tsalamandris et al, 1998). In the United Kingdom Prospective Diabetes Study (UKPDS), the baseline triglycerides concentration in people allocated to diet correlated with the values six months later (rs=0.72; CI 0.68 to 0.76) while the correlation between repeated measures of HDL cholesterol was lower (rs=0.52; CI 0.45 to 0.58) (Turner et al, 1998). An important source of biological variability for some lipid fractions is whether or not lipids are measured in the fasting state, particularly in relation to increasing the variability in the triglycerides levels. Diurnal and monthly variability of serum lipids were examined in 11 healthy subjects aged 32-63 years (Wasenius et al, 1990). Blood sample were drawn at 8am after 8 hour fasting, 12pm, 3pm, 6pm and 9pm for diurnal measurements, and were drawn weekly at 8am after 8 hour fasting for monthly measurements. The mean diurnal variability was 2.4% for total cholesterol, 3.5% for HDL cholesterol, 5.1% for LDL cholesterol, and 29.5% for triglycerides. The corresponding monthly variabilities were 4.2%, 4.1%, 5.2%, 20.7%, respectively. Implications for Clinical Practice Epidemiological and intervention studies in Type 2 diabetes have measured lipid levels after a 10 to 12 hour overnight fast and therefore evidence relating to lipid abnormalities and their treatment is based on this sampling method. Despite this, recommendations between

20

organisations have varied somewhat on this point. The National Cholesterol Education Program (NCEP) (The National Cholesterol Education Program Expert Panel, 2002) and the Heart Foundation of Australia (National Heart Foundation of Australia & The Cardiac Society of Australia and New Zealand, 2001) recommend sampling after a 12 hour fast when screening for lipid abnormalities. The UK Clinical Guidelines on Lipid Management for Type 2 diabetes (Collaborative Programme between: Royal College of General Practitioners, Diabetes UK, Royal College of Physicians, Royal College of Nursing) recommend fasting measurement if feasible (McIntosh et al, 2002). However it should be noted that there is little change in total cholesterol, HDL cholesterol and LDL cholesterol postprandially, so these lipid parameters can be measured satisfactorily in the non-fasting state. Taking the available information into account, it is recommended that lipid levels be assessed after an overnight fast of 10-12 hours. However it is recognised that only triglycerides (and to a small extent calculated LDL cholesterol) are affected by non-fasting. Depending on individual and practice circumstances it may not be feasible to measure lipids in the fasting state, however if lipid levels are not measured fasting, caution is required in interpreting an elevated triglycerides level and calculated LDL cholesterol. Because there is intra-individual variation over time in lipids in Type 2 diabetes, management decisions should generally be based on more than one measurement. There are no clinical trials on optimal frequency for re-assessment of lipid levels. The Clinical Practice Recommendations of the American Diabetes Association (ADA, 2003) state that “levels of LDL, HDL, total cholesterol, and triglycerides should be measured every year in adult patients. If values fall in the lower-risk levels, assessment may be repeated every 2 years”. The UK Clinical Guideline for Type 2 Diabetes on Lipid Management recommends annual assessment of lipid levels as part of the annual review (McIntosh et al, 2002). As with all recommendations, the frequency of re-assessment should be modified by clinical judgment. However in general, it is considered that lipid levels should be measured at the time of diagnosis in people with Type 2 diabetes and annually as part of the annual review. In people with lipid levels above target, levels should be re-evaluated 3 months after recommended lifestyle (diet/exercise) changes (See Section 2) and after improving glycaemic control (See Section 3), and after commencing lipid-lowering agents (See Sections 4 & 5). In people on long term lipid-lowering therapy, lipid levels would usually be measured at 6 monthly intervals. Apolipoprotein A1 is reduced, apolipoprotein B is increased, and lipoprotein(a) is not altered in Type 2 diabetes Apolipoprotein A1 (Apo A1) is the major apolipoprotein in HDL particles and consistent with the lower levels of HDL cholesterol, several studies have shown lower Apo A1 levels in Type 2 diabetes. In the Framingham Offspring Study (Siegel et al, 1996) the mean Apo A1 level was 134 mg/dl in 54 people with diabetes compared with 158 mg/dl in 1,879 people without diabetes (p<0.001). Apo A1 levels were also consistently lower in people with diabetes compared with people without diabetes for both sexes (100 v 105 mg/dl, p<0.01 in men; 107 v 116 mg/dl, p<0.01 in women) in a population based study in Finland (Rönnemaa et al, 1989). In a clinic based study (Billingham et al, 1989), the mean Apo A1 level was 94 mg/dl in 13 men at diagnosis of diabetes, compared with 114 mg/dl in 17 men without diabetes (p<0.05). In 9 women the mean Apo A1 level at diagnosis of diabetes was 107 mg/dl, compared with 125 mg/dl in 16 women without diabetes (p<0.05). However, Dean et al (1990) found that people with Type 2 diabetes (n=35) had a similar Apo A1 level compared with 35 control subjects (121.4±24.1 v 131.4±36.5 mg/dl, p=NS). Another case-control study showed that there was no significant difference in Apo A1 level between 120

21

people with diabetes and 30 control subjects (149±27 v 151±28.2 mg/dl) (Manzato et al, 1993). One apolipoprotein B (Apo B) molecule is present in each LDL and VLDL particle, so that Apo B level is a measure of the combined total number of these particles. In the Framingham Offspring Study (Siegel et al, 1996) mean Apo B level was 106 mg/dl in those with diabetes, compared with 83 mg/dl in controls (p<0.001). Apo B levels were also consistently higher in people with diabetes than in the controls (123 v 117 mg/dl in men, p<0.05; 125 v 119 mg/dl in women, p<0.05) in a population based study in Finland (Rönnemaa et al, 1989). In a clinic based study (Billingham et al, 1989) mean Apo B level was 95 mg/dl in 22 men and women at diagnosis of diabetes, compared with 75 mg/dl in 33 controls (p<0.05). Another clinic based study (Manzato et al, 1993) found mean Apo B level of 150 mg/dl in 120 people with diabetes compared with 135 mg/dl in 30 control subjects (p=0.02). In contrast, the clinic based study by Dean et al (1990) found no difference in Apo B between 35 people with and 35 people without diabetes (90.9±24.0 v 96.2±22.5 g/dl, p=NS). The higher Apo B levels in Type 2 diabetes indicate higher numbers of both VLDL and LDL particles, consistent with higher triglycerides levels and normal LDL cholesterol levels, but smaller, denser LDL particles. Apolipoprotein (a) is an apolipoprotein with structural homology to plasminogen. Bound to the Apo B moiety of a lipoprotein that closely resembles a LDL particle, it forms lipoprotein (a) [Lp(a)] that is potentially atherogenic and thrombogenic. Most studies of Lp(a) in Type 2 diabetes indicate that levels are not different to those found in the non-diabetic population (Haffner et al, 1992a; Csaszar et al, 1993; Velho et al, 1993; Chang et al, 1995). A population based study (Haffner et al, 1992a) showed a similar Lp(a) concentration for both men and women in people with and without diabetes (13.6±1.5 v 16.1±1.4 mg/dl; 12.6±0.8 v 15.9±1.3 mg/dl, respectively) (p=0.361). In a case control study (Csaszar et al, 1993), the mean Lp(a) concentration among people with Type 2 diabetes did not differ from those of control subjects in both Hungarian (12.2±17.9 v 10.5±13.5 mg/dl) and Austrian groups (14.6±21.0 v 12.2±16.5 mg/dl). Another case control study in a Chinese population also showed no difference in the Lp(a) levels between people with and without diabetes (22.3±2.2 v 20.7±1.9 mg/dl) (Chang et al, 1995). Velho et al (1993) compared Lp(a) levels in people with Type 2 diabetes, their normoglycaemic relatives, and healthy controls and found that Lp(a) levels were not significantly different (27.2±19.3 v 27.1±18.2 v 23.1±15.1 mg/dl, p=0.38). Lipid abnormalities are aggravated by increased body weight, poor glycaemic control, and diabetic renal disease In people with Type 2 diabetes, greater disturbance of lipid metabolism has been reported in association with increasing body weight, poor glycaemic control, diabetic renal disease and female gender. Increasing body mass index (BMI) and waist:hip ratio (WHR) within the Type 2 diabetes population have been linked with hypertrigyceridaemia and reduced HDL cholesterol in a number of studies (Table 1) in both men and women (Laakso et al, 1985; Uusitupa et al, 1986; Laakso & Pyorala, 1990; Byrne et al, 1994). Laakso et al (1985) reported that BMI had a statistically significant negative correlation with HDL levels (p<0.001 for both men & women) and a positive correlation with triglycerides (p<0.001 in men; p<0.05 in women) in people with Type 2 diabetes. Uusiputa et al (1986) also found a negative correlation of BMI with HDL cholesterol levels (p=0.014 in men; p=0.066 in women) and a positive correlation of BMI with triglycerides (p=0.023; p=0.046, respectively) in a population of 133 people with Type 2 diabetes. In a case control study, obesity was associated with a lower HDL cholesterol level (BMI >27.0 v <25.0 kg/m2: 1.06 v 1.33 mmol/L, p<0.001 in men; 1.09 v

22

1.48 mmol/L in women) and higher triglycerides levels (3.36 v 1.72 mmol/L, p<0.001; 3.63 v 1.74 mmol/L, p<0.001, respectively) in 305 people with Type 2 diabetes (Laakso & Pyorala, 1990). Byrne et al (1994) found that WHR had a positive association with triglycerides concentrations in people with diabetes (p<0.001 for men; p<0.01 for women). A correlation between measures of glycaemic control and HDL cholesterol has been reported (Laakso et al, 1985). After adjusting for age, physical activity and BMI, fasting plasma glucose (FPG) was significantly associated with HDL cholesterol in both men (p=0.003) and women (p<0.001) with Type 2 diabetes (Laakso et al, 1985). The influence of glycaemic control has important implications for determining decisions relating to the initiation of lipid-modifying therapy. Treatment of hyperglycaemia should generally precede initiation of treatment for lipid abnormalities especially when triglycerides are elevated or HDL cholesterol is reduced (see Lipids Section 3). The development of diabetic nephropathy is associated with a further reduction of HDL cholesterol and increase of triglycerides in Type 2 diabetes (Mattock et al, 1988; Niskanen et al, 1990; Suraniti et al, 1992; Nielsen et al, 1993). A cross-sectional study of 141 people with diabetes found there were significant correlations between albumin excretion rate and total triglycerides (r=0.214, p<0.05) and HDL cholesterol (r=-0.243, p<0.01) (Mattock et al, 1988). Among 123 people with diabetes, there were no differences in triglycerides and HDL cholesterol in people with (n=21) and without microalbuminuria (n=92) at baseline. However, at the 5-year examination, people with microalbuminuria had a significantly higher triglycerides levels (4.24±0.90 v 2.38±0.16 mmol/L, p<0.05) and a lower HDL cholesterol level (0.92±0.05 v 1.07±0.03 mmol/L, p<0.05) compared with those without microalbuminuria (Niskanen et al, 1990). A negative correlation of urinary albumin excretion to HDL cholesterol (p=0.0001) was found by Suraniti et al (1992) in 380 people with Type 2 diabetes. In a case control study, people with Type 2 diabetes and macroalbuminuria (>300 mg/24h) had a higher median triglycerides levels than in people with microalbuminuria (31-300 mg/24h) and people with normoalbuminuria (≤30 mg/24h) (2.01 [0.66-14.70] v 1.82 [0.69-3.96] v 1.30 [0.24-23.76] mmol/L, p<0.01) (Nielsen et al, 1993). There is insufficient evidence to draw any conclusion about the importance of lipoprotein oxidation in Type 2 diabetes Results of studies of lipoprotein oxidation in Type 2 diabetes have been variable. Some studies have reported increased lipid peroxidation products in plasma (Nacitarhan et al, 1995; Ceriello et al, 1997a; Freitas et al, 1997) but others have not (MacRury et al, 1993; Haffner et al, 1995). Nacitarhan et al (1995) measured malondialdehyde (MDA), a marker of lipid peroxidation, among people with Type 2 diabetes (n=78, including n=34 with hyperlipidaemia), people with hyperlipidamia (n=38), and healthy controls (n=28) and found that serum MDA level was significantly higher in people with diabetes (7.1±2.5; 6.2±1.7 nmol/L, respectively) and hyperlipidaemia (5.7±1.01 nmol/L) than in healthy controls (4.8±0.8 nmol/L) (all p<0.001). In the diabetic group, people with hyperlipidaemia had a higher serum MDA level than normolipidaemic people (p<0.02). Urine MDA levels in the diabetic group were higher than that of the non-diabetic hyperlipidaemic group (5.7±2.6; 5.7±2.3 nmol/L, respectively v 4.5±1.1 nmol/L, p<0.01). Ceriello et al (1997a) reported that total radical-trapping antioxidant parameter (TRAP), a marker of plasma antioxidant capacity, was significantly reduced in people with diabetes (n=46) compared with control subjects (n=47) (677±58 v 950.1±16.0 μmol/L, p<0.001). However, a study conducted by MacRury et al (1993) showed that the level of plasma antioxidant, caeruloplasmin, was

23

higher in people with diabetes than control subjects (19.3±6.9 v 14.2±5.1 μmol/L, p<0.01). A number of studies have reported increased lipid susceptibility to oxidation using plasma (Haffner et al, 1995) or LDL (Dimitriadis et al, 1995; Leonhardt et al, 1996) from subjects with Type 2 diabetes. Ceriello et al (1997b) reported the existence of lower antioxidant defenses in people with Type 2 diabetes. TRAP measured by fluorescence-based method and calculated by a mathematical formula were both lower in diabetic people (n=40) than controls (n=40) (690.4±16.5 v 961.9±16.7 μmol/L, p<0.001; 615.2±15.2 v 669.3±11.8 μmol/L, p<0.005, respectively). However, a study of 72 people with Type 2 diabetes and 94 non-diabetic controls did not find any difference in LDL susceptibility to oxidation, (Leinonen et al, 1998a). Another study by the same group of antioxidant defenses in 81 people with Type 2 diabetes and 102 controls showed no difference (Leinonen et al, 1998b). Nearly all studies have used non-specific measures of lipoprotein oxidation or have examined in vitro susceptibility to oxidation or antioxidant capacity. None of these measures gives a direct indication of the importance of lipoprotein oxidation in Type 2 diabetes. The results of these indirect tests have been variable and it is therefore not possible to draw any evidence-based conclusion about the importance of lipoprotein oxidation in Type 2 diabetes. Total cholesterol and LDL cholesterol predict cardiovascular disease in Type 2 diabetes Data from cross-sectional studies provide information on the association between lipid levels and cardiovascular disease while prospective cohort studies provide information on the relationship of lipid levels and the future development of cardiovascular disease. Cross-sectional studies Cross-sectional studies provide limited evidence for total and LDL cholesterol as risk factors for cardiovascular disease (CVD) in Type 2 diabetes (see Table 2). Nearly all studies have used a composite of macrovascular disease indicators and few studies have included more than 100 subjects. Some studies have found higher total and LDL cholesterol in association with CVD in Type 2 diabetes. The Milan Study on Atherosclerosis and Diabetes excluded people on insulin therapy, as well as those with clinical CVD or diabetes complications (MiSAD Group, 1997). In order to detect silent myocardial ischaemia, 925 people aged 40 to 65 years underwent exercise ECG, followed by exercise thallium scintigram if the ECG was abnormal. Total cholesterol was 5.83±1.12 mmol/L in the 59 subjects with both tests positive compared with 5.48±1.04 mmol/L in the other 866 subjects (p=0.014). Another hospital based study in London assessed people with Type 2 diabetes for CHD using resting ECG, history and standard questionnaire and for peripheral vascular disease using questionnaire and ankle/arm systolic blood pressure ratio (Seviour et al, 1988). Men with macrovascular disease (n=48) had higher total cholesterol and LDL cholesterol levels compared with men without evidence of macrovascular disease (n=47) (5.98±1.20 v 5.15±0.98 mmol/L, p=0.0001; 4.29±0.95 v 3.57±0.74 mmol/L, p=0.0001, respectively). The corresponding figures among women were 6.46±1.51 v 5.71±1.01 mmol/L (p=0.04); and 4.68±1.26 v 3.82±0.96 mmol/L (p=0.008), respectively. Two North American studies have also shown higher LDL cholesterol in association with prevalent CHD in Type 2 diabetes. Of 227 subjects with Type 2 diabetes in the Rochester Diabetic Neuropathy Study (O'Brien et al, 1994), 96 were defined as having CHD on the basis of history and ECG, abnormal non-invasive cardiovascular tests or abnormal coronary angiography. Total cholesterol was 5.26±1.03 mmol/L in this group, compared with

24

5.04±1.00 mmol/L in the 131 subjects without evidence of CHD on history and ECG (p=0.085), while LDL cholesterol was 3.40±0.87 mmol/L in those with CHD, compared with 3.13±0.88 mmol/L in those without CHD (p=0.039). A Canadian study used coronary angiography to classify 174 people with Type 2 diabetes as having mild, moderate or severe CHD. Although total and LDL cholesterol were not significantly different across the three groups, a multiple linear regression analysis model of the relation between coronary score and lipoproteins showed that LDL cholesterol made a significant and independent contribution to the model (p=0.008) (Tkac et al, 1997). In an Italian study of 3,862 people with Type 2 diabetes (aged ≥50 years), Giansanti et al (1999) reported that the prevalence of CHD was 20.3%. In the 50-59 year age group, more people with CHD had hypercholesterolaemia (≥5.8 mmol/L) compared with people without CHD (26 v 9.3%, p<0.001). People aged 60-69 years and ≥70 years with CHD had a significantly higher prevalence of hyperlipidaemia (total cholesterol ≥5.8 mmol/L plus triglycerides ≥2.26 mmol/L) than those without CHD in the same age group (28 v 17.9%, p<0.001; 21 v 14.8%, p<0.001, respectively). Some other cross-sectional studies have found little or no evidence for a link between total or LDL cholesterol and CVD in Type 2 diabetes. A population based study of men and women with Type 2 diabetes in East and West Finland identified subjects with previous myocardial infarction (MI) on the basis of ECG and medical records (Ronnemaa et al, 1989). For men with Type 2 diabetes from East Finland total cholesterol was higher in those with previous myocardial infarction. Total cholesterol was 7.15 mmol/L in 66 men with CHD compared with 6.71 mmol/L in 187 men without CHD (p<0.05). In men from West Finland and in women from East or West Finland total cholesterol was not significantly raised in the CHD positive groups. A large clinic based study of Type 2 diabetes in the US identified the presence of CVD (coronary heart disease, cerebrovascular disease and peripheral vascular disease) by self-administered questionnaire (Meigs et al, 1997). Mean cholesterol level was 5.92 mmol/L in 787 diabetic subjects with CVD and precisely the same in 752 subjects without CVD.

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Table 2: Lipid levels and cardiovascular disease in people with Type 2 diabetes

Reference Population Studied Total Cholesterol

LDL Cholesterol HDL Cholesterol Triglycerides

Fontbonne, 1989 (France)

Paris Prospective Study n=7,038 men 43-45 yrs 11-yr follow-up IGT 690; newly diagnosed Type 2 diabetes 158; known Type 2 diabetes 135 CHD No CHD

6.3 mmol/L 5.7† mmol/L

- -

- -

2.07 mmol/L 1.47††mmol/L

T-CHOL ≥5.2 mmol/L TG ≥2.26 mmol/L

Giansanti, 1999 (Italy)

n=3,862 Type 2 diabetes aged ≥50 yrs, cross-sectional study age 50-59 yrs age 60-69 yrs age ≥70 yrs

CHD+ 26%

17%

12%

CHD- 9.3%†††† (v CHD+)

13.3%

11.0%

- -

CHD+ 26%

28%

21%

CHD- 25.3%

17.9%†††† (v CHD+) 14.8%†††† (v CHD+)

Hanefeld, 1996 (Germany)

n=1,846 Type 2 diabetes; 11-yr follow-up age 30-55 yrs during follow-up, without IHD during follow-up, with IHD during follow-up, with MI

5.69 mmol/L 5.61 mmol/L 5.93 mmol/L

-

-

1.88 mmol/L 1.78 mmol/L

2.32†† mmol/L

HPS Collaborative Group, 2003

n=5,963 diabetes, 90% Type 2 diabetes age 40-80 yrs 5-yr follow-up

Before

5.7

After 5yrs

4.6

Before

3.2

After 5yrs

2.3

Before

1.06

After 5yrs

1.07

Before

2.3

After 5yrs

2.0

Lehto, 1997 (Finland)

n=1,059 Type 2 diabetes, 7-yr follow-up age 45-64 yrs without CHD with CHD

Men

6.29 6.96††††

(v CHD-)

Women

6.99 7.32

Men

4.18 4.80

Women

4.66 4.48

Men

1.19 1.09††††

(v CHD-)

Women

1.28 1.20

Men

2.22 2.84

Women

2.62 3.82

Meigs, 1997 (US)

n=1,539 Type 2 diabetes; 2-yr follow-up age 31-91 yrs CVD+ CVD-

5.91 5.91

-

1.09 1.14††

-

Between groups comparison † p<0.05, †† p<0.01, ††† p<0.005, †††† p<0.001 The results of HPS are baseline and after treatment comparison, no p value given in the paper

26




MiSAD, 1997 (Italy)

n=925 Type 2 diabetes aged 40-65 yrs, cross-sectional study CHD+ CHD-

5.83±1.12 5.48±1.04†

- -

1.16±0.29 1.21±0.32

2.14±1.03 1.71±0.99†††

O’Brien, 1994 (USA)

n=227 Type 2 Diabetes cross sectional study CAD+ CAD-

5.04 5.26

3.13 3.40††††

0.98 0.82 †

2.33 2.66 ††††

Ronnemaa, 1989 (Finland)

cross sectional study, age 45-64 yrs Type 2 East Finland: 253M;257W, MI+ MI- Type 2 West Finland: 328M; 221W, MI+ MI- Control East Finland: 313M; 336W, MI+ MI- Control West Finland: 325M;399W, MI+ MI-

Men 7.15 6.71†

(v MI+) 6.71 6.12

6.85 6.76

6.79 6.49

Women 8.14 7.32

7.78 6.64

7.83 7.06

7.38 6.84

- -

Men 1.14

1.26†††† (v MI+)

1.02 1.14††

(v MI+) 1.19 1.40†

(v MI+) 1.36 1.32

Women 1.19 1.32

1.22 1.26

1.63 1.62

1.41 1.63

Men 2.82

2.58†††† (v MI+)

2.72 2.09†††† (v MI+)

2.74 1.52†††† (v MI+)

1.52 1.47

Women 3.14 3.21

2.99 2.44†

(v MI+) 1.52 1.40

1.79 1.25†

(v MI+)

Saito, 2000 (Japan)

n=1,676 diabetes (type not stated) 8-yr follow-up CHD+ CHD-

5.97 5.68†††

3.83 3.63†

1.07 1.18††††

TG (log)

0.76 0.52††††

Seviour, 1988 (UK)

n=53 W, 95 M; mean age 63 yrs cross-sectional study MVD+ MVD-

Men

5.98 5.15††††

Women

6.46 5.71

Men

4.29 3.57††††

Women

4.68 3.82

Men

0.88 0.89

Women

0.95 1.28††††

Men

1.79 1.52

Women

1.83 1.33


27




Stamler, 1993 (US) MRFIT

n=5,163 men taking medication for diabetes; aged 35-75 yrs, 12-yr follow-up high CVD death low CVD death

4.66 7.25††††

- -

- -

- -

Tkac, 1997 (Canada)

n=174 Type 2 diabetes; mean age 57yrs cross sectional study mild CAD moderate CAD severe CAD

4.88 5.12 5.15

3.00 3.17 3.16

1.04 1.02 1.01

0.84 0.93 0.98

Turner, 1998 (UK)

UKPDS n=2,963 Type 2 diabetes; 7.9-yr follow-up age 25-65 yrs CHD lower third CHD upper third

4.88 5.77††††

3.02 3.89††††

0.95 1.15††††

1.22 1.87††††


28

Longitudinal studies Longitudinal studies provide more compelling evidence that total and LDL cholesterol levels predict CHD risk in Type 2 diabetes (see Table 2). The MRFIT study included 5,163 men who reported taking medication for diabetes. Of these men, 603 died from CVD, including 469 deaths from CHD over an average follow up period of 12 years (Stamler et al, 1993). Total cholesterol level was a significant predictor of CVD mortality. Mortality rates ranged from 61.7 per 10,000 person-years for a total cholesterol of <4.66 mmol/L to 130.4 per 10,000 person-years for a total cholesterol of ≥7.25 mmol/L, 2.1 times greater than in men with total cholesterol of <4.66 mmol/L. Higher total cholesterol was associated with greater absolute excess risk of cardiovascular death for men with diabetes compared with men without diabetes, ranging from 48 per 10,000 person-years follow up at total cholesterol <4.66 mmol/L to 84 per 10,000 person-years when total cholesterol was ≥7.25 mmol/L. Even though the distribution of total cholesterol was the same in Type 2 diabetes as in the general population, at each cholesterol level there was a higher absolute risk of CHD in the Type 2 diabetic population than in the non-diabetic population. Furthermore, the increase in risk associated with diabetes was greater at higher cholesterol levels. The Nurses’ Health Study provides comparable data for women with Type 2 diabetes (Manson et al, 1991). During 8 years of follow up the rate of nonfatal myocardial infarction and fatal CHD in women with total cholesterol ≥6.21 mmol/L was 452 per 100,000 person-years compared with 262 per 100,000 person-years when cholesterol was <6.21 mmol/L. The excess risk attributable to Type 2 diabetes was 225 per 100,000 person-years at the lower cholesterol levels and 319 per 100,000 person-years at higher levels. Analysis of risk factors for CHD was undertaken in 2,693 people in the UKPDS who had recently diagnosed Type 2 diabetes but no evidence of CVD at baseline (Turner et al, 1998). With a median duration of follow up of 7.9 years, both total and LDL cholesterol predicted development of CHD. Total cholesterol levels were divided into tertiles (<4.88 mmol/L, ≥4.88 to <5.77 mmol/L and ≥5.77 mmol/L). The hazard ratio (HR) for development of CHD (fatal or non-fatal myocardial infarction or clinical angina with an abnormal ECG at rest or after a treadmill test) was 1.79 for the middle tertile and 1.93 for the upper tertile compared with the lower tertile (p<0.0001). For LDL cholesterol the lower tertile was <3.02 mmol/L, the middle tertile ≥3.02 to <3.89 mmol/L and the upper tertile ≥3.89 mmol/L. The HRs compared with the lower tertile were 1.48 for the middle tertile and 2.29 for the upper tertile (p<0.0001). For each increment of 1 mmol/L in LDL cholesterol level there was a 1.57-fold (CI 1.37-1.79) increased risk of CHD (Turner et al, 1998). Another large prospective trial from Finland included 1,059 people with Type 2 diabetes aged 45 to 64 years who were followed for a mean of 7.2 years (Lehto et al, 1997), of whom 158 died of CHD during follow-up. The unadjusted HR for CHD mortality was 1.4 (CI 1.0-1.9, p=0.052) and for all CHD events was 1.4 (CI 1.1-1.8, p=0.012) when total cholesterol was ≥6.2 mmol/L compared with <6.2 mmol/L. The corresponding unadjusted HR was 1.3 (CI 0.9-1.9, p=NS), and 1.5 (CI 1.1-2.1, p=0.009), respectively, when LDL cholesterol was ≥4.1 mmol/L compared with < 4.1 mmol/L. Saito et al (2000) followed 1,676 people (mean age 54 years) with diabetes (type not stated) and no reported history of coronary heart disease for 8 years in the Atherosclerosis Risk in Communities Study. During the follow-up, 186 cases of coronary heart disease events were identified. People who had a coronary event had a higher total cholesterol (5.97 v 5.68

29

mmol/L, p=0.003) and LDL cholesterol (3.83 v 3.63 mmol/L, p=0.03) than those event-free subjects. The WHO Multinational Study of Vascular Disease in Type 2 Diabetes (Fuller et al, 2001) showed that among 3,483 people with Type 2 diabetes, total cholesterol predicted the incidence of fatal and nonfatal MI after adjusting for age (RR 1.3 [CI 1.1-1.4], p=0.0001 for men; RR 1.3 [CI 1.2-1.5], p=0.0001 for women, respectively); whereas serum triglycerides were not significantly associated with this endpoint in any groups, with a RR of 1.2 (CI 1.0-1.4, p=0.08) for men and of 1.2 (CI 1.0-1.4, p=0.06) for women. The multivariate analysis also showed total cholesterol was significantly associated with CVD mortality, with a RR of 1.2 (CI 1.1-1.3) for men and 1.3 (CI 1.2-1.5) for women. Triglycerides as a risk for increased CVD mortality was only observed in men with diabetes (RR 1.3, CI 1.1-1.6). In the Diabetes Atherosclerosis Intervention Study of 405 people aged 40-65 years with Type 2 diabetes, Vakkilainen et al (2003) reported that small LDL size was significantly associated with progression of coronary artery disease (CAD), which was assessed by coronary angiography, over a mean follow-up of 39.6 months. Small LDL size was shown to be associated with an increase in percentage diameter stenosis (r=-0.16, p=0.002), and decrease in mininum (r=-0.11, p=0.03) and mean lumen diameter (r=-0.16, p=0.0002). In multivariate analysis, the combination of small LDL size and LDL cholesterol level showed a statistically significant association with the progression of CAD (p<0.001). In the Heart Protection Study (HPS Collaborative Group, 2003), the mean total cholesterol was 5.7 mmol/L and LDL cholesterol was 3.2 mmol/L at baseline among 5,963 people with diabetes (90% Type 2 diabetes). Over the 5-year treatment period, the incidence of major vascular event in people assigned to the placebo group was 22.2% for those with initial total cholesterol <5.0 mmol/L, and was 26.1% for those with initial total cholesterol ≥5.0 mmol/L (0.05<p<0.10). The corresponding figure was 20.9% and 27.9% for those with initial LDL cholesterol <3.0 mmol/L, and ≥3.0 mmol/L, respectively, and this difference was statistically significant (p<0.001). However, there have been occasional exceptions to this finding. Total cholesterol was not a risk factor for CHD in the Diabetes Intervention Study, which was based in Germany and included people with recently diagnosed Type 2 diabetes (Hanefeld et al, 1996). From data obtained at 11 year follow up on 994 subjects aged 30 to 55 years, 112 suffered from myocardial infarction and 197 had died. The mean total cholesterol was 5.93 mmol/L and 5.70 mmol/L in people who suffered from myocardial infarction and people without clinical evidence of CHD respectively (p=NS). Similarly, the mean total cholesterol was 5.90 mmol/L and 5.70 mmol/L respectively among people who died during follow-up and people who survived (p=NS). The general conclusion from both prospective and cross-sectional studies is that total cholesterol and its main constituent LDL cholesterol are associated with and are predictive of CVD risk in Type 2 diabetes. Because the overall risk of CVD is greater in Type 2 diabetes, the absolute increment of risk associated with elevated total or LDL cholesterol is greater than in the general population and therefore the predictive importance of these parameters is greater in Type 2 diabetes.

30

HDL cholesterol and triglycerides predict cardiovascular disease in Type 2 diabetes HDL cholesterol and triglycerides are inversely related. There is clear evidence for an independent relationship between HDL cholesterol and CVD risk. The situation is less clear for triglycerides as an independent risk factor as opposed to a risk marker in people with Type 2 diabetes. Elevations of triglycerides can be confounded by changes in other lipids (most notably HDL cholesterol) and by non lipid factors including obesity, hypertension, diabetes and smoking. If elevated triglycerides are an independent risk factor then this is thought to be mediated by atherogenic triglycerides rich remnant lipoproteins which are cholesterol enriched and have many of the properties of LDL cholesterol (NCEP 2001; NCEP, 2002). Cross-sectional studies Elevated triglycerides and reduced HDL cholesterol are found in Type 2 diabetes and both have been associated with increased risk of CHD in Type 2 diabetes in some but not all studies (see Table 2). In the Milan Study on Atherosclerosis and Diabetes, the mean triglycerides level was 2.14±1.03 mmol/L in the 59 subjects with evidence of CHD compared with 1.71±0.99 mmol/L in the other 866 subjects (p=0.002). The mean HDL cholesterol level in the group with CHD was 1.16±0.29 mmol/L, not significantly different from the level of 1.21±0.32 mmol/L in the group without evidence of CHD (MiSAD Group, 1997). The study by Seviour and colleagues (1988) found that triglycerides and HDL cholesterol were risk factors in women but not in men. In women with macrovascular disease triglycerides were 1.83 mmol/L and HDL cholesterol 0.95 mmol/L, compared with 1.33 mmol/L and 1.28 mmol/L (p=0.05 and p=0.0001 respectively) in women without macrovascular disease. In men with macrovascular disease triglycerides were 1.79 mmol/L and HDL cholesterol 0.88 mmol/L, compared with 1.52 mmol/L and 0.89 mmol/L (both p=NS) in men without evidence of macrovascular disease. For men from the population-based study of Type 2 diabetes in East and West Finland, higher triglycerides and lower HDL cholesterol were both associated with CHD (Ronnemaa et al, 1989). Men with CHD from East Finland had mean triglycerides of 2.81 mmol/L compared with 2.58 mmol/L in men without CHD and in West Finland the levels were 2.72 and 2.09 mmol/L (both p<0.001). In men from East Finland mean HDL cholesterol was 1.14 mmol/L in those with CHD compared with 1.26 mmol/L in those without CHD and in West Finland the levels were 1.02 and 1.14 mmol/L (p<0.001 and p<0.01 respectively). In women from West Finland triglycerides were 2.99 mmol/L in those with CHD compared with 2.44 mmol/L in those without CHD (p<0.05), but triglycerides were not different between women with and without CHD in East Finland. The presence of CHD was not associated with reduction of HDL cholesterol in women from either East or West Finland. The Rochester Diabetic Neuropathy Study reported mean triglycerides levels of 2.66 mmol/L and HDL cholesterol levels of 0.82 mmol/L in the CHD positive group. In comparison, the CHD negative group reported triglycerides levels of 2.33 mmol/L and HDL cholesterol levels of 0.98 mmol/L (p=0.055 for triglycerides and p=0.0001 for HDL cholesterol) (O'Brien et al, 1994). In the Canadian angiography study triglycerides and HDL cholesterol levels were not significantly different between the mild, moderate and severe groups, but the number of triglycerides-rich lipoprotein particles were greater in those with moderate and severe disease than in those with mild disease (p=0.001); and there was a correlation between the coronary score and the triglycerides-rich lipoprotein (p=0.006) (Tkac et al, 1997). The US clinic based study that identified CVD by self-administered questionnaire reported a mean HDL

31

cholesterol of 1.09 mmol/L in 787 diabetic people with CVD and 1.14 mmol/L in 752 people without CVD (p=0.01). Triglycerides levels were not reported (Meigs et al, 1997). Longitudinal studies As with total and LDL cholesterol, longitudinal studies provide more compelling evidence for triglycerides and HDL cholesterol levels as predictors of CHD risk in Type 2 diabetes (see Table 2). The meta-analysis by Hokanson and Austin (1996) supports an independent role for triglycerides after adjustment for other confounding risk factors but these analyses do not include any specific information on diabetes. This analysis included a total of 17 population-based, prospective studies reporting the association between fasting triglycerides levels and incident cardiovascular endpoints. Among 57,277 subjects aged 15-81 years (diabetes not specified), a 1 mmol/L increase in mean triglycerides levels was significantly associated with increased risk of CVD in both men (n=46,413) (RR 1.32, CI 1.26-1.29) and in women (n=10,864) (RR 1.76, CI 1.50-2.07). After adjustment for HDL cholesterol and other risk factors, there was still a 14% increased CVD risk (RR 1.14, CI 1.05-1.28) in men and a 37% increased CVD risk (RR 1.37, CI 1.13-1.66) in women. In the UKPDS, both triglycerides and HDL cholesterol levels predicted risk of development of CHD (Turner et al, 1998). Triglycerides levels were divided into tertiles, the lower tertile being <1.22 mmol/L, the middle tertile ≥1.22 to <1.87 mmol/L and the upper tertile ≥1.87 mmol/L. The HR for development of CHD was 1.63 for the middle tertile and 1.93 for the upper tertile (p<0.0001). For HDL cholesterol the lower tertile was <0.95 mmol/L, the middle tertile ≥0.95 to <1.15 mmol/L and the upper tertile ≥1.15 mmol/L. The HRs compared with the lower tertile were 0.87 for the middle tertile and 0.51 for the upper tertile (p<0.0001). Two European studies have emphasised the role of triglycerides levels as a risk factor in states of abnormal glucose metabolism. The Paris Prospective Study investigated mortality from CHD in 7,038 men, 690 with IGT and 293 with Type 2 diabetes. The mean triglycerides levels in the 26 people with diabetes who died from CHD during 11 years of follow-up were 2.07 mmol/L compared with 1.47 mmol/L in those who did not die from CHD (p<0.006). The RR of CHD death for subjects with triglycerides levels over 1.5 mmol/L was 3.28 (p<0.01) (Fontbonne et al, 1989). At the 11 year follow up evaluation in the Diabetes Intervention Study, triglycerides levels were 2.32 mmol/L in people who suffered from myocardial infarction compared to 1.88 mmol/L in those without clinical evidence of CHD (p<0.01). Triglycerides were also higher among people who died during follow up than people who survived (2.30 v 1.90 mmol/L, p<0.01) (Hanefeld et al, 1996). HDL cholesterol levels were not reported for either of these studies. The largest study from Finland found the unadjusted HR for all CHD events was 1.8 (1.4-2.3) and for CHD mortality was 2.2 (1.6-3.1) when triglycerides were >2.3 mmol/L compared with ≤2.3 mmol/L (both p<0.001). The corresponding ratio was 1.6 (1.2-2.0) and 1.9 (1.4-2.7), respectively when HDL cholesterol was <1.0 mmol/L compared with ≥1.0 mmol/L (p=0.001; p<0.001, respectively) (Lehto et al, 1997). A 15 year follow-up of a separate, smaller cohort in the same city, found the baseline triglycerides levels of 2.59 mmol/L in the group who developed CHD (n=48) were not significantly different from the level of 2.31 mmol/L in the group that did not have CHD (n=85). However, baseline HDL cholesterol was 0.99 mmol/L in the group that developed CHD, significantly lower than the level of 1.12 mmol/L in the group that remained without CHD (p=0.005) (Niskanen et al, 1998). In this prospective study of 252 people with diabetes (mean age 58 years) (Hanninen et al, 1999), the prevalence of hypertension was 42% and coronary heart disease was 23% at baseline. During 5-year follow-up the mortality rate during was 8.3%. Initial CHD (p=0.001),

32

lower mean HDL cholesterol level (p=0.019) and higher level of albuminuria (≥20 μg/min) (p=0.0007) were significantly related to mortality. In a study of 1,172 diabetic subjects with an average of 7 years follow-up after coronary artery bypass graft surgery, women with triglycerides in the highest quartile (>3.12 mmol/L) had a HR of 1.49 (CI 1.06-2.08, p=0.02) for adverse events (myocardial infarction, revascularisation or death), while in men with triglycerides in the highest quartile (>2.90 mmol/L) the HR was 1.28 (CI 0.99-1.66, p=0.06). Neither total cholesterol in the highest quartile, nor HDL cholesterol in the lowest quartile was associated with an increased HR, but information on use of lipid modifying therapy was not available (Sprecher et al, 2000). Saito et al (2000) showed that people who suffered from a coronary event had a higher level of triglycerides (0.76 v 0.52 mmol/L, p<0.001) and a lower level of HDL cholesterol (1.07 v 1.18 mmol/L, p<0.001) compared with those did not have an event in a 8-year follow-up study of 1,676 people with diabetes (type not stated) and no reported history of CHD at baseline. In addition, after adjusting for sex, age and ethnicity, the incidence of CHD was negatively associated with HDL3 level when comparing the highest tertile (≥1.02 mmol/L) with the lowest tertile (<0.67 mmol/L), with a RR of 0.41 (CI 0.35-0.66, p<0.001). Abu-lebdeh et al (2001) reported important predictors of macrovascular disease among 449 people with Type 2 diabetes (mean age 57 years) in a prospective cohort study. At baseline, 170 people (38%) had triglycerides levels greater than 2.7 mmol/L, and 36 (8%) greater than 4.5 mmol/L. During a mean follow-up of 13 years, 216 cases of coronary artery disease had developed. In the multivariate analysis, the significant predictors of future CAD events were age (per decade) (HR 1.45 [CI 1.27-1.67], p<0.001), baseline glucose level (per 1 natural log unit) (HR 1.63 [CI 1.17-2.25], p=0.003), baseline triglycerides levels (per 1 natural log unit) (HR 1.49 [CI 1.15-1.92], p=0.002) and smoking (HR 1.45 [CI 1.10-1.91], p=0.008). In the Atherosclerosis Risk in Communities (ARIC) Study, Sharrett et al (2001) reported 725 CHD events occurred over a mean of 10 years follow-up among 12,339 middle-aged people (45-64 years, number with diabetes not specified) who had no evidence of CHD and had fasting triglycerides <4.52 mmol/L at study entry. Both men and women with subsequent CHD had a higher baseline total, LDL cholesterol and triglyceride levels, and a lower HDL cholesterol level than those without CHD (p<0.005 for all comparisons). A 1 mmol/L increase in LDL cholesterol was associated with an increased risk of CHD events in both men and women after adjusting for age and race (RR 1.40 for men, p<0.01; RR 1.23 for women, p<0.01). The RR was similar for a 0.70 mmol/L increment in triglycerides but was only observed in women (RR 1.29, p<0.01), not in men (RR 1.07, p=NS). In comparison, a 0.40 mmol/L increment in HDL cholesterol was associated with greater CHD protection (RR 0.64 for men, p<0.01; RR 0.69 for women, p<0.01). Overall, after adjustment for blood pressure, smoking, and diabetes, LDL and HDL cholesterol, triglycerides were only an independent predictor of CHD in women with a RR of 4.9 (90% CI 3.9-5.7). HDL cholesterol was an independent CHD risk factor in both men and women in all multivariate models. In the Heart Protection Study (HPS Collaborative Group, 2003), the mean HDL cholesterol was 1.06 mmol/L and triglycerides was 2.3 mmol/L at baseline among 5,963 people with diabetes. Over the 5-year treatment period, the incidence of initial major vascular event in people assigned to the placebo group was 21.3% for those with baseline HDL cholesterol ≥0.9 mmol/L, and was 31.1% for those with HDL cholesterol <0.9 mmol/L (p<0.001). The correspording figures were 22.8% and 27.6% for people with initial triglycerides <2.0 mmol/L and ≥2.0 mmol/L, respectively (p<0.03).

33

In the Hoorn Study (Bos et al, 2003), 408 cases of cardiovascular disease were identified in 1,817 people aged 50-75 years during a 10-year follow-up. High triglycerides concentrations which were defined by the cut off point of 1.4 mmol/L in men and 1.3 mmol/L in women were associated with increased risk of cardiovascular disease (HR 1.35, CI 1.11-1.64) after adjustment for age and sex. However, triglycerides were not a risk factor in people with normal glucose metabolism (HR 0.94, CI 0.73-1.22), but in people with abnormal glucose metabolism which included people with Type 2 diabetes and people with IGT (number of each not given), the HR for cardiovascular disease was 1.54 (CI 1.07-2.22). The contribution of increased lipoprotein (a) to risk of cardiovascular disease in Type 2 diabetes is uncertain Lp(a) consists of an LDL like particle covalently linked with an apolipoprotein that has strong sequence homology to plasminogen. Possibly through both atherogenic and thrombogenic properties, Lp(a) is an independent risk factor for CHD. A number of cross-sectional studies have reported raised Lp(a) levels in association with CHD in people with Type 2 diabetes. A hospital based study in France measured Lp(a) in 71 people with CHD, defined mainly by documented myocardial infarction or by coronary angiogram. Mean Lp(a) levels were 29 mg/dl in this group, compared with 18 mg/dl (p=0.19) in a comparable group of 67 people with diabetes who were defined as free from CHD mainly on the basis of coronary angiography and dipyridamole myocardial thallium scintigraphy tests. Elevated Lp(a) was defined as a level ≥30 mg/dl and 33.8% of the CHD positive group had elevated levels, compared with 13.4% of the CHD negative group (p=0.005) (Ruiz et al, 1994). Using the same threshold to define elevated Lp(a), a study in Italy measured levels in 355 people with Type 2 diabetes and 145 people with Type 1 diabetes. CHD was determined by history and ECG, and peripheral vascular disease by history, ankle arm blood pressure ratio and Doppler velocimetry, with 30.6% of the total group found to have macroangiopathy (CHD and/or peripheral vascular disease). Median Lp(a) level was 13 mg/dl in the group with macroangiopathy compared with 9 mg/dl in the group without (p<0.05). Logistic regression analysis with Lp(a) ≥30 mg/dl as a categorical variable showed that it was a significant predictor of macroangiopathy with an OR of 2.11 (p<0.003) and that the association was independent of the type of diabetes (James et al, 1995). The association between elevated Lp(a) and increased risk of coronary artery disease (CAD) has not been confirmed in elderly people. In a cross-sectional study of 400 elderly people aged 65 to 84 years by Solfrizzi et al (2002) which included 13% with Type 2 diabetes, levels of Lp(a) were similar in 70 people with CAD (18.3±19.0 mg/dl) and 330 without CAD (17.4±19.4 mg/dl) (p=0.7). However, the combined effect of high Lp(a) (≥20 mg/dl) and high LDL cholesterol (≥3.63 mmol/L) in people with Type 2 diabetes significantly increased coronary risk, with an OR of 6.65 (CI 1.25-35.40). However, other cross–sectional studies have not found Lp(a) to be elevated in people with Type 2 diabetes who have CHD. In the Rochester Diabetic Neuropathy Study mean Lp(a) level was 19 mg/dl in the group with CHD, compared with 17 mg/dl in the group without (p=0.36) (O'Brien et al, 1994). There is little information available from longitudinal studies of Lp(a) as a risk factor for CHD in Type 2 diabetes. From the Wisconsin Epidemiological Study of Diabetic Retinopathy, Lp(a) was measured in 24 subjects with onset of diabetes after the age of 30 years who had died from CHD. Mean Lp(a) level was 12.7 mg/dl in this group, compared with 15.4 mg/dl (p=0.60) for 24 people in the study, matched by age and gender, who

34

remained alive (Haffner et al, 1992b). A Japanese study defined high Lp(a) as a level ≥20 mg/dl and selected 113 people with low Lp(a) and 108 people with high Lp(a), all with Type 2 diabetes and apparently free of CVD. After follow-up of 2.2-3.1 years, 7 people with high Lp(a) had a cardiac or peripheral vascular event and only 1 person with low Lp(a) had an event (p=0.032) (Hiraga et al, 1995). Although there is some evidence to support Lp(a) as an independent risk factor for CHD in people with Type 2 diabetes, at present there is insufficient evidence that measurement of Lp(a) level is useful to stratify risk of CHD and aid in the choice of lipid modifying interventions. There is limited evidence linking lipid levels and diabetic nephropathy A limited number of studies have examined the association between lipid and lipoprotein levels and diabetic nephropathy in Type 2 diabetes (see Table 3). As detailed in Table 3 there have not been any consistent findings in cross-sectional studies (Seghieri et al, 1990; Suraniti et al, 1992; Nielsen et al, 1993). Two prospective studies have examined different aspects of the relationship between lipid levels and diabetic nephropathy. In a study in Israel, 574 people with recent onset of Type 2 diabetes were followed for a mean of 7.8 years. A baseline total cholesterol level ≥5.25 mmol/L was associated with an OR of 20.59 (CI 12.67-33.59) for the development of microalbuminuria, LDL cholesterol ≥3.21 mmol/L with an OR of 6.24 (CI 4.80-13.35) and HDL cholesterol <1.14 mmol/L with an OR of 7.76 (CI 5.17-11.64) (all p<0.001) (Ravid et al, 1998). In a study in Finland of 133 people with Type 2 diabetes (Niskanen et al, 1990) people with persistent microalbuminuria (>30 mg/24h) had significantly lower levels of HDL and LDL cholesterol and higher triglycerides after 5-year follow-up (0.92±0.03 v 1.07±0.03 mmol/L, p<0.05; 3.65±0.22 v 4.00±0.11 mmol/L; and 4.24±0.90 v 2.35±0.16 mmol/L, p<0.05, respectively). Neither study reported usage of lipid lowering therapy.

35

Table 3: Lipid levels and diabetic nephropathy

Lipid levels Reference Population Studied Mean Total

Cholesterol (mmol/L)

Mean LDL Cholesterol (mmol/L)

Mean HDL Cholesterol (mmol/L)

Mean Triglycerides

(mmol/L)

Niskanen, 1990 (Finland)

n=133, age 45-64 yrs; Type 2 diabetes; 5-yr follow-up no microalbuminuria microabuminuria control (n=144)

Baseline

6.36

6.66 6.75

5yr

6.44

6.88 6.71

Baseline

4.16

4.19 4.57

5yr

4.00† (v AU+)

3.65 4.28

Baseline

1.07

1.07 1.38

5yr

1.07† (v AU+)

0.92 1.28

Baseline

2.39

2.45 1.44

5yr

2.38† (v AU+)

4.24 1.55

Nielsen, 1993 (Denmark)

n=549 Type 2 diabetes age <66 yrs; Nephropathy Microalbuminuria Normoalbuminuria Control

6.5 †† (v AU & normal)

5.6

5.6

6.1

3.83

3.63

3.56

4.06

1.18

1.12

1.23

1.46

2.01 †† (v normal & control)

1.82 †† (v control)

1.30

1.09

Ravid, 1998 (Israel)

n=574 Type 2 diabetes age 40-60 yrs 2-9yr follow-up

<5.25 >5.25

OR of nephropathy

1.0 20.59

<3.21 >3.21

OR of nephropathy

1.0 6.24

<1.14 >1.14

OR of nephropathy

7.76 1.0

- -

Seghieri, 1990 (Italy)

n=77 Type 2 diabetes; mean age 57 yrs; no microalbuminuria microalbuminuria

<5 yrs diabetes duration

5.1 6.2††

>5 yrs diabetes duration

5.8 5.8


3.0 4.1†


3.7 3.7


1.3 1.1


1.1 1.2

- -

Suranti, 1992 (France)

n=380 Type 2 diabetes age 40-75 yrs no microalbuminuria microalbuminuria

5.88 5.90

-

1.31 1.21††††

1.67 1.82

Between groups comparison † p<0.05, †† p<0.01, ††† p<0.005, †††† p<0.001. AU: microalbuminuria

36

There is limited evidence that lipid levels predict the development of hard exudes in diabetic retinopathy Very few studies have addressed the issue of a link between lipid levels and diabetic retinopathy in people with Type 2 diabetes (see Table 4). A case-control study in the UK of 26 hypertensive people with Type 2 diabetes and exudative maculopathy, compared lipid levels with 26 well matched diabetic hypertensive people without retinopathy. There were no significant differences in mean LDL or HDL cholesterol, or triglycerides levels (Dodson & Gibson, 1991). However, people with maculopathy had a higher total cholesterol level (6.65±2.20 v 5.90±1.30 mmol/L) and a higher prevalence of hyperlipidaemia (54 v 35%) as compared to people without maculopathy. The US based Early Treatment Diabetic Retinopathy Study (ETDRS) measured lipid levels in 2,709 people with diabetic retinopathy, 60% of whom were classified as having Type 2 diabetes (Chew et al, 1996). At baseline, a total cholesterol ≥6.21 mmol/L and LDL cholesterol ≥4.14 mmol/L were associated with the presence of hard exudate in eyes assigned to deferral of photocoagulation (OR 2.00,CI 1.35-2.95; OR 1.97, CI 1.31-2.96, respectively) compared with a total cholesterol of <5.17 mmol/L, and LDL cholesterol of <3.36 mmol/L, respectively. Over a 7-year follow-up period, the time to development of retinal hard exudate in eyes assigned to deferral of photocoagulation was 50% faster in people with total cholesterol ≥6.21 mmol/L, or triglycerides ≥4.50 mmol/L, or LDL cholesterol ≥4.14 mmol/L than people with total cholesterol <5.17 mmol/L (OR 1.54, CI 1.17-2.02, p<0.001), or triglycerides <2.30 mmol/L (OR 1.46, CI 1.07-2.02, p=0.01), or LDL cholesterol <3.36 mmol/L (OR 1.36, CI 1.06-1.83). Table 4: Lipid levels and diabetic retinopathy

Lipid levels

Reference Population Studied

Mean Total Cholesterol (mmol/L)



Mean Triglycerides

(mmol/L)

Chew, 1996 (US)

n=3,711 Type 2 diabetes 5yr follow-up

Range <5.17

5.17-6.21 >6.21

OR 1.00 1.25 2.00

Range <3.36

3.36-4.14 >4.14

OR 1.00 1.26 1.97

Range <0.91

0.91-1.68 >1.68

OR 0.86 0.89 1.00

Range <2.3

2.3-4.5 >4.5

OR 1.00 1.07 1.27

Dodson, 1991 (UK)

n=26 Type 2 diabetes; age 57 yrs, case control maculopathy control

6.65±2.20 5.90±1.30

2.88±1.60 2.95±0.98

1.49±0.40 1.31±0.31

1.73±1.05 1.60±0.70

p values were not reported for the Dodson study

37

Summary- Lipid levels and Type 2 diabetes • In people with Type 2 diabetes average triglycerides levels are approximately 2.2 mmol/L

compared with 1.6 mmol/L in the non-diabetic population • The overall crude prevalence of elevated triglycerides levels in people with Type 2

diabetes is approximately 30% which is some 3-fold higher than the prevalence in people without diabetes

• Reduced HDL cholesterol is on average approximately 0.2 mmol/L lower in people with

Type 2 diabetes compared with the non-diabetic population • The overall crude prevalence of reduced HDL cholesterol levels in people with Type 2

diabetes is approximately 2-fold higher than in people without diabetes • Most studies have found similar LDL cholesterol levels in Type 2 diabetes and non-

diabetic people • LDL cholesterol composition is more atherogenic in people with Type 2 diabetes with

particle size being smaller and denser • Total cholesterol levels in people with diabetes are similar to non-diabetic people in most

studies. • Intra-individual variations of lipid and lipoprotein levels over time are observed in people

with Type 2 diabetes due mainly to biological variation • Triglycerides levels are increased in the non-fasting state but there is little change in total

cholesterol, HDL cholesterol and measured LDL cholesterol postprandially • Measurement of fasting lipids is recommended but it is recognised that only triglycerides

(and to a lesser extent calculated LDL cholesterol) are substantially affected by non-fasting

• Lipid levels in people with Type 2 diabetes should be measured after a 10-12 hour

overnight fast to avoid further variability particularly in triglycerides levels • Apolipoprotein A1 levels are lower in people with Type 2 diabetes compared with the

general population • Apolipoprotein B concentrations are higher in people with Type 2 diabetes compared

with the general population • Lipoprotein(a) levels are not altered in people with Type 2 diabetes

• Increased body weight, poor glycaemic control and diabetic nephropathy aggravate lipid

abnormalities in people with Type 2 diabetes • Results of lipoprotein oxidation studies in people with Type 2 diabetes have been variable

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• Total cholesterol and LDL cholesterol levels are strong predictors of cardiovascular

disease risk and death from CHD in Type 2 diabetes, just as they are in the general population

• Although the distribution of cholesterol levels is the same in Type 2 diabetes as in the

general population, at any total or LDL cholesterol level there is a higher absolute risk of CHD than in the non-diabetic population

• HDL cholesterol is inversely related to triglycerides levels and both parameters have been

linked with CHD risk in prospective studies, the data being more consistent for low HDL cholesterol level as an independent risk factor for CHD than for high triglycerides

• Although there is some evidence to support lipoprotein (a) as an independent risk factor

for CHD in people with Type 2 diabetes, there is insufficient evidence that measurement of lipoprotein (a) level is useful to stratify risk of CHD and aid in the choice of lipid modifying interventions

• There is limited evidence linking lipid levels and diabetic nephropathy • Data linking lipid levels with progression of diabetic retinopathy are limited

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Evidence Table: Section 1

Lipid levels and Type 2 diabetes

Evidence Level of Evidence

Author

Level Study Type Quality Rating

Magnitude Rating

Relevance Rating

Abu-Lebdeh HS (2001) (Adults – US) III-2 Cohort Medium High T+ High

Assmann G (1998) (Adults – Germany) III-2 Cohort High High T+ C+ H+ L+

Lp(a)+ High

Barret-Connor E (1982) (Adults – US) III-2 Case-control Medium HighT+ High

Billingham MS (1989) (Adults – UK) III-2 Cross-sectional Medium High C+, L+, H+,T+ High

Bos G (2003) (Adults – The Netherlands) III-2 Cohort High High T+ High

Burchfiel CM (1990) (Adults – US) III-2 Case-control High High H+, T+ High

Byrne CD (1994) (Adults – UK) III-2 Cross-sectional High High T+, H+ High

Castelli WP (1992) (Adults – US) III-2 Cohort Medium High H+, T+ Low

Ceriello A (1997a) (Adults – Italy) III-2 Case-control Medium High T+ High

Ceriello A (1997b) (Adults – Italy) III-2 Case-control Medium High T+ High

Chang C-J (1995) (Adults – Taiwan) III-2 Case-control Medium High H+, T+ Medium

Chen Z (1991) (Adults – China) III-2 Cohort High High C+ Low

Chew EY (1996) (Adults – US) III-2 Cohort High High C+ L+ High

Cowie CC (1994) (Adults – US) III-2 Cross-sectional High High H+, T+ High

Csaszar A (1993) (Adults – Hungary & Austria)

III-2 Case-control Medium Low High

Dean JD (1990) (Adults – UK) III-2 Case-control Medium High C+, H+ High

Dimitriadis E (1995) (Adults – Ireland) III-2 Case-control Medium High L+ High

Dodson PM (1991) (Adults – UK) III-2 Case-control Medium High C+ High

Fontbonne A (1989) (Adult men – France) III-2 Cohort High High T+ High

Freitas JP (1997) (Adults – Portugal) III-2 Case-control High Low High

Fuller JH (2001) (Adults – UK) III-2 Cohort High High T+ High

Giansanti R (1999) (Adults – Italy) III-2 Cross-sectional High High C+, T+ High

Haffner SM (1992a) (Adults – US) III-2 Case-control High High T+, H+ High

Haffner SM (1992b) (Adults – US) III-2 Case-control Medium Low High

Haffner SM (1994) (Adults – US) III-2 Cross-sectional High High H+, T+ High

Haffner SM (1995) (Adults – US) III-2 Cross-sectional High High+ Low

Hanefeld M (1996) (Adults – Gremany) III-2 Cohort High High T+ High

Hanninen J (1999) (Adults – Finland) III-2 Cohort High High H+ High

Heart Protection Study (2003) (Adults – UK)

II RCT High High C+, L+ High

Hiraga T (1995) (Adults – Japan) III-2 Cohort High High Lp(a)+ Low

For magnitude rating: + abnormalities associated with Type 2 diabetes; High = clinically important & statistically significant, Medium = small clinical importance & statistically significant, Low = no statistically significant effect. Criteria for Quality and Relevance ratings are detailed in Appendix 9. C= total cholesterol; L= LDL-cholesterol; H= HDL-cholesterol; T= triglycerides.

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Evidence Table: Cont


Author


Magnitude Rating

Relevance Rating

Hokanson JE (1996) I meta-analysis High High T+ Low

Hughes K (1998) (Adults – Singapore) III-2 Cross-sectional Medium High T+ Medium

James RW (1995) (Adults – Italy) III-2 Cross-sectional High High Lp(a)+ high

Laakso M (1985) (Adults – Finland) III-2 Case-control Medium High L+, H+, T+ High

Laakso M (1990) (Adults – Finland) III-2 Case-control Medium High H+, T+ High

Lehto S (1997) (Adults – Finland) III-2 Cohort High High C+, L+, H+, T+ High

Leinonen JS (1998a) (Adults – Finland) III-2 Case-control High Low High

Leinonen J (1998b) (Adults – Finland) III-2 Case-control High Low High

Leonhardt W (1996) (Adults – Germany) III-2 Case-control Medium High T+ High

MacRury SM (1993) (Adults – UK) III-2 Case-control High High T+ High

Manninen V (1992) (Adults – Finland) II RCT High High T+ Low

Manson JE (1991) (Adult women – US) III-2 Cohort High High C+ High

Manzato E (1993) (Adults – Italy) III-2 Case-control High High C+ High

Mattock MB (1988) (Adults – UK) III-2 Cross-sectional High High C+, H+ High

Meigs JB (1997) (Adults – US) III-2 Cross-sectional Medium High H+ High

MiSAD (1997) (Adults – Italy) III-2 Cross-sectional Medium High C+ T+ High

Nacitarhan S (1995) (Adults – Turkey) III-2 Case-control Medium High C+, L+, H+, T+ Medium

Nielsen FS (1993) (Adults – Denmark) III-2 Case-control Medium High T+ High

Niskanen L (1990) (Adults – Finland) III-2 Cohort High High H+, T+ L+ High

Niskanen L (1998) (Adults – Finland) III-2 Cohort Medium High H+ High

O’Brien T (1994) (Adults – US) III-2 Case-control High High H+ L+ High

Ravid M (1998) (Adults – Israel) III-2 Cohort High High C+, L+, H+, T+ Medium

Ronnemaa T (1989) (Adults – Finland) III-2 Case-control Medium High C+ H+ T- High

Ruiz J (1994) (Adults – France) III-2 Case-control High HighC+ Lp(a)+ High

Saito I (2000) (Adults – Japan) III-2 Cohort High High C+ L+ H+ T+ Low

Salomaa VV (1992) (Adults – Finland) III-2 Cross-sectional High High C+, H+, T+ High

Scheffer PG (2003) (Adults – The Netherlands)

III-2 Case-control Medium High C+, H+, T+ High

Seghieri G (1990) (Adults – Italy) III-2 Case-control High High C+ L+ T+ High

Seviour PW (1988) (Adults – UK) III-2 Case-control Medium High C+ L+ H+ T+ High

Sharrett AR (2001) (Adults – Austria) III-2 Cohort High High L+ H+ T+ Low

For magnitude rating: + abnormalities associated with Type 2 diabetes; High = clinically important & statistically significant, Medium = small clinical importance & statistically significant, Low = no statistically significant effect. Criteria for Quality and Relevance ratings are detailed in Appendix 9. C= total cholesterol; L= LDL-cholesterol; H= HDL-cholesterol; T= triglycerides.

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Author


Magnitude Rating

Relevance Rating

Siegel RD (1996) (Adults – US) III-2 Case-control Medium High C+, L+, H+, T+ High

Smith SJ (1993) IV Case series Medium High C+, T+ Low

Solfrizzi V (2002) (Adults – Italy) III-2 Cross-sectional Medium Low High

Sprecher DL (2000) (Adults – US) III-2 Cohort High High T+ High

Stamler J (1993) (Adult men – US) III-2 Cohort High High C+ High

Suraniti S (1992) (Adults – France) III-2 Cross-sectional High High H+ ApoA1+ High

Tkac I (1997) (Adults – Canada) III-2 Cross-sectional Medium High L+ High

Tsalamandris C (1998) (Adults – Australia) IV Case series Medium Low High

Turner RC (1998) (Adults – UK) III-2 Cohort High High C+, L+, H+, T+ High

UKPDS 11 (1994) (Adults – UK) III-2 Case-control High High C+, L+, H+, T+ High

Uusitupa M (1986) (Adults – East Finland) III-2 Case-control Medium High L+, H+, T+ High

Vakkilainen J (2003) (Adults – Sweden) III-2 * RCT High High L+ High

Velho G (1993) (Adults – France) III-2 Case-control Medium Low High

Wasenius A (1990) (Adults – Norway) IV Case series Medium Low Low

For magnitude rating: + abnormalities associated with Type 2 diabetes; High = clinically important & statistically significant, Medium = small clinical importance & statistically significant, Low = no statistically significant effect. Criteria for Quality and Relevance ratings are detailed in Appendix 9. C= total cholesterol; L= LDL-cholesterol; H= HDL-cholesterol; T triglycerides. * RCT but only the epidemiological data from this study were used in support of the relevant evidence statement

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What are the effects of diet and exercise on lipids in people with Type 2 diabetes?

Recommendation

Specific dietary advice should be given to all people with Type 2 diabetes and elevated lipids which emphasises weight reduction in the overweight

Evidence Statements • Weight loss can improve lipid levels in people with Type 2 diabetes in the short term

Evidence level I • The composition of the diet influences lipid levels in people with Type 2 diabetes

High carbohydrate (55-65%) low fibre diets increase triglycerides in the short term but not in the longer term Evidence level II

Low glycaemic index diets may produce small improvements in lipid levels Evidence level II

Replacing some complex carbohydrate (up to 20% of total energy) with sucrose or fructose does not have an adverse effect on lipid levels Evidence level II

Replacing some complex carbohydrate (10-20% of total energy) in high-carbohydrate (50-60%) diets with mono-unsaturated fatty acids (MUFA) lowers plasma triglycerides in the short-term Evidence level I

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Longer term (greater than 1 month) studies have failed to show consistent differences in lipid levels when some complex carbohydrate in high carbohydrate (50-60%) diets is replaced with mono-unsaturated fatty acids (MUFA) Evidence level II

Diets high in polyunsaturated fatty acids (PUFA) and MUFA have similar

effects on lipid levels Evidence level II

Fish oil supplementation can reduce triglycerides but increases LDL cholesterol

Evidence level I

Increasing fish intake may improve the lipid profile although data are limited Evidence level II

There are few data on the effects of changes in dietary protein content on lipid

levels in people with Type 2 diabetes Evidence level II

Increasing the fibre content of the diet can lower total and LDL cholesterol but has little effect on triglyceride or HDL cholesterol levels Evidence level II

Plant sterol enriched margarines have a modest effect on lipid levels

Evidence level II

There is no direct evidence that alcohol alters the lipid profile in people with Type 2 diabetes Evidence level III-2

Anti-oxidant therapy may reduce susceptibility of LDL particles to oxidation

Evidence level II • Exercise may have a modest beneficial effect on lipid levels in people with Type 2

diabetes Evidence level III-2

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Background – Diet and Exercise and Lipids In people with Type 2 diabetes there is often a cluster of metabolic disturbances, including lipid abnormalities, which are associated with insulin resistance (see Section 1). Lipid levels in Type 2 diabetes are characterised by high fasting triglycerides and low HDL cholesterol with changes in the structure of LDL particles (reviewed in Section 1), superimposed on the range of levels of total and LDL cholesterol seen in the general population. Insulin resistance, some components of elevated lipids and hyperglycaemia are partly influenced by lifestyle factors including diet and physical activity. The components of the diet that may be important include total energy intake and the quantity and quality of both fat and carbohydrate. Consensus statements such as those of the American Diabetes Association (2003) advocate lifestyle measures as an initial step in the management of elevated lipids in adults with diabetes. Although diet is important in all people with diabetes, it has particular importance in people with elevated lipids. This Section reviews the evidence for lifestyle intervention in the treatment of elevated lipids in people with Type 2 diabetes. Central obesity is a major contributing factor to insulin resistance and both obesity and insulin resistance are important determinants of lipid levels in Type 2 diabetes (Brunzell & Hokanson, 1999). Insulin resistance not only reduces triglyceride clearance, but also allows increased free fatty acid release from a larger mass of intra-abdominal adipose tissue promoting hepatic synthesis of triglycerides that are secreted by the liver as very low-density lipoproteins (Garg, 1996). Reduction of intra-abdominal fat is therefore likely to improve the lipid profile in Type 2 diabetes. Exercise is recommended as an adjunct to diet in the management of people with Type 2 diabetes. The American Diabetes Association recommends that individuals should accumulate 30 min of moderate physical activity on most days of the week to improve glycaemic control and cardiovascular risk factors (American Diabetes Association, Clinical Practice Recommendations, 2003). Because exercise can enhance insulin sensitivity, reduce intra-abdominal fat and improve glycaemic control, improvement of the lipid profile might be anticipated (Ruderman & Schneider, 1992).

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Evidence - Diet and Exercise on Lipids Weight loss can improve lipid levels in people with Type 2 diabetes Studies of the effects of weight loss on lipid and lipoprotein levels in Type 2 diabetes vary greatly in study characteristics such as:

• study design • study duration • nutritional composition of study diet • the use of a comparative isocaloric dietary period • combining a weight loss and exercise program

A meta-analysis of 89 research studies which promoted weight loss in people with Type 2 diabetes was conducted by Brown et al (1996). The mean initial body weight of the 1,800 subjects was 96 kg or 147% ideal body weight. The most effective weight loss strategy was diet alone and the mean weight loss was about 9 kg, associated with a mean reduction in the absolute value of HbA1c of 2.7%. Weighted-effect size estimates of the impact of weight reduction on the lipid profile demonstrated significant and similar reductions of total cholesterol (0.62±0.43, p<0.05, 15 studies) and triglycerides (0.56±0.40, p<0.05, 16 studies), but no significant effect on LDL or HDL cholesterol levels. The beneficial effect on lipids was greatest with very low calorie diets (VLCD), with weighted-effect size of 0.69±0.46 (p<0.05) for total cholesterol and 0.61±0.42 (p<0.05) for triglycerides. The effects were seen immediately and for up to 6 months in some studies, but not in studies of 12 months or longer. The magnitude of the short term reduction in lipid levels is illustrated by the following study, the largest study of weight loss in Type 2 diabetes which was conducted by Barnard et al (1994). During an intensive 26-day residential lifestyle program of diet combined with aerobic exercise, 652 people with Type 2 diabetes lost an average of 4.4 kg (5%) of initial body weight. Participants followed the Pritikin diet which is high in complex carbohydrate (75%) and fibre and very low in fat (<10%) but does not emphasise energy restriction. Mean total cholesterol fell an average of 22% from 6.2 to 4.8 mmol/L, 6.1 to 4.9 mmol/L and 6.2 to 4.8 mmol/L in subjects on insulin, oral agents and diet alone respectively (all p<0.001) while triglycerides levels fell an average of 33% from 2.8 to 2.0 mmol/L, 2.8 to 2.0 mmol/L and 3.0 to 1.8 (all p<0.001) respectively. However in everyday clinical practice the reductions in lipids are more modest. In the UKPDS (Manley et al, 2000), 2,906 people with newly diagnosed Type 2 diabetes underwent 3 months dietary intervention with a hypocaloric diet with 50% of energy from unrefined carbohydrate and less than 35% of energy from fat. At baseline 58% of men and 81% of women were obese, weighing more than 120% of their ideal body weight. After 3 months body weight decreased by a mean of 4.5 kg (p<0.001) in both men and women. Glycaemic control improved with HbA1c falling by 2.03% from 8.9% in men, and by 1.78% from 9.1% in women (both p<0.001). Plasma total cholesterol fell by 0.28 mmol/L (p<0.001) in men and 0.09 mmol/L in women (p<0.01), with a similar reduction in LDL cholesterol in men and women (both p<0.001). Triglycerides decreased by 0.41 mmol/L in men (p<0.001) and 0.23 mmol/L in women (p<0.001). HDL cholesterol rose in men by 0.02 mmol/L (p<0.001) and in women by 0.01 mmol/L (p<0.05). The effects on lipid levels of longer term weight loss studies are less impressive. Wing et al (1994) have studied the effects over 12 months in a randomised cross over trial of people with Type 2 diabetes assigned to a low calorie diet (LCD) of 1,000 to 1,200 kcal/day (4,200 to 5,040 kJ/day) with less than 30% calories as fat (n=41) or a LCD supplemented with 2×12 week periods of a very low calorie diet (VLCD) of 400 to 500 kcal/day (1,680 to 2,100 kJ/day) (n=38). Subjects also participated in a behavioural treatment program with weekly

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meetings including exercise lectures that stressed walking. At one year there was a trend of more weight loss in the VLCD group than in the LCD group (14.2±10.3 v 10.5±11.6 kg, p=0.057). Total and LDL cholesterol decreased in the LCD group (5.3 to 5.0 mmol/L; 3.2 to 3.1 mmol/L, both p=NS). Triglycerides reduced from 2.5 to 1.7 mmol/L (p< 0.001) and HDL cholesterol rose from 1.09 to 1.17 mmol/L (p<0.001) in the same group. In contrast, total and LDL cholesterol did not change in the VLCD group where as triglycerides decreased significantly from 2.2 to 1.5 mmol/L (p<0.001) and HDL cholesterol increased from 1.12 to 1.25 mmol/L (p<0.001). The mean HbA1c fell from 10.2% to 8.8% in the LCD group and from 10.5% to 9.2% in the VLCD group after one year on diet (no p value given). In a multi-centre randomised double-blind placebo-controlled trial, the pancreatic lipase inhibitor orlistat (120 mg) or placebo were given 3 times daily for 52 weeks to 391 people, mean age 55 years, with Type 2 diabetes treated with sulphonylurea therapy (Hollander et al, 1998). All participants were prescribed a mildly hypocaloric weight loss diet with about 30% of energy intake as fat, 50% as carbohydrate and 20% as protein. After 57 weeks the orlistat group had lost 6.2% of initial body weight (mean initial body weight 99.6 kg) compared with 4.3% in the placebo group (mean initial body weight 99.7 kg). Over the period of the study weight loss with orlistat was significantly greater than with placebo (p<0.001). During the 52 week treatment period total cholesterol fell by an average of 0.08 mmol/L in the orlistat group but rose by 0.39 mmol/L in the placebo group (p<0.001 for difference between orlistat and placebo); LDL cholesterol fell by 0.13 mmol/L with orlistat and rose by 0.22 mmol/L with placebo (p<0.001), triglycerides level fell by 0.01 mmol/L with orlistat and rose by 0.21 mmol/L with placebo (p=0.036) and HDL cholesterol rose by 0.06 mmol/L with orlistat and rose by 0.08 mmol/L with placebo (p=NS). HbA1c was about 7.5% at randomisation in both groups. On orlistat HbA1c fell by a mean absolute amount of 0.28% compared with an increase of 0.18% in the placebo group (p<0.001). Other studies which have achieved lesser weight loss (<3%) have shown little effect on lipid levels. Franz et al (1995) used a randomised controlled trial design to compare medical nutrition therapy using practice guidelines (n=94) with basic nutrition care (n=85) provided by dietitians over a 6 month period. In the intensive diet therapy group body weight fell by 1.4 kg from 93.8 kg (1.5% reduction). Total cholesterol fell from 5.6 to 5.4 mmol/L (p<0.05) and triglycerides from 2.6 to 2.4 mmol/L (p<0.05). LDL and HDL cholesterol levels did not change significantly. HbA1c fell from 8.3% to 7.4% (p<0.001). In the basic nutrition care group body weight fell by 1.7 kg from 93.7 kg (1.8% reduction), but none of the lipid parameters changed significantly. HbA1c fell from 8.3% to 7.6% (p<0.001). Another dietary intervention trial in people with Type 2 diabetes studied an energy restricted diet (Milne et al, 1994). In the weight management group (n=21) weight was 78.3 kg at baseline and the average between 9 and 18 months was 79.8 kg. Total cholesterol was 6.4 mmol/L at baseline and 6.1 mmol/L at 9-18 months, LDL cholesterol was 4.5 and 4.2 mmol/L, triglycerides 1.7 and 1.6 mmol/L and HDL cholesterol 1.24 and 1.18 mmol/L. HbA1 was 9.0% at baseline and 8.9% at 9-18 months. In the modified lipid diet group (n=22) weight was 83.1 kg at baseline and the average between 9 and 18 months was 82.1 kg. Total cholesterol was 6.0 mmol/L at baseline and 5.7 mmol/L at 9-18 months, LDL cholesterol was 4.2 and 3.6 mmol/L, triglycerides 1.8 and 2.0 mmol/L and HDL cholesterol 1.15 and 1.22 mmol/L. HbA1 was 9.8% at baseline and 9.7% at 9-18 months. None of these results was significant. In summary, weight loss (≥5%) can decrease triglycerides by 10-40% and total cholesterol by 5-15% while the effects on HDL and LDL cholesterol are variable. These improvements in the lipid profile are seen in the short-term but are difficult to sustain in the longer term.

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The composition of the diet influences lipid levels in people with Type 2 diabetes Since dietary protein contributes 10-20% of total dietary energy intake the remaining 80-90% is distributed between carbohydrate (CHO) and fat (and alcohol if consumed). A number of studies have examined the effects on lipids of varying the quantity and quality of fat and/or carbohydrate in people with Type 2 diabetes. There are very few studies on the effects of different levels of protein on lipids in people with Type 2 diabetes. Epidemiological studies provide some information on the effect on lipids of dietary composition. A study by Mayer-Davis et al (1999) reported associations between macronutrient intake and lipoprotein profile in people with Type 2 diabetes who participated in two epidemiological studies. Diet was assessed by 24-hour recall in 421 participants in the San Luis Valley Diabetes Study and by food frequency interview in 437 participants in the Insulin Resistance Atherosclerosis Study. The major finding in all subgroups was an association between total dietary fat and increased levels of LDL cholesterol (p<0.05). Reported intake of total and saturated fat was associated with total cholesterol, but not consistently across all subgroups. Higher reported carbohydrate intake was associated with increased triglycerides levels (p<0.01) only among people with previously undiagnosed diabetes or who gained weight (>2.5 kg). Most intervention studies have been of relatively short duration. Only studies of at least 1 month duration are considered below. High-carbohydrate diets Coulston et al (1989) compared diets containing either 40 or 60% carbohydrate with reciprocal changes in fat content from 40 to 20% (polyunsaturated/saturated ratio 1.0-1.1) consumed for 6 weeks in random order in a crossover design study in 8 people with Type 2 diabetes treated with sulphonylureas or diet alone. The high-carbohydrate diet significantly increased plasma glucose levels between 0800 and 1600 h (p<0.001), although the mean fasting glucose level was not different. Fasting triglycerides levels increased by 30% from about 1.9 to 2.4 mmol/L (p<0.001) after 1 week on the 60% carbohydrate diet and the hypertriglyceridaemia persisted over the 6-week period. Total cholesterol remained unchanged with both diets. These diets contained low amounts of fibre (14.3 and 18.1 g/day, respectively) and, judging by the meal plans, high glycaemic index carbohydrates (eg cornflakes, banana, potato). In another study of postprandial lipid metabolism, 9 people with Type 2 diabetes treated with sulphonylureas were randomly assigned isocaloric diets. They were low in fibre and either high in carbohydrate (55% CHO, 30% fat and 15% protein, 15 g/day of fibre) or high in fats (40% CHO, 45% fat including 25% monounsaturated fat and 15% protein, 11 g/day of fibre) for a period of 6 weeks (Chen et al, 1995). As with earlier studies, they showed that the high carbohydrate diet led to higher glucose and triglyceride levels compared with the high-fat diet based on 24-hour measurements (both p<0.001). Garg and colleagues have reported 2 studies of a high carbohydrate diet in men with Type 2 diabetes, but not currently on hypoglycaemic medication. Both studies were performed during hospitalisations with crossover design using controlled isocaloric diets. One of the studies gave 10 men with Type 2 diabetes a liquid formula diet high in carbohydrate (65% of total energy) particularly refined carbohydrate (glucose 31%, sucrose 24%) and low in fibre for 28 days and compared the metabolic effects with a high fat (45% of total energy), high monounsaturated fat (MUFA) (31% of total energy) diet (Garg et al, 1992a). There was no change in weight on either of the diets. On the high carbohydrate diet, mean fasting glucose level was 6.6 mmol/L at baseline and 6.6 mmol/L after 28 days, but the glucose response to a

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high-carbohydrate meal tolerance test rose significantly (p<0.05). On the high MUFA diet, fasting glucose was 7.2 mmol/L at baseline and 6.6 mmol/L after 28 days and the glucose response to the high carbohydrate meal tolerance test fell, but not significantly. The high carbohydrate diet adversely affected plasma triglycerides increasing from 3.0 mmol/L at baseline to 4.2 mmol/L. However on the high MUFA diet triglycerides fell to 2.5 mmol/L (p=0.002). The total cholesterol did not change on the high carbohydrate diet from a baseline of 5.2 mmol/L to 5.1 mmol/L while on the high MUFA diet it fell to 4.4 mmol/L (p=0.003). No significant changes were observed in LDL or HDL cholesterol levels on either diet. These short term effects are not supported by longer term studies. Milne et al (1994) randomised 21 people with Type 2 diabetes to a high carbohydrate diet in an 18-month study. The diet consisted of 55% carbohydrate, 30% fat and 15% protein, with 30g/day fibre and results were compared with 22 people assigned to a modified fat diet containing 45% carbohydrate, 36% fat (saturated fatty acid [SFA]:polyunsaturated fatty acid [PUFA]:MUFA=1) and 19% protein. Mean triglycerides levels in the high carbohydrate diet group were 2.5 mmol/L at randomisation and the average levels from 9-18 months were 2.4 mmol/L. Mean triglycerides levels in the modified fat diet group were 1.8 mmol/L at baseline and the average levels from 9-18 months were 2.0mmol/L. Total cholesterol in the high carbohydrate diet group was 6.6 mmol/L at randomisation and the average level from 9-18 months was 6.2 mmol/L; corresponding LDL cholesterol levels were 4.2 and 4.0 mmol/L and HDL cholesterol levels were 1.23 and 1.19 mmol/L. There was no evidence that the high carbohydrate diet had unfavourable long-term effects on the lipid profile or that it had less favourable effects than the modified lipid diet, although the difference in carbohydrate content of the 2 diets was not as great as in the short-term studies. It should also be noted that the fibre content of the high carbohydrate diet was considerably higher than that of the high carbohydrate diets in the short-term studies. A total of 35 obese people with Type 2 diabetes (mean age 58 years, mean BMI 33 kg/m2) were randomised to one of 3 1,600 kcal/day energy restricted diets for 12 weeks (Heilbronn et al, 1999). The diets were high carbohydrate (n=12) (72% CHO, 10% fat, 4% saturated fatty acids (SFA)), high MUFA (n=13) (50% CHO, 32% fat, 15% MUFA, 7% SFA) and high SFA diet (n=10) (50% CHO, 31% fat, 17% SFA). Despite differences in dietary composition, weight loss was significant in all groups (p<0.01) with subjects losing an average of 6.6±0.9 kg (CI 2.7-12.4 kg) after 12 weeks of energy restriction. Total cholesterol decreased by 7.2% with the high carbohydrate diet and by 14.6% with the high MUFA diet (p<0.001) and increased by 8% with the high SFA diet (p=0.002). Similarly, LDL was 10% and 17% lower with the high-carbohydrate and high MUFA diets respectively, whereas no change was observed with the high SFA diet (p<0.001). HDL cholesterol was transiently reduced on the high carbohydrate diet at weeks 1, 4 and 8 (p<0.01). Triglycerides did not change during 12 weeks. Glycaemic control was also similar with the 3 diets. Compared with baseline levels, FPG was reduced by 14% (p<0.001) and HbA1c by 14% (p<0.001) in all 3 groups at week 12. In summary: • short-term (< 6 weeks) high carbohydrate (55 to 65% energy) low fibre diets in people

with Type 2 diabetes increase triglycerides levels by about 25% • long-term intake of a high carbohydrate diet does not appear to increase triglycerides

levels Low glycaemic index diets The glycaemic index (GI) is a classification of carbohydrate containing foods on the basis of the incremental blood glucose responses produced by that food as a percentage of the response produced by the same amount of carbohydrate as either glucose or white bread.

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Reducing the GI of high carbohydrate diets has been found consistently to improve glycaemic control but the effect on lipids in people with Type 2 diabetes has been variable (see Table 5). One of the earliest studies of the effects of a low GI diet on the lipid profile in Type 2 diabetes was an Australian study by Brand et al (1991). Sixteen people were randomly assigned to a low GI (77) or high GI (91) diet for periods of 12 weeks in a crossover design. The diets contained comparable amounts of carbohydrate (44-46% of energy), fat (30-31%) and fibre (26g/day). On the low GI diet mean HbA1c was 7.0% v 7.9% on the high GI diet (p<0.05). However, the lipid profile did not differ significantly on the 2 diets. Mean total cholesterol was 5.8 mmol/L on the low GI diet compared with 5.8 mmol/L on the high GI diet, LDL cholesterol was 2.7 compared with 3.0 mmol/L, triglycerides were 1.7 mmol/L compared with 1.6 mmol/L and HDL cholesterol was 1.19 compared with 1.08 mmol/L. None of these differences was significant. Another Australian study by Luscombe et al (1999) randomised 21 people with Type 2 diabetes to 4-week periods on diets with low GI (GI 43; 51% CHO, 23% fat, 30g/day fibre), high GI (GI 63; 53% CHO, 21% fat, 30g/day fibre). and high MUFA/high GI. Fasting glucose and fructosamine levels were not significantly different between low and high GI diets. Mean total cholesterol was 5.5 mmol/L at baseline, 5.4 mmol/L after the low GI diet and 5.4 mmol/L after the high GI diet, LDL cholesterol was 3.8 mmol/L on low GI and 3.8 mmol/L on high GI diet and triglycerides were 1.5 mmol/L on low GI and 1.8 mmol/L on high GI diet (no p values reported). HDL cholesterol was 0.93 mmol/L on the low GI compared with 0.88 mmol/L on the high GI diet (p<0.05 for high GI v low GI and high MUFA). Effects of high MUFA/high GI diet are described below in the section on high MUFA diets. A different study design was used by Frost et al (1994) who randomly assigned 51 people with newly diagnosed Type 2 diabetes to receive standard dietary advice (n=26) or low GI dietary advice (n=25) and assessed glycaemic control and lipids after 12 weeks. Dietary advice on increased use of low GI foods (whole grains, rye bread, barley, oats, pasta, legumes and fruit) was given, rather than a specific dietary prescription. The group assigned to low GI advice had a carbohydrate intake of 49%, fat intake 25% and the GI of the diet was 77 compared with 44% carbohydrate, 32% fat and a GI of 82 in the standard dietary advice group. In the low GI diet group fructosamine fell from 380 to 320 µmol/L but remained at 360 µmol/L in the high GI group (p<0.05 for low GI v high GI). Total cholesterol fell from 6.2 to 5.5 mmol/L in the low GI group compared with 5.6 to 5.3 mmol/L in the high GI group (p<0.05) and triglycerides from 1.9 to 1.4 mmol/L in the low GI group compared with 2.5 to 2.1 mmol/L in the high GI group (p<0.05). LDL and HDL levels did not change significantly on either diet. In a study by Tsihlias et al (2000) 91 people with Type 2 diabetes were randomised to receive 10% energy from a low GI cereal, a high GI cereal, or a MUFA breakfast for 6 months. At baseline there were no significant differences in glycaemic control or use of lipid-lowering agents among the 3 diet groups. Changes in HbA1c, body weight, total and LDL cholesterol, and triglycerides did not differ significantly between diets. However, HDL cholesterol was persistently higher (about 12%) in the MUFA group than in either the high GI or low GI cereal groups (p=0.002). Heilbronn et al (2002) used a randomised, controlled trial design to compare a high GI (75 units) (n=21) with a low GI (43 units) diet (n=24) (1,440 kcal/day, 60% carbohydrate, 18% fat, 5% SFA, and 22% protein) in 45 obese people with Type 2 diabetes (mean BMI 33.2 kg/m2, mean age 56.7 years). Before randomisation, all subjects consumed a high SFA diet

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(50% CHO, 32% fat, 17% SFA, and 20% protein) for 4 weeks. During the 8-week study period, there was significant weight loss with both high GI diet (93.2 to 88.4 kg, p<0.05) and low GI diet (91.7 to 87.3 kg, p<0.05). HbA1c fell by 4.6% on the high GI diet (p=0.03) and by 9.1% on the low GI diet (p=0.002). Total cholesterol reduced by 8% with high GI diet and 10% with low GI diet (both p<0.05); LDL cholesterol fell by 10%, and 16%; and triglycerides fell by 6% and 10%, respectively (all p<0.05). HDL cholesterol did not change on both diets. Overall, there were no differences in glycaemic control, lipid profile and body weight between the two groups. In summary: • Lowering the glycaemic index of the diet may produce small improvements in lipid levels

of people with Type 2 diabetes Sucrose/fructose The study with the largest variation in sucrose intake was performed by Abraira & Derler (1988). Dietary intake was closely regulated in 18 people with diet treated Type 2 diabetes who were hospitalised for the 40 days of the study. After a baseline period, subjects were randomised to diets of similar composition (50% CHO, 35% fat, 15% protein) with either 220g sucrose or 3g sucrose daily. There was no difference in glycaemic control or in total, LDL and HDL cholesterol or triglycerides between the two groups. An Australian study by Cooper et al (1988) compared daily supplements of 28g sucrose with 30g starch and saccharin (isocaloric and equal sweetness with sucrose) over 6 week periods in 17 people with Type 2 diabetes on oral hypoglycaemic therapy using a randomised crossover design. The addition of sucrose had no effect on fasting glucose (sucrose diet v saccharin diet: 9.2 v 8.9 mmol/L) or on total (5.8 v 5.8 mmol/L), LDL (3.75 v 3.78 mmol/L) and HDL cholesterol (1.08 v 1.06 mmol/L) or on triglycerides (2.0 v 2.0 mmol/L). Similarly, another Australian study with randomised crossover design (Colagiuri et al, 1989) showed that the addition of sucrose (45 g/day, 9% of total daily energy) or an equivalent sweetening quantity of aspartame to the usual diet (43% CHO, 39% fat, 18% protein, 29 gram/day fibre) of 9 people with Type 2 diabetes on diet alone or sulphonylurea therapy had no deleterious effects on glycaemic control (fasting glucose 6.2 v 6.0 mmol/L) or lipid levels (total cholesterol 5.3 v 5.4 mmol/L, HDL cholesterol 0.96 v 0.93 mmol/L, triglycerides 2.1 v 2.1 mmol/L) over a 6 week period. Bantle et al (1993) also used a randomised crossover study to assess the effect of dietary sucrose on glycaemia and lipids in 12 people with Type 2 diabetes on diet alone, oral hypoglycaemic therapy or insulin. The substitution of starch with sucrose (19% of total energy in the diet compared with 3% in the control diet) in standard diabetic diets (55% CHO, 30% fat and 15% protein) had no adverse effect on fasting glucose, total, LDL and HDL cholesterol or on triglycerides over 4 weeks. In a similar study by Malerbi et al (1996) a diet with 19% total energy as sucrose (55% CHO, 30% fat, 23 g/day fibre) was compared with a diet with only 5% of energy from sugars (50% CHO, 35% fat, 23g/day fibre) in 16 people with Type 2 diabetes treated with diet alone or sulphonylurea therapy. After 28 days there were no significant differences in fasting glucose, total, LDL and HDL cholesterol or triglycerides. There was also a high fructose intake arm to this study as discussed below. The results of studies on addition of fructose to the diet in people with Type 2 diabetes are very similar (see Table 5). Osei et al (1987) evaluated the effects of supplementation of the

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diet with 60 g/day fructose in 2 groups of people with Type 2 diabetes most of whom were on insulin therapy. Over 12 weeks HbA1c fell from 11.6% to 10.2% in 9 people taking fructose, but rose from 11.5% to 13.0% in the 9 control subjects (p<0.02 for difference between the groups). Mean total cholesterol, LDL and HDL cholesterol did not change significantly on either diet. On the fructose diet, triglycerides remained unchanged at the baseline level of 1.04 mmol/L but in the control diet group triglycerides rose from 1.7 to 2.7 mmol/L (p<0.02). A subsequent study by the same group (Osei & Bossetti, 1989) used a randomised crossover design with 6-month study periods in 13 people with Type 2 diabetes treated with sulphonylurea and/or insulin therapy. HbA1c fell from 11.3% to 9.9% on the fructose diet (p<0.05) but rose from 10.4% to 11.2% on the control diet (p<0.02 for difference at 6 months between the diets). No significant changes were observed in total, LDL and HDL cholesterol or triglycerides on either diet and the 6 months results did not differ between diets. A daily intake of 30g fructose was evaluated over 2 months by Grigoresco et al (1988) in a randomised crossover study of 8 people with Type 2 diabetes, treated with diet alone or oral hypoglycaemic agents. Both diets contained 50% of total energy intake as carbohydrate, 30% fat, 20% protein, 20g/day fibre, with replacement of 30g starch with 30g of fructose in the fructose diet. Mean HbA1c was 6.8% at baseline, 6.4% on the fructose diet and 5.9% on the control diet (p=NS). Total and HDL cholesterol did not change significantly on either diet. Triglycerides rose from 1.2 mmol/L to 1.5 mmol/L (p<0.05) on the fructose diet, but were not significantly different from the level of 1.4 mmol/L on the control diet. The study by Malerbi et al (1996) described above included a dietary period with 20% of energy intake from fructose (same composition as the sucrose diet). Over a 28-day period there were no significant differences in fasting glucose, total, LDL and HDL cholesterol or triglycerides. In summary • Inclusion of sucrose or fructose in the diet of people with Type 2 diabetes (up to 20% of

total energy) does not adversely affect lipid levels Diets high in Monounsaturated Fatty Acids (MUFA) Garg (1998) performed a meta-analysis comparing the effects of high MUFA diets (35-40% CHO, 37-50% total fat, 22-33% MUFA, 14-21% protein) with high carbohydrate diets (49-60% CHO, 20-32% fat, 10-13% MUFA, 14-21% protein) on carbohydrate and lipid metabolism in people with Type 2 diabetes. Nine studies with randomised, crossover design using isocaloric diets were included in this meta-analysis (Garg et al (1988), Rivellese et al (1990), Garg et al (1992b), Parillo et al (1992), Campbell et al (1994), Garg et al (1994), Lerman-Garber et al (1994) and Parillo et al (1996)). Eight out of nine studies were of short duration (2-4 weeks) and were performed in metabolic wards. There was only one outpatient study of 6 weeks duration which was continued for 14 weeks in a subgroup of 21 people (Garg et al, 1994a). From this meta-analysis high MUFA diets compared with high carbohydrate diets were accompanied by a significant 19% reduction of fasting triglycerides (-0.36 mmol/L [CI -0.43, -0.26]), a 3% reduction of total cholesterol (-0.15 mmol/L [CI -0.24, -0.06]), a 4% increase in HDL cholesterol (+0.05 mmol/L [CI 0.03-0.07]), but no significant change in LDL cholesterol (-0.01 mmol/L [CI -0.10, 0.08]). FPGalso fell by 0.23 mmol/L (CI -0.39, -0.06) with consumption of the high MUFA diet. The only study of more than 4 weeks duration was an outpatient-based study by Garg et al (1994a) which was a 4–centre randomised crossover study in 42 people with Type 2 diabetes on sulphonylurea treatment. All food was supplied for the diets which consisted of 55% carbohydrate, 30% fat (10% MUFA), 15% protein, 15g/4,200 kJ fibre for the high carbohydrate diet and 40% carbohydrate, 45% fat (25% MUFA), 15% protein, 11g/4,200 kJ

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fibre for the high MUFA diet. After 6 weeks fasting glucose, HbA1 and body weight did not differ significantly on the two diets. Mean fasting triglycerides levels were 2.2 mmol/L on the high carbohydrate diet and 1.8 mmol/L on the high MUFA diet (p<0.0001). Total, LDL and HDL cholesterol did not differ significantly between the two diets. Day long plasma glucose was increased by 12% (p<0.0001) and day long triglycerides by 10% (p=0.03) on the high carbohydrate diet. A subgroup of 21 people continued the diet for a further 8 weeks and the differences in glucose and lipid metabolism were sustained for the total of 14 weeks. The study by Bonanome et al (1991) was not included in the above meta-analysis because the dietary phases were not randomised. This study included 19 people with Type 2 diabetes who were studied during 3 dietary phases, each of two month duration. The first and third phases were high carbohydrate diets (60% CHO, 25% fat, 15% protein, 15 g/day fibre), the second phase was a high MUFA diet (45% CHO, 40% fat, 25% MUFA, 15% protein, 15 g/day fibre). There was no difference in fasting glucose, glycosylated Hb, total and LDL cholesterol, triglycerides or HDL cholesterol between the high carbohydrate and high MUFA diets. An Australian study published since the meta-analysis compared 4 week randomised, crossover periods of a high MUFA, high GI diet (42% CHO, 35% fat, 18% MUFA, 21% protein, 34 g/day fibre), a high GI diet and a low GI diet as described above in the section on the Glycaemic Index (Luscombe et al, 1999). In the 21 people with Type 2 diabetes, glycaemic control did not differ between the diets. Mean HDL cholesterol was higher on the high MUFA diet (0.93±0.04 mmol/L) and the low GI diet (0.93±0.04 mmol/L) compared with the high GI diet (0.88±0.04 mmol/L) (p<0.05). There was no difference in total and LDL cholesterol or triglycerides between the diets. One study has compared the effects on lipids of a very low carbohydrate, high MUFA and a high carbohydrate hypocaloric diets. Low et al (1996) in a randomised controlled trial stratified for metabolic parameters studied 8 people with Type 2 diabetes assigned to a high carbohydrate diet (70% CHO, 10% fat, 20% protein) and 9 people assigned to a high MUFA diet (10% CHO, 70% fat, 49% MUFA, 20% protein). Energy intake was set for 6 weeks at a 50% deficit based on pre-diet weight maintenance requirements, then for 4 weeks at weight maintenance requirements during a period of re-feeding. Mean weight loss was similar in the two groups (8.3 kg on the high CHO diet v 7.3 kg on the high MUFA diet). Mean fasting glucose fell from 12.6 to 8.0 mmol/L on the high MUFA diet compared with 11.2 to 8.8 mmol/L on the high carbohydrate diet (p<0.05 for high MUFA v high CHO). Total cholesterol fell from 5.0 to 3.9 mmol/L on the high MUFA diet compared with 4.4 to 4.0 mmol/L on the high carbohydrate diet (p<0.05 for high MUFA v high CHO) and triglycerides from 3.2 to 1.4 mmol/L compared with 2.7 to 2.2 mmol/L (p<0.05 for high MUFA v high CHO). LDL cholesterol and HDL cholesterol levels did not change significantly on either diet. Changes in total cholesterol and triglycerides were better maintained with re-feeding on the high MUFA diet than the high carbohydrate diet. The same study was subsequently reported Gumbiner et al (1998). In summary:

• Replacing some complex carbohydrate (10-20% of total energy) in high carbohydrate (50-60%) diets with mono-unsaturated fatty acids (MUFA) lowers plasma triglycerides in the short-term

• Studies of more than 1 month duration have failed to show consistent differences in lipid levels when some complex carbohydrate in high carbohydrate (50-60%) diets is replaced with mono-unsaturated fatty acids (MUFA)

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Diets high in Polyunsaturated Fatty Acids (PUFA) or Saturated Fatty Acids (SFA) There are few studies that have specifically examined the use of diets high in PUFA or SFA (see Table 5). One study compared diets high in PUFA with diets high in MUFA. In a crossover design study, Parfitt et al (1994) randomised 13 men with Type 2 diabetes treated with diet alone or oral hypoglycaemic agents to 6 week periods on diets with high PUFA (35% CHO, 47% fat, 17% PUFA, 18% protein) or high MUFA (35% CHO, 50% fat, 28% MUFA, 15% protein). Mean total cholesterol was 5.3 mmol/L at baseline, 4.9 mmol/L on high PUFA and 4.7 mmol/L on high MUFA, LDL cholesterol 3.7 mmol/L, 3.5 mmol/L 3.2 mmol/L respectively, triglycerides 1.9 mmol/L at baseline and on both diets and HDL cholesterol 0.94 mmol/L, 0.90 mmol/L and 0.99 mmol/L respectively. None of these changes was significant. Heine et al (1989) studied 14 people with Type 2 diabetes in a crossover study with 30-week treatment periods on diets with PUFA/SFA ratio 1.0 or 0.3. Glycaemic control did not differ on the two diets. On the high PUFA diet (40% CHO, 38% fat, 11% linoleic acid, 17% protein, 5% alcohol, 21 g/day fibre) total and LDL cholesterol levels were lower (5.5±0.4 v 5.9±0.5 mmol/L, p<0.01; 3.7±0.3 v 4.1±0.4 mmol/L, p<0.01, respectively) than on the low PUFA diet (40% CHO, 38% fat, 4% linoleic acid, 17% protein, 5% alcohol, 21 g/day fibre); whereas triglycerides and HDL cholesterol were similar with both diet. Christiansen et al (1997) compared 3 diets with fat predominantly from SFA or MUFA (cis-MUFA from nuts, avocado and olive oil in one arm and trans-MUFA from margarine in another). Energy composition of the diets was the same, with carbohydrate 50%, fat 30%, SFA/cis-MUFA/trans-MUFA 20%, protein 20%, 29 g/day fibre. In a randomised crossover design, 16 people with Type 2 diabetes on diet alone followed each diet for periods of 6 weeks. Mean fasting glucose was 8.9 mmol/L with SFA, 8.1 mmol/L with cis-MUFA and 8.7 mmol/L with trans-MUFA diets. Total cholesterol was 6.3 mmol/L with SFA and 6.0 mmol/L with both cis-MUFA and trans-MUFA diets; LDL cholesterol was 3.7 mmol/L with SFA, 3.5 mmol/L with cis-MUFA and 3.6 mmol/L with trans-MUFA diets. Triglycerides were 2.7 mmol/L with SFA, 2.5 mmol/L with cis-MUFA and 2.7 mmol/L with trans-MUFA diets; HDL cholesterol was 1.12 mmol/L with both SFA and cis-MUFA diets and 1.10 mmol/L with trans-MUFA diet. None of these values was significantly different between the diets. In summary:

• Diets high in PUFA and MUFA have similar effects on lipid levels in people with Type 2 diabetes

• Diets with a high SFA have not been shown to consistently adversely affect lipid levels in people with Type 2 diabetes

Fish and fish oils rich in ω-3 polyunsaturated fatty acids Dietary supplementation with fish oil capsules has been considered as a pharmacological, rather than a dietary intervention and has been reviewed in more detail in Section 4. There have been many studies of the effects of fish oil supplementation on lipid levels in people with Type 2 diabetes (see Table 5). A meta-analysis of 18 randomised, placebo controlled trials, including 823 people with Type 2 diabetes followed for a mean of 12 weeks on doses of fish oil ranging from 3-18 g/day (Montori et al, 2000), reported a mean reduction of triglycerides of 0.56 mmol/L (CI -0.71 to -0.41) and a mean elevation of LDL cholesterol

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of 0.21 mmol/L (CI 0.02-0.41). There was no significant effect on total cholesterol, HDL cholesterol, or on glycaemic control. There have been very few studies on the effects of dietary fish (as distinct from dietary supplementation with fish oil) on lipid levels in people with Type 2 diabetes. Described in the section on exercise, the Australian study by Dunstan et al, (1997) used a randomised 2×2 design to test the effects of moderate exercise and daily fish intake on lipid and lipoprotein levels in 55 people with Type 2 diabetes with serum triglycerides >1.8 mmol/L and/or HDL cholesterol <1.0 mmol/L (4 groups of 11 to 14 subjects). One fish meal per day (3.6g ω-3 fatty acids) for 8 weeks reduced triglycerides by 0.8 mmol/L (p=0.03) and improved the composition of HDL cholesterol (HDL3 reduced by 0.05 mmol/L, p=0.02; HDL2 increased by 0.06 mmol/L, p=0.03). Mean HbA1c increased by an absolute amount of 0.5% (p=0.05). In summary: • Fish oil supplementation can reduce triglycerides but increases LDL cholesterol • Increasing fish intake may also improve the lipid profile although data are limited Diets high in protein There have been few studies in people with Type 2 diabetes on the impact on lipids of a higher protein intake. Parker et al (2002) compared the effect of a high protein diet with a low protein diet on weight loss, lipid profile and glycaemic control. 54 obese people with Type 2 diabetes were randomised to the high protein diet (HP) (28% protein, 42% carbohydrate, 28% fat) or the low protein diet (LP) (16% protein, 55% carbohydrate, 26% fat) in this 12-week study including an 8-week energy restriction phase (1,600 kcal/day) and a 4-week energy balance phase with the same macronutrient composition. Both men and women lost weight on both diets, with an average weight loss of 5.2±1.8 kg. Women on the HP diet lost significantly more weight compared with the women on the LP diet (5.3 v 2.8 kg, p=0.009) whereas there was no difference in men between the diets (3.9 v 5.1 kg). Over 12 weeks, total and LDL cholesterol levels decreased more on the HP diet than on the LP diet (5.2 to 4.8 v 5.2 to 5.2 mmol/L, p<0.01; 3.3 to 3.1 v 3.2 to 3.3 mmol/L, p<0.01, respectively). Triglycerides were reduced significantly on both diets (2.0 to 1.7 mmol/L; 2.2 to 1.9 mmol/L; both p<0.001). HbA1c decreased by 9.4% between baseline and week 12 (p<0.001) without significant difference between diets. This effect could be related more to differences in weight loss than to the protein composition of the diets. Hermansen et al (2001) randomised 20 people with Type 2 diabetes to treatment with the soy product Abalon or placebo for 6 weeks in a crossover study. Abalon provided a daily amount of 50g isolated soy protein and cotyledon fibre (20g/d); whereas the placebo provided a daily amount of 50g casein and 20g cellulose. After Abalon treatment significantly lower mean values for LDL cholesterol (-10±15%, p<0.05), triglycerides (-22±43%, p<0.05) and LDL/HDL ratio (-12±18%, p<0.05) were obtained. The mean value for total cholesterol tended to be lower but did not reach significance (-8±15%, p=0.08). No change in HDL cholesterol occurred. There were no significant changes in glycaemic control on both treatments. In summary:

• There are few data on the effects of changes in dietary protein content on lipid levels in people with Type 2 diabetes

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Diets high in fibre Foods with high fibre content Chandalia et al (2000) used a randomised crossover design in 13 people with Type 2 diabetes treated with diet alone or sulphonylurea therapy to compare the ADA diet which contained 24g fibre (8g soluble/16g insoluble) with a high-fibre diet (50g/day fibre, 25g soluble/25g insoluble). After 6 weeks, the high fibre diet reduced the mean total cholesterol by 14% (5.1 v 5.4 mmol/L, p=0.02), triglycerides by 21% (2.1 v 2.3 mmol/L, p=0.02) and VLDL cholesterol by 5% (0.91 v 1.03 mmol/L, p=0.01). No significant changes in HDL (0.73 v 0.75 mmol/L, p=0.8) and LDL cholesterol (3.4 v 3.7 mmol/L, p=0.11) occurred. The mean plasma glucose concentration was lower when people consumed the high-fibre diet (7.2 v 7.9 mmol/L, p=0.04) but HbA1c was similar (6.9 v 7.2%, p=0.09). Wolever et al (2003) randomly assigned 67 people with Type 2 diabetes to receive a diet in which 10% energy was from a low-fibre breakfast cereal (LF) (n=22), a high-fibre breakfast cereal (HF) (n=25), or MUFA (n=22) for 6 months. Changes in total cholesterol did not differ significantly between diets. However, triglycerides fell on the MUFA diet (-0.22±0.17 mmol/L, p<0.05) and increased on the LF diet (+0.04±0.11 mmol/L,) and the HF diet (+0.32±0.18 mmol/L, p<0.05), with the difference between groups being significant (p=0.002). LDL cholesterol increased more on the MUFA diet (+15%, p<0.05) than on either the LF (+1.2%) or the HF (-0.8%) diets. There was no significant change in HbA1c over 6 months. Fibre supplements Niemi et al (1988) studied the effects of 15g/day guar gum (5g with each meal) over 12 weeks in 18 people with Type 2 diabetes. There was no improvement in glycaemic control (HbA1c 12.1% at baseline, 11.8% at 12 weeks) but mean total cholesterol fell from 6.6 to 5.9 mmol/L (p<0.01). During the 12 weeks prior to the guar gum treatment subjects ingested 15g/day of microcrystalline cellulose, an indigestible, unabsorbable fibre. This did not have any effect on glycaemia or cholesterol. Groop et al (1993) have reported a long term study with guar gum 15g/day in 15 people with Type 2 diabetes. The 48-week treatment period was preceded and followed by 8 week periods on placebo. Glycaemic control improved during guar gum treatment with fructosamine decreasing from 3.77 mmol/L at the end of the first placebo period to 3.31 mmol/L at the end of treatment (p=0.003) and rose again to 3.45 mmol/L after the second placebo period (p=0.092). Mean total cholesterol fell from 6.1 to 5.7 mmol/L on guar gum (p=0.048) and rose to 6.6 mmol/L (p=0.001) during the second placebo period. LDL cholesterol fell from 3.9 to 3.6 mmol/L (p=0.029) and then rose to 4.3 mmol/L (p=0.001). Triglycerides and HDL cholesterol levels did not change significantly during the study. Plantago psyllium is a soluble, gel-forming fibre which is derived from the husks of blonde psyllium seeds and is readily available in Australia. The effects on glycaemia and lipid levels have been evaluated by Gupta et al (1994) in a sequential study of psyllium 3.5g twice daily for 90 days, then follow up for a further 90 days in 24 people with Type 2 diabetes and hyperlipidaemia. Glycaemic parameters did not change significantly but the lipid profile improved. Mean total cholesterol fell from 7.2 to 5.8 mmol/L and LDL cholesterol fell from 5.3 to 4.0 mmol/L (both p<0.001). Triglycerides fell from 2.2 to 1.6 mmol/L (p<0.005) and HDL cholesterol rose from 0.76 to 0.87 mmol/L (p<0.05). These positive changes almost completely reversed during the follow up period off psyllium treatment. Rodriguez-Moran et al (1998) performed a double-blind, placebo controlled study of the effect of psyllium 4g three times daily for 6 weeks in people with Type 2 diabetes (over 90%

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on sulphonylurea therapy), 63 on psyllium and 60 on placebo. At the end of the treatment period FPG was 10.3 mmol/L in the placebo group and 7.6 mmol/L in the psyllium group (p<0.01). Mean total cholesterol was 5.0 mmol/L in the group on psyllium and 5.6 mmol/L in the placebo group (p=0.03); LDL cholesterol levels were 3.1 and 3.6 mmol/L (p=0.01), triglycerides 1.6 mmol/L and 2.1 mmol/L (p=0.005) and HDL cholesterol levels 1.32 and 0.91 mmol/L (p<0.0001) respectively. Anderson and colleagues (1999) evaluated the effects of psyllium on glucose and lipids in 34 men aged 30-70 years with Type 2 diabetes who were randomised to receive 5.1g psyllium (n=18) or placebo (n=16) twice daily for 8 weeks. At baseline lipid profiles were comparable in the two groups. After 8 weeks total cholesterol was significantly lower in the psyllium group than in the placebo group (-2.1% v +6.9%, p<0.05) and LDL cholesterol was non significantly lower in the psyllium group (-4.7% v +8.3%, p=0.07). There were no differences in triglycerides and HDL cholesterol levels between groups. Postprandial glucose concentration was 19.2% lower in the psyllium group (-6.5% v +12.7%, p<0.05), but HbA1c did not differ between the two groups. Soluble fibre in the form of oat bran concentrate can be incorporated into the diet as oat bran concentrate bread muffins and cereal. Pick et al (1996) performed a randomised controlled crossover trial of added fibre from oat bran concentrate over 2 periods of 12 weeks in 8 men with Type 2 diabetes on diet alone or oral hypoglycaemic therapy. Subjects consumed diets with either 34g/day fibre (18g from oat bran concentrate) or 19g/day fibre. The response of fasting glucose and glycated Hb were not reported. Mean total cholesterol during the oat bran concentrate period was 4.6 mmol/L compared with 5.3 mmol/L for the control period, (p<0.01) and LDL cholesterol levels were 2.6 compared with 3.4 mmol/L (p<0.01). Triglycerides and HDL cholesterol did not change significantly. Another soluble fibre, pectin from fruit, was used by Sheehan et al (1997) in a study in 15 people with Type 2 diabetes treated over 8 weeks with 20g/day fish oil. Fish oil alone lowered triglycerides from 3.9 to 2.3 mmol/L (p<0.01) but did not affect total, LDL or HDL cholesterol levels. The addition of 15g/day apple pectin after 4 weeks reduced total cholesterol from 6.2 to 5.7 mmol/L (p<0.001) and LDL cholesterol from 4.4 to 4.0 mmol/L (p<0.05) but there was no further reduction in plasma triglycerides. In summary:

• Increasing the fibre content of the diet can lower total and LDL cholesterol but has little effect on triglycerides or HDL cholesterol levels

Plant sterols Plant sterols, particularly sitosterol, have been shown to reduce plasma cholesterol by inhibiting cholesterol absorption, but the large doses required have limited its use. Sitostanol, a 5α-saturated derivative of sitosterol, is more effective than sitosterol and is completely unabsorbed in humans. In 11 men with Type 2 diabetes treated with diet alone or oral hypoglycaemic agents, Gylling & Miettinen (1994) showed in a double blind crossover study with 6 week treatment periods that 3g/day of sitostanol ester dissolved in rapeseed margarine reduced mean total cholesterol from 6.0 to 5.6 mmol/L (p<0.05) and LDL cholesterol from 3.8 to 3.5 mmol/L (p<0.05). Triglycerides were unchanged but HDL cholesterol increased from 1.13 to 1.24 mmol/L (p<0.05). Cholesterol absorption was reduced from 25% to 9% (p<0.001). There was no significant change in fasting glucose or glycated Hb. Another study by the same group in 8 men with Type 2 diabetes (Gylling & Miettinen, 1996) showed that the LDL cholesterol lowering effects of sitostanol ester margarine combined with the HMG CoA reductase inhibitor pravastatin were greater (-44%) than sitostanol (-14%) or pravastatin (-38%) alone.

57

In a randomised controlled trial, Lee et al (2003) compared the effect of a phytosterol-enriched low-fat spread (equivalent to 1.6g phytosterols) with a low-fat spread on lipid levels in 85 people with Type 2 diabetes with good to moderate glycaemic control (mean HbA1c 7.6%). People did not receive additional dietary counselling during the 3-month study period. At baseline all lipid levels were comparable between the 2 groups. At week 4, total cholesterol and LDL cholesterol were reduced by 5.2% and 6.8%, respectively (each p<0.05) in the phytosterol group compared with an increase of 1.1% and 1.5%, respectively in the placebo group (overall differences between the two groups p=0.003 and p=0.027 respectively). After 8 and 12 weeks, these reductions became smaller and were not significant compared with baseline. HDL increased significantly from baseline in the phytosterol group after 8 weeks (p<0.05), but the difference between groups did not reach significance (p=0.057). Triglycerides was significantly lower after 4 and 8 weeks compared to baseline in the phytosterol group (both p<0.05), but again there were no significant differences between the groups. Glycaemic control improved in the phytosterol group, but the difference between groups in HbA1c was statistically significant only at week 4 (p<0.05). In summary:

• Plant sterol enriched margarines have a modest effect on lipid levels in people with Type 2 diabetes

Alcohol The literature search found few studies of the effects of alcohol on lipid levels in people with Type 2 diabetes. Ben et al (1991) compared lipid levels in 46 people with Type 2 diabetes who habitually consumed an average of 45g/day of alcohol with a control group of 35 people with Type 2 diabetes who consumed no alcohol. Chronic alcohol intake was associated with higher fasting blood glucose levels (9.1 v 7.8 mmol/L; p<0.05) and HbA1c (6.8 v 6.1% p<0.05). However no significant differences were found in total cholesterol (both 5.7 mmol/L), triglycerides (1.6 v 1.5 mmol/L) or HDL cholesterol (both 1.3 mmol/L) levels between the drinkers and the control group. With admission to hospital and abstinence from alcohol for 7 days, fasting glucose levels in the two groups both fell to about 7.4 mmol/L and there was no change in any of the lipid parameters. Bell et al (2000) examined the relationship between alcohol intake and cardiovascular disease risk factors in a cross-sectional study of 1,196 people. The prevalence of diabetes ranged from 17.3% to 39.0% among participants according to their daily alcohol consumption (never, <0.5, 0.5-0.99, 1-2.99, and ≥3 drinks/day, respectively). After adjustment for age, sex, ethnicity, smoking status and physical activity, the lowest triglycerides levels were seen in the 1-2.99 drinks/day category (3.1 v 3.5 mmol/L in never drinkers, p<0.05). HDL cholesterol gradually increased with increasing alcohol intake - 1.15mmol/L, 1.23 mmol/L, and 1.36 mmol/L for 0.5-0.99, 1-2.99, and ≥3 drinks/day, respectively, compared with 1.01 mmol/L for never drinkers (all p<0.001). Rimm et al (1999) conducted a meta-analysis on the effect of moderate alcohol intake on lipids in non-diabetic people. The studies that assessed HDL cholesterol level found it increased by 0.0034 mmol/L per gram of alcohol consumed a day. Consuming 30g of alcohol per day would be expected to increase HDL cholesterol by 0.10 mmol/L (CI 0.08-0.12), compared with those who abstain, an 8.3% increase from pretreatment values. The studies which assessed triglycerides concentration found an increase of 0.0049 mmol/L per gram of alcohol consumed or 0.15 mmol/L (CI 0.06-0.23) per 30g of alcohol consumed per day, a 5.9% increase over baseline.

58

In summary • There is no direct evidence that alcohol alters the lipid profile in people with Type 2

diabetes • Epidemiological data suggest that HDL cholesterol and triglycerides increase with

increasing alcohol intake. Anti-oxidants Based on the evidence that oxidation of LDL particles increases their atherogenicity, there has been considerable interest in the use of antioxidants, either natural (vegetables and fruits) or supplemented (vitamin C, vitamin E, β-Carotene). There are significant inconsistencies between the results of epidemiological studies and randomised controlled trials regarding the effects of antioxidants in the prevention of macrovascular disease in Type 2 diabetes (see Macrovascular Disease Guideline). However there may be an effect on intermediate outcomes, such as oxidisability of lipids. The most frequently studied antioxidant additive in Type 2 diabetes is α-tocopherol. Reaven (1995) showed that after treatment for 10 weeks with 1,600 IU/day α-tocopherol, LDL lag time to start of oxidation in 10 men with Type 2 diabetes was prolonged compared with 11 men given placebo. After 10 weeks the dense LDL subfraction from the vitamin E group was more resistant to oxidation than that from the placebo group (p<0.05). A strong correlation was observed between LDL vitamin E content and lag time of total LDL (r=0.69, p<0.05) and dense LDL (r=0.78, p<0.05). Devaraj & Jialal (2000) used 1,200 IU/day α-tocopherol for 3 months to treat people with Type 2 diabetes with and without macrovascular complications. LDL oxidisability was reduced in both groups. Lipid levels did not change significantly with vitamin E treatment in any of these studies. In this 4-week study, Upritchard et al (2000) gave 800 IU/day α-tocopherol to 12 people with Type 2 diabetes for 4 weeks and found that lag time in isolated LDL oxidation was increased by 54% (from 74±16 to 114±26 min, p=0.001). Plasma total cholesterol increased significantly (0.50 mmol/L [0.19-0.81]) in people treated with vitamin E and did not change significantly in those treated with tomato juice (-0.10 mmol/L [-0.45 to 0.25]), vitamin C (0.04 mmol/L [-0.17 to 0.25]) and placebo (0.03 mmol/L [-0.25 to 0.30]). Vitamin C supplementation was studied in a randomised, double blind, crossover study by Paolisso et al (1995) in 40 people with Type 2 diabetes treated with sulphonylureas. After 4 months on vitamin C 500mg twice daily, total cholesterol was 5.8 mmol/L compared with 7.3 mmol/L on placebo (p<0.03), LDL cholesterol was 4.1 compared with 5.6 mmol/L (p<0.05), triglycerides were 2.1 compared with 2.6 mmol/L (p<0.05) and HDL cholesterol was 1.1 v 1.0 mmol/L (p=NS). HbA1c was 7.2% on vitamin C compared with 8.0% on placebo (p<0.05). Fasting plasma free radicals were also reduced. Similar effects were found in a randomised, double blind, crossover study comparing the effects of vitamin C 2g/day and magnesium 600mg/day (Eriksson & Kohvakka, 1995). On vitamin C mean total cholesterol improved from 6.2 to 5.9 mmol/L (p<0.05) and triglycerides from 2.5 to 2.2 mmol/L (p<0.05). HbA1c also improved from 9.3 to 8.5% (p<0.05). Magnesium had no effect on lipids or glycaemic control. An earlier double blind crossover study with a lower dose of vitamin C (500mg daily) for 4 months in 50 people with Type 2 diabetes did not show any effect on cholesterol or triglycerides levels (Bishop, 1985), nor did the study by Upritchard et al (2000) in 12 people with Type 2 diabetes on 500mg/day vitamin C for 4 weeks. The effect of antioxidant vitamin supplementation on cardiovascular outcome was examined in the Medical Research Council/British Heart Foundation Heart Protection Study (Heart Protection Study Collaborative Group, 2002b). This study of 20,536 people included 5,963 people with Type 2 diabetes, randomised to treatment with simvastatin 40mg daily or placebo

59

and in a 2×2 factorial design to antioxidant vitamin therapy (600mg vitamin E, 250mg vitamin C, 20mg β-carotene) or matching placebo. Over a mean of 5 years follow-up, anti-oxidant treatment did not result in any significant differences (vitamin versus placebo) in all-cause mortality (14.1 v 13.5%), death due to vascular (8.6 v 8.2%) or nonvascular event (5.5 v 5.3%). There were also no significant differences in nonfatal myocardial infarction or coronary death (10.4 v 10.2%), and fatal or nonfatal stroke (5.0 v 5.0%) between the two groups. In summary: • Anti-oxidant therapy may reduce susceptibility of LDL particles to oxidation but

cardiovascular outcomes are not improved

60

Table 5: Effects of diet on lipid levels in Type 2 diabetes

Effects on Lipids Mean Total Cholesterol (mmol/L)



Mean Total Triglycerides

(mmol/L)

Body Weight (kg) HbA1c(%) Reference Population Studied

Before After Before After Before After Before After Before After Before After

Abraira, 1988 (US)

n=18 Type 2 diabetes 40-day follow-up RCT CHO diet (50-60%) Sucrose diet (220g/day)

5.00 5.10

4.61* 5.00

3.03 3.34

3.19 2.62

0.98 0.96

0.98 0.98

2.12 1.77

2.20 1.88

85.4 82.6

83.8 80.9

- -

Anderson, 1999 (US)

n=34 Type 2 diabetes 8-wk follow-up RCT n=18 psyllium n=16 placebo

5.69 5.39

5.57† 5.76

3.81 3.39

3.63 3.67

0.88 0.85

0.89 0.87

2.54 2.50

2.71 2.84

89.6 87.1

89.3† 88.4

7.3 7.5

6.85 7.56

Bantle, 1993 (US)

n=12 Type 2 diabetes 28 day follow-up Sucrose diet (19% ) Starch diet

5.32 5.20

5.05 4.90

3.32 3.21

3.12 3.08

1.07 1.08

1.05 1.02

2.03 2.02

1.91 1.77

86.0 86.9

- - -

Bell, 2000 (US)

n=1,196 17.3-39.0% with Type 2 diabetes alcohol consumption: never <0.5 drinks/d 0.5-0.99 1-2.99 ≥3 drinks/day

- -

1.01 1.06† (v never) 1.15†† (v never) 1.23†† (v never) 1.36†† (v never)

3.53 3.47 3.42

3.13† (v never) 3.07

- -

Bishop, 1985 (UK)

n=50 Type 2 diabetes 4-mth crossover RCT vitamin C 500mg/d first placebo first

6.8 6.8

6.5 6.7

- -

2.35 2.35

2.76 † 3.25

10.0 10.0

9.8 9.7

Bonanome, 1991 (US)

n=19 Type 2 diabetes 2-month follow-up CHO diet 1 MUFA fat CHO diet 2

6.2 6.5 6.4

4.2 4.3 4.3

1.2 1.3 1.3

1.8 1.9 1.7

76.8 76.7 76.6

6.2 6.0 6.5

Before/After comparison * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between groups comparison † p<0.05, †† p<0.01, ††† p<0.005, †††† p<0.001

61






(mmol/L)



Brand, 1991 (Australia)

n= 16 Type 2 diabetes 24-wk crossover RCT High GI (12 wks) Low GI (12 wks)

5.81 5.81

5.80 5.79

3.09 3.09

2.98 2.72

-

1.59 1.59

1.57 1.67

75.9 75.9

76.0 75.9

7.7 7.7

7.9 7.0†

Chandalia, 2000 (US)

n=13 Type 2 diabetes 6-wk crossover RCT 50g fibre diet v 24g fibre diet

- -

5.08† 5.44

- -

3.44 3.68

- -

0.73 0.75

- -

2.08† 2.32

- -

90.5 90.7

6.9% 7.2%

Chen, 1995 (US)

n=9 Type 2 diabetes 6-wk cross-over 40% CHO diet 55% CHO diet

5.6 5.6

- -

- -

2.3 2.3

2.1 2.8††††

- -

Christiansen, 1997 (Denmark)

n=16 Type 2 diabetes 12-wk follow-up RCT SFA diet cis-MUFA diet trans-MUFA diet

5.8 5.8 5.8

6.3 6.0 6.0

3.66 3.66 3.66

3.68 3.48 3.58

1.22 1.22 1.22

1.12 1.12 1.10

2.19 2.19 2.19

2.55 2.51 2.65

98 98 98

96 96 96

7.7 7.7 7.7

7.8 7.7 7.9

Colagiuri, 1989 (Australia)

n=9 Type 2 diabetes 12-wk follow up RCT Sucrose: 45g added Aspartame added

5.2 5.2

5.3 5.4

- -

0.91 0.91

0.96 0.93

1.9 1.9

2.1 2.1

75.7 75.7

75.9 75.3

GHb

7.2 7.2

GHb

7.5 7.3

Cooper, 1988 (Australia)

n=17 Type 2 diabetes 6-wk follow-up RCT Sucrose diet (28-30g) Saccharin added

6.2 6.2

5.8* 5.8*

4.10 4.10

3.75** 3.78**

1.10 1.10

1.08 1.06

2.0 2.0

2.0 2.0

69.1 69.1

69.3 68.9

GHb

8.1 8.1

GHb

6.8** 8.0

Coulston, 1989 (US)

n=8 Type 2 diabetes 12-wk follow-up 40% CHO diet 60% CHO diet

- decreased when

consuming the 60% CHO diet†

decreased when consuming the 60%

CHO diet††††

increased when consuming the 60%

CHO diet -

FPG conc. increased on the 60%

CHO diet††††


62






(mmol/L)



Devaraj, 2000 (US)

n=25 Type 2 diabetes n=25 Type 2 diabetes +MVD n=25 controls 3-mth follow-up vitamin E 1200 IU/d

no sig. change no sig. change

no sig. change


no sig. change


no sig. change


no sig. change

- -

Dunstan, 1997 (Australia)

n=55 Type 2 diabetes 8 week follow-up RCT Fish & moderate exercise Fish & light exercise Moderate exercise only Light Exercise (Control)

4.9 5.0 4.7

5.4

4.74 4.81 4.47

-

3.2 3.3 2.8

3.8

3.47* 3.55 2.84

-

0.83 0.89 0.96

0.85

0.78 0.85 0.90

-

2.0 1.7 2.3

2.1

0.80****

0.48**** 1.62 (v

control) † -

85.7 89.4 85.6

88.4

83.3* 88.0 83.5*

87.8

GHb

8.3 8.0 8.8

8.1

GHb

8.11 7.51 8.77

-

Eriksson, 1995 (Finland)

n=27 Type 2 diabetes 3-mth crossover RCT vitamin C magnesium

6.2 6.2

5.9* † 6.2

-

1.16 1.16

1.10 1.13

2.5 2.5

2.2* † 2.6

-

9.3 9.3

8.5* † 8.9

Frost, 1994 (UK)

n=51 Type 2 diabetes 18-mth follow-up Standard dietary advice Low glycaemic advice

5.6 6.2

5.3 5.5* †

3.4 4.4

3.3 3.7

1.0 1.2

1.1 1.2

2.5 1.9

2.1 1.4* †

85.0 84.9

82.9 84.8

- -

Garg, 1992a (US)

n=10 men Type 2 diabetes 28-day follow-up RCT High CHO diet (65%) High MUFA

5.15 5.15

5.09 4.44†††

3.09 3.09

2.73 2.67

0.85 0.85

0.83 0.9††

2.98 2.98

4.18 2.49†††

86.3 86.2

86.1 85.4

GHb

8.9 8.4

GHb

8.6 8.4

Garg, 1994a (US)

n=42 Type 2 diabetes 8-wk follow-up RCT High CHO diet (55%) High MUFA

- -

5.07 4.97

- -

3.36 3.36

- -

0.92 0.96

- -

2.19 1.75†††

- -

82.3 82.2

-


63






(mmol/L)



Garg, 1998 (US)

Meta-analysis of RCTs 10 studies, lasting 2-6 wks High MUFA diet (33%) v High CHO (65%)

high MUFA v high CHO

↓ 0.15 mmol/L† (CI-0.24, -0.06)


↓ 0.01 mmol/L (CI-0.10, 0.08)


↑ 0.05 mmol/L† (CI 0.03-0.07)


↓ 0.36 mmol/L† (CI-0.24, -0.06)

-

high MUFA v high CHO FPG

↓ 0.23 mmol/L† (CI -0.39, -0.06)

Grigoresco, 1988 (France)

n=8 Type 2 diabetes 2-mth follow-up RCT Fructose diet (30g) Control diet

4.49 4.49

4.54 4.64

- -

1.01 1.01

0.95 1.03

1.16 1.16

1.47* 1.36

74.3 74.3

72.5 72.4

6.8 6.8

5.9 6.4

Groop, 1993 (Finland)

n=15 Type 2 diabetes 8-wk placebo 48-wk guar gum 15g/d 8-wk placebo again

6.11 5.74

5.74* 6.61**

3.90 3.57

3.57* 4.32**

1.18 1.26

1.26 1.33

2.21 2.02

2.02 2.12

- -

9.0 8.5

8.5* 8.5

Gumbiner, 1998 (US)

n=17 Type 2 diabetes 10-wk follow-up RCT High MUFA High CHO diet

5.3 4.5

↓↓* † ↓*

3.1 2.5

↓ ↓

1.0 1.0

↓* † ↓↓*

2.8 2.2

↓↓* † ↓*

101.8 110.4

94.5 102.1

- -

Gupta, 1994 (India)

n=24 Type 2 diabetes 90-day follow-up psyllium 3.5g twice a day

6.0

5.6**

3.8

3.5**

1.13

1.24*

2.2

1.6***

-

no sig. change

Gylling, 1994 (Finland)

n=11 Type 2 diabetes 6-wk crossover rapeseed oil margarin added sitostanol ester 3g/d

5.98 5.62*

3.83 3.46*

1.13 1.24*

2.14 2.08

- -

Gylling, 1996 (Finland)

n=8 Type 2 diabetes 4 7-wk periods margarin (control) sitostanol ester 3g/d pravastatin 40mg/d sitostanol ester+pravastatin

6.64 5.94 4.53 4.29

5.29 ↓ ↓

- - - -

↓ 14% ↓ 38% ↓ 44%

-

2.43 2.38 1.74 1.70

no effect ↓†(v ester) ↓†(v ester)

-

7.0 7.3 8.1 7.1

- - - -


64






(mmol/L)



Heart Protection Study Collaborative Group, 2002b

n=20,536 n=5,963 Type 2 diabetes 5-yr follow-up antioxidant vitamin v placebo

during follow-up

4.89 4.74

during follow-up

2.82 2.74

during follow-up

1.10 1.13

during follow-up

2.13 1.92

- -

Heilbronn, 1999 (Australia)

n=35 Type 2 diabetes 12-wk follow-up RCT high CHO diet high MUFA diet high SFA diet

5.82 5.97 5.00

5.40 5.10*** 5.40***

3.91 3.99 3.16

3.52** 3.28** 3.46

0.96 0.82 1.06

0.93 0.86 1.14

2.13 3.28 2.12

2.11 2.14 2.18

↓ 6.6 kg ↓ 6.6 kg ↓ 6.6 kg

8.51 7.75 7.46

7.00**** 6.75**** 6.55****

Heilbronn, 2002 (Australia)

n=45 Type 2 diabetes mean age 56.7 yrs 12-wk follow-up RCT high GI diet (n=21) low GI diet (n=24)

5.15 5.58

4.75* 5.01*

3.25 3.45

2.91* 2.91*

1.10 1.25

1.12 1.26

1.78 1.96

1.60 1.84

93.2 91.7

88.4* 87.3*

6.35 6.65

6.06* 6.04*

Heine, 1989 (The Netherlands)

n=14 Type 2 diabetes 60-wk follow-up RCT Low P:S diet High P:S diet

after 24 wks

5.92 5.47††

after 24 wks

4.08 3.68††

-

after 24 wks

2.42 2.22

after 24 wks

77.9 78.0

after 24 wks

9.2 9.2

Hermansen, 2001 (Norway)

n=20 Type 2 diabetes RCT, 6-wk crossover Abalon (soy protein + cotyledon fibre) v placebo

5.68

5.59

5.11

5.45

3.63

3.64

3.01*

3.33

1.31

1.28

1.38

1.33

1.70

1.70

1.63*

1.79

-

no sig. change

Lee, 2003 (Germany)

n=85 Type 2 diabetes 3-mth follow-up phytosterols placebo

during follow-up

↓ 5.2%* ††† ↑ 1.1%

during follow-up

↓ 6.8%* † ↑ 1.5%

during follow-up ↑

during follow-up ↓ -

during follow-up

↓ † only at 4 wks

Low, 1996 (US)

n=17 Type 2 diabetes 10-wk follow-up RCT High CHO diet High MUFA diet

4.4 5.0

4.0 3.9* †

2.4 2.8

2.4 2.5

0.8 0.7

0.7 0.7

2.7 3.2

2.2 1.4* †

110.4 101.8

102.1 94.5

-

-


65






(mmol/L)



Luscombe, 1999 (Australia)

n=21 Type 2 diabetes 12-wk follow-up RCT High GI Low GI High MUFA

5.46

5.46 5.46

5.44

5.38 5.35

- - -

3.75

3.79 3.62

- - -

0.88† (v both)

0.93 0.93

1.94

1.94 1.94

1.80

1.47 1.77

87.1

87.1 87.1

86.5

86.2 86.6

-

Malerbi, 1996 (Brazil)

n=16 Type 2 diabetes 18-wk follow-up RCT Starch diet: (50-55% CHO) Fructose diet: (20% CHO) Sucrose diet: (19% energy)

5.1 5.1 5.0

5.1 5.0 5.1

3.4 3.4 3.4

3.4 3.3 3.5

1.0 1.0 1.0

1.0 1.0 1.0

1.3 1.2 1.4

1.3 1.3 1.4

65.4 65.5 65.9

65.3 65.3

66.0† (v starch)

FPG

7.3 7.3 6.8

FPG

7.2 6.7 7.5

Milne, 1994 (NZ)

n=64 Type 2 diabetes 18-mth follow-up Weight-management High-CHO/fibre Modified-lipid

6.4

6.6 6.0

6.1

6.2 5.7

4.5

4.2 4.2

4.2

4.0 3.6

1.24

1.23 1.15

1.18

1.19 1.22

2.0

2.7 2.1

1.6† (v high CHO)

2.4 2.0

79.1

80.9 82.8

79.8

80.7 82.1

GHb

9.5

9.4 10.9

GHb

8.9

8.5 9.7

Montori, 2000 (Meta-analysis)

n=18 RCT studies Type 2 diabetes Mean 12-wk follow-up Fish oil supplementation

0.007 mmol/L (-0.13, 0.15)

0.21 mmol/L*

(0.02-0.41)

0.02 mmol/L (0.01-0.05)

-0.56mmol/L* (-0.71, -0.41)

- 0.15% (-0.08, 0.37)

Niemi, 1988 (Finland)

n=18 Type 2 diabetes 12-wk crossover RCT guar gum 15g/d microcrystalline cellulose

6.6 6.1

5.9**

6.2

- - - -

12.1 11.4

11.8 12.2

Osei, 1987 (US)

n=18 Type 2 diabetes 12-wk follow-up RCT 60g added fructose without added fructose

4.92 5.28

5.02 5.80

3.19 3.42

3.26 3.68

1.30 1.11

1.30 1.27

1.04 1.65

1.04 2.71*

82.8 82.5

83.8 83.0

11.57 11.48

10.20* † 12.97

Osei, 1989 (US)

n=13 Type 2 diabetes 6-mth follow-up RCT Fructose: 60g no Fructose

5.98 5.21

5.24 5.64

3.10 2.73

3.07 3.41

0.93 1.06

1.03 0.85

1.25 1.34

1.42 1.31

87.7 88.3

89.5 87.0

GHb

11.3 10.4

GHb

9.9* † 11.2


66






(mmol/L)



Paolisso, 1995 (Italy)

n=40 Type 2 diabetes 4-mth crossover RCT vitamin C placebo

7.2 7.2

5.8** † 7.3

5.7 5.7

4.1* † 5.6

1.1 1.1

1.1 1.0

2.6 2.6

2.1* † 2.6

-

8.1 8.1

7.2* †

8.0

Parfitt, 1994 (UK)

n=13 Type 2 diabetes 17-wk follow-up RCT MUFA diet PUFA diet

5.3 5.3

4.7 4.9

3.7 3.7

3.2 3.5

0.94 0.94

0.99 0.90

1.9 1.9

1.9 1.9

- - - -

Parker, 2002 (Australia)

n=54 Type 2 diabetes 12-wk follow-up high protein diet (28%) low protein diet (16%)

5.16 5.16

4.81†† 5.15

3.32 3.23

3.13†† 3.32

0.93 0.92

0.92 0.96

2.02 2.17

1.68**** 1.94****

Men

-3.9 kg -5.1 kg

Women

-5.3kg††

-2.8kg

6.42 6.30

5.88**** 5.79****

Pick, 1996 (Canada)

n=8 Type 2 diabetes 12-wk crossover oat bran bread first white bread first

4.65 4.65

4.56 5.30

- -

2.59 3.36

- -

1.04 0.96

2.26 2.26

2.03 2.14

82.9 82.9

82.9 82.9

7.0 7.0

- -

Reaven, 1995 (US)

n=21 Type 2 diabetes 10-wk follow-up vitamin E 1600 IU/d placebo







Rimm, 1999 (Meta-analysis)

n=42 experimental studies of alcohol comsuption up to 100g/day - -

↑ 0.0034 mmol/L per g alcohol/day ↑ 0.10 mmol/L

per 30g alcohol/day

↑ 0.0049 mmol/L per g alcohol/day ↑ 0.15 mmol/L

per 30g alcohol/day

- -

Rodriguez-Moran M, 1998 (Mexico)

n=123 Type 2 diabetes 6-wk follow-up n=63 psyllium 12g/d n=60placebo

5.72 6.01

5.05† 5.57

3.78 4.07

3.06†† 3.62

0.88 0.83

1.32†††† 0.91

2.10 2.26

1.55††† 2.08

70.6 73.3

70.5 73.9

- -

7.6 10.3


67






(mmol/L)



Sheehan, 1997 (US)

n=15 Type 2 diabetes 8-wk follow-up fish oil alone 4 wks fish oil + apple pectin 15g/d 4 wks

6.57 6.57

6.15 5.69†

4.32 4.32

4.40 4.01†

0.88 0.88

0.88 0.85

3.87 3.87

2.28 2.38

76.5 76.5

76.8 76.3

7.0 7.0

6.5 6.7

Tsihlias, 2000 (Canada)

n=91 Type 2 diabetes 6-mth follow-up RCT n=29 high GI n=30 low GI n=32 MUFA

5.23 5.00

5.73† (v low GI)

not differ

b/w gps

3.18 2.95 3.69

not differ

b/w gps

1.10 0.97 1.14

- -

↑ 10%††

(v high & low GI)

2.41 2.70 2.08

not differ

b/w gps

not differ b/w gps

not differ b/w gps

Upritchard, 2000 (New Zealand)

n=57 Type 2 diabetes 4-wk follow-up RCT tomato juice n=15 vitamin E n=12 vitamin C n=12 placebo n=13

5.87 5.65 5.96 6.48

5.75 6.15*

6.00 6.51

-

1.01 1.14 1.10 0.93

- - - -

2.38 1.86 1.75 2.70

- - - -

-

6.0 6.7 6.7 6.6

- - - -

Wolever, 2003 (Canada)

n=67 Type 2 diabetes 6-mth follow-up n=22 low fibre n=25 high fibre n=22 MUFA

5.63 5.37 6.14

5.64 5.25 6.35

2.56 2.37 2.83

2.59 2.35 3.26*

1.01 0.90 1.02

1.08 0.86 1.08

2.16 2.34 1.75

2.20 2.66*

1.53* ††† (v both)

75.6 79.3 78.2

74.6 79.5 77.8

8.0 7.9 8.0

8.20 8.08 8.31


68

Exercise may have a modest beneficial effect on lipid levels in people with Type 2 diabetes Effects of short-term exercise programs (6 weeks to 26 weeks) These studies are summarised in Table 6. The majority have prescribed a program of aerobic exercise, three times a week for 20 to 60 minutes at 50-80% VO2max. In 13 diabetic men and women with mean age 52.5 years, 45 minutes of aerobic exercise (walking, jogging, skiing) at 70% VO2max 5-7 times per week was examined. This reduced total cholesterol from 6.7 to 6.4 mmol/L (p=NS), LDL cholesterol from 4.6 to 4.3 mmol/L (p<0.05), triglycerides from 2.2 to 1.9 mmol/L (p=NS) and increased HDL cholesterol from 1.22 to 1.29 mmol/L (p<0.05) after 4 months (Ronnemaa et al, 1988). There was no significant change in the lipid profile in 12 control subjects. Mean body weight fell from 85.2 to 83.2 kg (p<0.05) but in the control group rose form 82.8 to 83.3 kg (p=NS). Mean HbA1c fell from 9.6 to 8.6% (p<0.01) in the exercise group and from 10.0 to 9.9% (p=NS) in the control group. Raz et al (1994) randomly assigned 40 people with Type 2 diabetes, mean age 57 years, to control or exercise groups in a 12 week aerobic exercise program (bicycle, treadmill and rowing machine) for 55 minutes three times per week at 65% VO2max. There were significant improvements in the exercise group compared with the control group in triglycerides (1.9 v 2.2 mmol/L, p<0.05) but not total or HDL cholesterol. There was no significant change in body weight in either group, but HbA1c fell significantly in the exercise group (12.5±2.9 to 11.7±2.6%, p<0.05; exercise v control, p<0.05). Lehmann et al (1995) studied the effects of a 3 month aerobic program (50-70% VO2max for 30-45 min three times per week) on cardiovascular risk factors in 16 people with Type 2 diabetes whose mean age was 54 years. Compared with a control group of 13 people with Type 2 diabetes in whom the lipid profile did not change, exercise resulted in significant improvements in lipids with a reduction in mean triglycerides levels from 2.8 to 2.2 (p<0.05). Total cholesterol was unchanged and HDL cholesterol increased from 1.15 to 1.35 (p<0.001). Body weight did not change during the study, but there was a significant reduction of body fat (measured by a near-infrared interactance device) from 35.3±7.2% at baseline to 33.0±8.6% at 3 months (p<0.001) and of waist:hip ratio from 0.96±0.10 to 0.92±0.10 (p<0.001). HbA1c did not change from the baseline level of 7.5%. In a 26 week randomised control trial, 25 people with Type 2 diabetes, mean age 63 years, were instructed in an aerobic training program 3 times/wk for 50 min at 60-80% VO2max (Ligtenberg et al, 1997). For 6 weeks exercise was performed under supervision, for another 6 weeks at home according to personalised training advice and for a further 14 weeks at home, but without regular encouragement. Total cholesterol was 5.9 mmol/L at baseline, 5.6 mmol/L at 6 weeks, 5.7 mmol/L at 12 weeks and 6.0 mmol/L at 26 weeks. LDL cholesterol was 3.7 mmol/L at baseline, 3.5 mmol/L at 6 weeks, 3.6 mmol/L at 12 weeks and 3.7 mmol/L at 26 weeks. Triglycerides levels were 2.4 mmol/L at baseline, 2.2 mmol/L at 6 weeks, 2.7 mmol/L at 12 weeks and 2.6 mmol/L at 26 weeks. HDL cholesterol was 0.93 mmol/L at baseline, 1.0 mmol/L at 6 weeks, 1.1 mmol/L at 12 weeks and 1.2 mmol/L at 26 weeks. Compared with a control group of 26 people with Type 2 diabetes, triglycerides levels were lower at 6 weeks (2.2 v 2.5 mmol/L, p=0.05) and total cholesterol was lower at 12 weeks (5.7 v 6.0 mmol/L, p=0.05). Weight, waist circumference and waist:hip ratio were unchanged in both groups throughout the study. HbA1c was 8.9% at baseline, 8.9% at 6 weeks, 9.2% at 12 weeks and 8.7% at 26 weeks. An Australian study (Dunstan et al, 1997) used a randomised 2x2 design to test the effects of moderate exercise and daily fish intake on lipid and lipoprotein levels in people with Type 2

69

diabetes (4 groups of 11 to 14 subjects). Moderate exercise training consisted of 30 min stationary cycling at 50-55% VO2max for the first week and then 55-65% VO2max for 7 weeks. Relative to control subjects who participated in a light exercise program (heart rate <100 bpm), moderate exercise alone reduced triglycerides by 0.68 mmol/L (p=0.03) but had no effect in combination with fish, compared with fish alone. The rise of 0.06 mmol/L in HDL cholesterol with exercise alone was not significant (p=0.06) and again there was no effect of exercise and fish compared with fish alone. Moderate exercise improved aerobic fitness (VO2max) by 12% (from 1.87 to 2.07 l/min, p=0.0001). Mean weight loss was 2.1 kg in the moderate exercise group and 0.6 kg in the light exercise group. HbA1c reduction of 0.34±0.07% (p=0.07) was associated with moderate exercise. Lehmann et al (2001) examined the effects of physical activity on lipid profiles and glycaemic control in 10 obese people with Type 2 diabetes (mean BMI 32.4 kg/m2) who participated in a 3-month exercise program at 50-70% VO2max. The control group consisted of 6 people who were matched for sex, age, diabetes duration and therapy. All subjects had a prescribed diabetic diet with 50% carbohydrate, 35% fat and 15% protein content. After 3 months, there was a significant decrease in waist:hip ratio (p<0.01) but no overall change in body weight in the exercise group. With regard to lipids, triglycerides reduced from 2.4±0.33 to 2.0±0.33 mmol/L (p<0.05), HDL cholesterol increased from 1.04±0.07 to 1.28±0.12 mmol/L (p<0.001) and HDL3 cholesterol from 0.71±0.08 to 0.86±0.08 mmol/L (p=0.01); whereas total and LDL cholesterol remained unchanged. In contrast, all lipid parameters did not change significantly during 3 months in the control group. Glycaemia control was similar in both groups. In a Spanish study (Rigla et al, 2003), 13 people with Type 2 diabetes, mean age 55.8 years, participated in a 3-month physical exercise program at the intensity of 60-65% VO2max in the first 1 to 2 week and 65-75% VO2max for the rest of the study period. After 3 months, both total cholesterol and LDL cholesterol decreased significantly (5.6 to 5.2 mmol/L, p<0.05; 3.7to 3.4 mmol/L, p<0.01, respectively). In contrast, HDL cholesterol and triglycerides did not change. Glycaemic control remained stable (HbA1c 7.4% to 7.3%) and there was no reduction in body weight (73.5 to 73.6 kg) during the study period. The effect of resistance training, rather than aerobic endurance exercise, was studied by Honkola et al (1997) in 18 people with Type 2 diabetes, mean age 62 years, compared with a control group of 20 people. After 5 months of individualised, progressive, resistance training sessions twice a week, total cholesterol decreased significantly in the intervention but not the control group (6.0 to 5.3 mmol/L, p<0.01 and 6.1 to 5.9 mmol/L, p=NS respectively). Similar results were observed for LDL cholesterol (3.9 to 3.4 mmol/L, p<0.01 and 3.9 to 3.8 mmol/L, p= NS respectively) and triglycerides (1.9 to 1.5 mmol/L, p<0.01 and 2.6 to 2.2 mmol/L, p= NS respectively). There was no significant change in HDL cholesterol levels in the intervention group, but there was a small, significant rise in the control group (1.28 to 1.30 mmol/L, p=NS and 1.14 to 1.21 mmol/L, p<0.05 respectively). Body weight in the exercise group fell from 87.3 to 86.6 kg (p<0.05), but not in the control group (p=NS). HbA1c in the exercise group was 7.5% at baseline and 7.4% at 5 months, in the control group 7.7% at baseline and 8.1% at 5 months (p<0.01). Effects of long-term exercise programs (1-2 years) There have been few long-term studies on the effects of exercise in people with Type 2 diabetes (see Table 6). Schneider et al (1992) reported an outpatient exercise program which recruited 255 people with diabetes (including 200 with Type 2 diabetes) and 58 healthy controls. Over the initial 3 months, triglycerides levels decreased during training in people with Type 2 diabetes from 2.2±0.18 to 1.7±0.25 mmol/L (p<0.01). No significant changes in total and HDL cholesterol

70

were observed. In the Type 2 diabetes group, both body weight and BMI were reduced from baseline (83.9±1.5 to 81.5±1.9 kg, p<0.05; 28.1±0.5 to 25.9±0.9 kg/m2, p<0.01, respectively). A lower VO2max was found in people with Type 2 diabetes compared with healthy controls (age >40 yr: 24.5±0.7 v 32.2±1.7 ml/kg/min, p<0.01; age <40 yr: 23.1±1.5 v 39.9±1.7 ml/kg/min, p<0.05). After 3 months VO2max remained lower in people with Type 2 diabetes than the controls. They concluded that a regular aerobic training program can be safely and effectively used in an outpatient population with diabetes for up to 3 months. Vanninen et al (1992) studied the effects on lipid levels of a one-year exercise program in 21 men and 17 women with Type 2 diabetes. Intervention consisted of oral and written instructions for effective exercise training, with monitoring of daily exercise records and encouragement at 2 monthly review visits. The goal was to achieve 3 to 4 exercise sessions per week, each of 30 to 60 minutes. HDL cholesterol increased significantly with exercise in both men and women (1.03 to 1.11 mmol/L, p<0.05 and 1.09 to 1.25 mmol/L, p<0.01 respectively). A significant decrease in triglycerides was found only in men (3.0 to 2.0 mmol/L, p<0.01). There was a significant relationship between changes in aerobic capacity and HDL cholesterol, independent of changes in body weight or metabolic control. Total and LDL cholesterol levels did not change significantly. BMI fell from 31.1 to 30.5 kg/m2 in men (p<0.05) and from 33.4 to 32.6 kg/m2 in women (p=NS). Mean HbA1c was 7.1% at baseline and 7.0% at 12 months in men (p=NS), 7.1% at baseline and 6.2% in women (p<0.05). The only significant change in the control group of 24 men and 16 women was an increase of BMI from 30.1 to 30.9 kg/m2 in men (p<0.01). The longest reported study was a small 2 year study by Skarfors et al (1987) in which 48 men were screened but 39 were excluded because of other diseases or treatment that made regular training difficult and one person who took digoxin 0.25 mg daily was also excluded. Eight men, mean age 59 years, were scheduled for exercise at 75% VO2max for 45 min twice weekly under supervision and one training session of their own on an additional occasion per week. The average participation rate over 2 years was 53%. Total cholesterol was 6.1 mmol/L at baseline and 5.8 mmol/L at 2 years, LDL cholesterol was 4.1 mmol/L at baseline and 4.1 mmol/L at 2 years, triglycerides levels were 2.8 mmol/L at baseline and 2.9 mmol/L at 2 years and HDL cholesterol was 1.04 mmol/L at baseline and 1.07 mmol/L at 2 years. Fasting glucose was 11.0 mmol/L at baseline and 9.6 mmol/L after 2 years. Body weight was 78.3 kg at baseline, but was not reported at 2 years. Lipid profile did not change over 2 years in a control group of 8 people. In summary: • Exercise in people with Type 2 diabetes may have a modest effect on lipid levels • Improvement of the lipid profile with exercise is more likely to occur if there is reduction

of body weight and improvement of glycaemic control

71

Table 6: Effect of exercise on lipid levels





(mmol/L)

Body Weight (kg) HbA1c Reference Population Studied


Brown, 1996

n=89 studies systematic review Type 2 diabetes Direction change not given Diet only Behaviour only Exercise only Diet + behaviour + exercise

Effect sizes

0.62* 0.09 0.06 0.11

Effect sizes

0.12 - - -

Effect sizes

0.17 -

0.02 0.00

Effect sizes

0.56* 0.12 0.20 0.31*

BMI Effect sizes

0.71 0.81

- -

FPG Effect sizes

1.76* 0.31* 0.34* 0.48*

Dunstan, 1997 (Australia)

n=55 Type 2 diabetes 8-wk follow-up RCT Fish & moderate activity Fish & light activity Moderate exercise Light Exercise (Control)

4.9 5.0 4.7

5.4

4.74 4.81 4.47

-

3.2 3.3 2.8

3.8

3.47* 3.55 2.84

-

0.83 0.89 0.96

0.85

0.78 0.85 0.90

-

2.0 1.7 2.3

2.1

0.79**** 0.48**** 1.62 (v

control)† -

85.7 89.4 85.6

88.4

83.3* 88.0 83.5*

87.8

8.3 8.0 8.8

8.1

8.11 7.51 8.77

-

Honkola, 1997 (Finland)

n=38 Type 2 diabetes 5-mth follow-up Resistance training Control

6.0 6.1

5.3** 5.9

3.90 3.94

3.35**

3.79

1.28 1.14

1.30 1.21*

1.91†† 2.60

1.53**†† 2.23

87.3 77.1

86.6* 78.8

7.5 7.7

7.4 8.1**

Lehmann, 1995 (Switzerland)

n=16 Type 2 diabetes 6-mth follow-up Exercise training: 3 times/wk; 6 months Control (n=13): 3 months

5.6 -

5.5 -

3.12

3.51

3.10

3.19

1.15 -

1.35** -

2.81 -

2.36** -

87.3

86.8

87.4

86.8

7.5

7.8

7.5

8.4

Lehmann, 2001 (Switzerland)

n=16 Type 2 diabetes 3-mth follow-up n=10 exercise gp n=6 control gp

5.2 -

5.1 -

2.9 -

2.8 -

1.04 -

1.28****

-

2.38 -

1.95*

-

92.3 89.2

91.7 89.8

7.2 7.0

7.2 7.5


72






(mmol/L)



Ligtenberg, 1997 (The Netherlands)

n=58 Type 2 diabetes 26-wk follow-up RCT n=30 training gp n=28 control gp supervised training, v control at 6 wks encouraged training, v control at 12 wks home training 3 times/wk v control at 26 wks

5.9 5.7

5.6 5.7 5.7* 6.0 6.0 6.0

3.7 3.7

3.5 3.6 3.6 3.7 3.7 3.7

0.93 0.87

1.0 0.97 0.94 0.90 1.02 1.03

2.4 2.5

2.2** 2.5 2.7 3.1 2.6 2.6

no sig difference

no sig difference

no sig difference

8.9 8.8

8.9 9.1 9.2 9.4 8.7 9.0

Raz, 1994 (Israel)

n=38 Type 2 diabetes 12-wk follow-up RCT exercise: 3 times/wk control

5.7 6.0

5.6 6.0

-

-

1.1 1.1

1.1 1.1

2.0 2.1

1.9* †

2.2

-

-

12.5 12.4

11.7* † 12.9

Rigla, 2003 (Spain)

n=13 Type 2 diabetes mean age 55.8 yrs 3-mth follow-up exercise program

5.57

5.20*

3.65

3.37**

1.26

1.23

1.46

1.32

73.5

73.6

7.4

7.3

Ronnemaa, 1988 (Finland)

n=25 Type 2 diabetes 4-mth follow-up RCT exercise: 5-7 times/wk controls

6.74 6.20

6.37 6.10

4.62 4.19

4.29* 4.11

1.22 1.22

1.29* 1.26

2.16 1.91

1.91 1.75

85.2 82.8

83.2* 83.3

9.6 10.0

8.6**

9.9

Schneider, 1992 (US)

n=111 Type 2 diabetes 10-yr follow-up case-control exercise 3-4/wk for 3 mths n=20 controls

5.83† 5.08

5.67† 5.41

-

-

1.14 1.24

1.11 1.32

2.18† 0.95

1.71** †

1.01

83.9 79.3

81.5* 80.4

-

-

Skarfors, 1987 (Sweden)

n=8 men, Type 2 diabetes 2-yr follow-up Training group (2 times/wk) Control (n=8)

6.06 5.96

5.81 5.96

4.11 4.21

4.09 4.21

1.04 0.93

1.07 0.93

2.82 2.72

2.87 2.72

- - - -


73






(mmol/L)



Vanninen, 1992 (Sweden)

n=78 Type 2 diabetes 12-mth follow-up RCT Men - intervention (6 visits/yr) - conventional group Women - intervention - conventional group

6.3 6.1

6.0 6.5

6.0 6.2

6.0† 6.7

- -

1.00 1.10

1.13 1.25

1.11* 1.15

1.25** 1.29

2.9 2.3

2.1 2.3

2.0** 2.3

2.0 2.5

- -

7.1 7.3

7.1 8.1

7.0 7.4

6.2* † 7.2


74

Summary – Diet and Exercise on Lipid Levels • Weight loss (≥ 5%) decreases triglycerides and to a lesser extent total cholesterol. The

effect on LDL and HDL cholesterol is variable • High-carbohydrate (55-60%), low-fat (20-30%) low fibre diets (11-18 grams/day)

increase triglycerides levels by about 25% in short term, but not longer term studies • Reducing the glycaemic index of a high carbohydrate diet improves blood glucose control

and may improve lipids in people with Type 2 diabetes but it is not possible to determine whether these effects are interrelated or independent

• The inclusion of limited amounts of refined carbohydrate (sucrose, fructose) does not

adversely affect lipid levels • Compared with high carbohydrate diets, iso-caloric diets which are high in

monounsaturated fatty acids • reduce fasting triglycerides and VLDL cholesterol in the short term • have no effect on HDL cholesterol or LDL cholesterol The long-term effects on plasma lipids and weight in a free-living situation remain untested

• Soluble fibre consistently lowers cholesterol in people with Type 2 diabetes but has a variable effect in lowering triglycerides

• In studies which have examined the effect of exercise on lipid levels

• There is often a modest improvement in lipid levels • the magnitude of change has been small (average triglycerides reduction 0.3mmol/L,

HDL cholesterol increase 0.08 mmol/L, LDL cholesterol decrease 0.2mmol/L, total cholesterol decrease 0.3mmol/L) and,

• it has been difficult to separate an independent effect of exercise from concurrent changes in diabetes control and body weight

75


Effects of diet and exercise on lipids in people with Type 2 diabetes


Author


Magnitude Rating

Relevance Rating

Abraira C (1988) (Adults – US) II RCT High High D+ High

Anderson JW (1999) (Adults – US) II RCT Medium High P+ High

Bantle JP (1993) (Adults – US) II RCT High Low High

Barnard RJ (1994) (Adults – US) III-2 Cohort Medium High D,E+ High

Bell RA (2000) (Adults – US) III-2 Cross-sectional High High A+ Low

Ben G (1991) (Adults – Italy) III-2 Case-control Low Medium A+ High

Bishop N (1985) (Adults – UK) II RCT High Low High

Bonanome A (1991) (Adults – Italy) III-2 Cohort High Low High

Brand JC (1991) (Adults- Australia) III-2 RCT Medium MediumGI+ High

Brown SA (1996) I Meta-analysis Medium Low Low

Chandalia M (2000) (Adults- US) II RCT Low HighD+ Medium

Chen Y-DI (1995) (Adults – US) III-2 Cohort Medium High D- High

Christiansen E (1997) (Adults – Denmark) II RCT Medium Low High

Colagiuri S (1989) (Adults – Australia) II RCT High Low High

Cooper PL (1988) (Adults – Australia) II RCT Medium High D+ High

Coulston AM (1989) (Adults – US) II RCT Medium High D- High

Devaraj S (2000) (Adults – US) III-2 Case-control High HighVE+ High

Dunstan W (1997) (Adults – Australia) II RCT High High FO+ High

Eriksson J (1995) (Adults – Finland) II High High HighVC+ High

Franz MJ (1995) (Adults – US) II RCT High High PGC+ High

Frost G (1994) (Adults – UK) II RCT High High GI+ High

Garg A (1992a) (Adult men – US) II RCT Medium High MUFA+ High

Garg A (1994) (Adults – US) II RCT High High D- High

Garg A (1998) I Meta-analysis High High MUFA+ High Grigoresco C (1988) (Adults – France) II RCT Medium Medium F+ High

Groop PH (1993) (Adults – Finland) III-1 Non RCT Medium High G+ High

Gumbiner B (1998) (Adults – US) II RCT Medium High D+ High

Gupta RR (1994) (Adults – India) III-2 Cohort Medium High P+ Medium

Gylling H (1994) (Adult men- Finland) II RCT Medium High PS+ High

For magnitude rating: +diet/exercise improves lipid levels; High = clinically important & statistically significant; Medium = small clinical importance & statistically significant; Low = no statistically significant effect. Criteria for Quality and Relevance ratings are detailed in Appendix 9. A= alcohol; D= low calorie diet; DD= diet & drug; E= exercise; F= fructose; FO= fish oil; G= guar gum; GI= low glycaemic index diet; MUFA= high monounsaturated fat diet; O= oatbran concentrate; P= psyllium; PGC= practice guidelines nutrition care; PS= Plant sterol-margarine; PUFA= polyunsaturated fatty acid diet; VC= vitamin C; VE= vitamin E.

76



Author


Magnitude Rating

Relevance Rating

Gylling H (1996) (Adult men – Finland) II RCT Medium High PS+ High

Gylling H (1999) (Adult women – Finland) II RCT Medium High PS+ Low

Heart Protection Study (2002b) (Adults – UK) II RCT High Low High

Heilbronn LK (1999) (Adults – Australia) II RCT High High MUFA+ High

Heilbronn LK (2002) (Adults – Australia) II RCT High High GI+ High

Heine RJ (1989) (Adults – Netherlands) II RCT Medium Low High

Hermansen K (2001) (Adults – Norway) II RCT High High PS+ High

Hollander PA (1998) (Adults- US) II RCT Medium High DD+ High

Honkola A (1997) (Adults – Finland) III-2 Case-control Low High E+ High

Lee Y-M (2003) (Adults – Germany) II RCT High High PS+ High

Lehmann R (1995) (Adults – Switzerland) III-2 Case-control Medium High E+ High

Lehmann R (2001) (Adults – Switzerland) III-2 Case-control Medium High E+ High

Ligtenberg PC (1997) (Adults – The Netherlands) II RCT Medium High E+ High

Low CC (1996) (Adults – US) II RCT Medium Medium MUFA+ Low

Luscombe ND (1999) (Adults – Australia) II RCT Medium Medium GI+ High

Malerbi DA (1996) (Adults – Brazil) II RCT Medium Low Low

Manley SE (2000) (Adults – UK) III-2 Cohort High High D+ High

Mayer-Davis EJ (1999) Adults – US) III-2 Cohort Medium Medium D+ High

Milne RM (1994) (Adults – New Zealand) II RCT Medium Medium D+ High

Montori VM (2000) I Meta-analysis High High FO+ High Niemi MK (1988) (Adults – Finland) II RCT Medium Medium G+ High

Osei K (1987) (Adults – US) II RCT Low Low High

Osei K (1989) (Adults – US) II RCT Medium Low High

Paolisso G (1995) ( Adults – Italy) II RCT High High VC+ High

Parfitt VJ (1994) (Women – UK) II RCT Medium Medium D+ High

Parker B (2002) (Adults – Australia) II RCT Medium High D+ High

Pick ME (1996) (Adults – Canada) II RCT Low High O+ High

Raz I (1994) (Adults – Israel) II RCT Low Medium E+ Medium

Reaven P (1995) (Adults – US) II RCT Medium Low High

Rigla M (2003) (Adults – Spain) III-2 Cohort High High E+ High


77



Author


Magnitude Rating

Relevance Rating

Rimm EB (1999) I Meta-analysis Medium High A+ Low

Rodriguez-Moran M (1998) (Adults – Mexico) II RCT High High D+ Low

Ronnemaa T (1988) (Adults – Finland) II RCT Medium Medium E+ High

Schneider SH (1992) (Adults – US) III-2 Case-control Low Medium E+ High

Sheehan JP (1997) (Adults – US) II RCT Low High D+ High

Skarfors ET (1987) (Adults – Sweden) III-2 Case-control Medium Low High

Upritchard J (2000) (Adults – New Zealand) II RCT High High VC,VE+ High

Vanninen E (1992) (Adults – Sweden) II RCT Medium Medium E+ High

Wing RR (1994) (Adults – US) II RCT Medium Low High

Wolever TMS (2003) (Adults – Canada) II RCT Medium High MUFA+ High


78

Section 3: Lipids

Issue

What is the effect of improved blood glucose control on lipids in Type 2 diabetes?

Recommendation

In people with Type 2 diabetes whose lipid levels are above target and who have unsatisfactory diabetes control, efforts should be made to improve their blood glucose control before considering lipid modifying medication

Evidence Statement

• Improving blood glucose control with hypoglycaemic agents has a modest beneficial

effect on lipids in people with Type 2 diabetes although the effectiveness of different agents varies

Evidence level II

79

Background – Improved blood glucose control and lipids Poor blood glucose control may be a contributing factor to the lipid abnormalities of Type 2 diabetes and improving blood glucose control per se, irrespective of how it is achieved, normally leads to some correction of the lipid abnormalities (Stern et al, 1992). Type 2 diabetes results from impaired insulin secretion, reduced peripheral insulin sensitivity or a combination of both. Treatment options include changes to diet and physical activity, oral hypoglycaemic agents and insulin. Initially people are usually treated with advice on diet and physical activity. If glycaemic targets are not achieved either a biguanide (metformin), which reduces hepatic glucose production and improves insulin sensitivity, or a sulphonylurea, which stimulates insulin secretion is commenced. The natural history of Type 2 diabetes is that glycaemic control deteriorates over time and therapy needs to be intensified with either combination therapy (sulphonylurea plus metformin), the addition of other hypoglycaemic agents (α-glucosidase inhibitor or a thiazolidenedione) or insulin. Improving diabetes control usually reduces triglycerides, largely due to reduced VLDL triglycerides and sometimes increases HDL cholesterol (Haffner, 1998). However, because ideal glycaemic control is often not achieved, lipid abnormalities frequently persist. Even when good glycaemic control is achieved, insulin resistance generally remains and therefore lipid abnormalities are only partially corrected. This Section reviews the effects on lipids of biguanides, sulphonylureas, acarbose, thiazolidenediones, insulin and combinations of these medications in people with Type 2 diabetes. Evidence – Improved blood glucose control and lipids Improving blood glucose control with hypoglycaemic agents has a modest beneficial effect on lipids in people with Type 2 diabetes although the effectiveness of different agents varies Many studies have examined the effects of improving blood glucose control with various oral agents and insulin on lipids and lipoproteins in people with Type 2 diabetes. The overall trend of these studies has shown a modest beneficial effect although a number of studies have not shown any benefit. The results of studies in which there was an improvement in diabetes control are detailed below, categorised by the individual hypoglycaemic(s) agent(s) studied. Although the UKPDS reported and compared various intensive therapies in people with newly diagnosed Type 2 diabetes, these analyses were performed on an intention to treat basis and it is not possible to determine the actual treatment received by individuals during the course of the study. Therefore the results of the UKPDS study on lipid levels are not considered in this Section. Metformin (Table 7) Metformin monotherapy Studies of 3 to 7 months duration with metformin monotherapy in people with Type 2 diabetes who had persistent hyperglycaemia despite advice on diet and physical activity, have evaluated its hypoglycaemic and lipid modifying efficacy and its effects on body weight. Metformin in doses of 0.5-3.0g per day significantly improved glycaemic control in all

80

studies as judged by falls in HbA1c and fasting blood glucose (FBG) levels. Metformin caused no significant increase in body mass index (BMI) in any of these studies despite significant improvements in blood glucose control. Rains et al (1988) evaluated the effects of 3 months metformin treatment (1-3g/day) in 35 people with Type 2 diabetes with inadequate glycaemic control. Metformin reduced HbA1c by 1.5% (CI -2.23, -0.83%, p<0.0001), but there was no effect on triglycerides or HDL cholesterol. However, total cholesterol was reduced by 0.39 mmol/L (p<0.01) and LDL cholesterol by 0.34 mmol/L (p<0.01). The largest study of lipid changes with metformin monotherapy in Type 2 diabetes was reported by DeFronzo et al (1995). In this 29 week study metformin 1.7 to 2.55g daily (n=143) was compared with placebo (n=146) in people with mean BMI 29.6 kg/m2. HbA1c was significantly lower in the metformin group than in the placebo group (7.1±0.1 v 8.6±0.2%, p<0.01). Triglycerides and HDL cholesterol levels did not change significantly with metformin therapy, but total and LDL cholesterol levels both fell by 0.28 mmol/L and the change was significantly different from the change in the placebo group (p=0.001 and p=0.019 respectively). Another randomised trial of 6 months duration (Hoffmann & Spengler, 1997) compared metformin (n=31) with acarbose (n=31) and with placebo (n=32). Metformin 1.7g/day significantly reduced FBG and HbA1c compared with placebo (7.8 v 9.2 mmol/L, p<0.0001; 8.7 v 9.8%, p<0.0001, respectively), but had no significant effects on triglycerides and total, LDL or HDL cholesterol. A direct comparison of metformin (up to 2.55g daily, n=30) with insulin therapy (twice daily, intermediate acting insulin, n=30) was made by Fanghanel et al (1996) in people with Type 2 diabetes and secondary failure to high dose sulphonylurea therapy. HbA1c was reduced to the same degree by metformin (12.8 to 8.9%, p=0.002) and by insulin (12.3 to 8.2%, p=0.0001). However, metformin also reduced total cholesterol from 6.1 to 5.2 mmol/L (p=0.009), LDL cholesterol from 3.9 to 3.2 mmol/L (p=0.0015) and triglycerides from 2.6 to 2.1 mmol/L (p=0.0013) while raising HDL cholesterol from 1.04 to 1.12 mmol/L (p=0.05). Insulin therapy reduced plasma triglycerides from 2.5 to 2.1 mmol/L (p=0.05), but did not improve other lipid parameters. The authors concluded that metformin was more effective than insulin in modifying lipids in people with Type 2 diabetes and secondary failure to sulphonylureas.

81

Table 7: The effects of metformin therapy on lipids in people with Type 2 diabetes

Effects on Lipids




Mean Triglycerides (mmol/L)

HbA1c (%)

Body Weight (kg) NOTE Reference Population Studied Drug Dose

Before After Before After Before After Before After Before After Before After Before After

Dailey, 2002 (NS)

n=828 Type 2 diabetes 52-wk follow-up mean age 55.7 yrs metformin+glyburide

bid 1.25/250mg 2.5/500mg

HbA1c ≤9.0% ↓ 0.07 *

HbA1c >9.0% ↓ 0.34 *

HbA1c ≤9.0% ↓ 0.31 *

HbA1c >9.0% ↓ 1.10 *

no sig. changes

HbA1c ≤9.0% ↓ 0.21 *

HbA1c >9.0% ↓ 0.60 *

8.7 7.0 ↑ 3.28 kg after treatment -

FPG (mmol/L) Study1 Type 2 diabetes n=289, mean age 53 yrs RCT 29-wk follow up metformin placebo

2.55g/d

5.46 5.49

5.21††† 5.52

3.52 3.57

3.19†† 3.50

1.01 1.06

1.04 1.06

2.36 2.09

2.18 2.16

8.4 8.2

7.0†††† 8.6

no sig. changes 13.40 13.22

10.6††††

13.55 FPG (mmol/L)

DeFronzo, 1995 (US)

Study 2 Type 2 diabetes n=632, mean age 55 yrs metformin+glyburide metformin alone (M) glyburide alone (G)

2.55g+10mg

2.55g/d

10mg/d

5.59

5.49

5.59

5.34††† (v G) 5.39††† (v G) 5.70

3.55

3.47

3.52

3.32†††† (v G)

3.34†††† (v G) 3.65

1.01

0.96

0.96

1.04

1.01

0.98

2.44

2.61

2.37

2.19†††† (v G) 2.50††† (v G) 2.57

8.8

8.9

8.5

7.1†††† (v G) 8.5

8.7

↑†††† (v G) ↓

no sig. changes

13.94

14.11

13.72

10.44†††† (v G) 14.01

14.50

FBG (mmol/L) Fanghanel, 1996 (Mexico)

n=60 Type 2 diabetes: RCT 3-mth follow up mean age 52 yrs metformin insulin

/day 0.85-2.55g

24u

6.09 5.91

5.23** 5.68†††

3.86 3.71

3.17*** 3.65††††

1.04 1.07

1.13*** 1.06†††

2.60 2.47

2.28*** 2.11*

12.8 12.3

8.9*** 8.2****

- -

14.95 15.04

8.87*** 7.49****††

Giugliano, 1993 (Italy)

n=50 Type 2 diabetes RCT 6-mth follow up mean age 60 yrs metformin+Ins (n=27) placebo+Ins (n=23)

0.85g×2/d

5.90 6.03

5.69* 6.00 †

-

1.03 1.00

1.16* 1.01†

2.87 2.75

2.56* 2.70 †

11.5 11.7

9.8* 11.1†

no sig. changes

insulin dose ↑†

fasting insulin ↑†

in placebo gp

Before/ After comparison * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between groups comparison † p<0.05, †† p<0.01, ††† p<0.005, †††† p<0.001

82

Table 7: The effects of metformin therapy on lipids in people with Type 2 diabetes

Effects on Lipids




Mean Triglycerides (mmol/L)

HbA1c (%)

Body Weight (kg) NOTE Reference Population Studied Drug Dose

Before After Before After Before After Before After Before After Before After Before After FPG (mmol/L)

Hermann, 1994 (Sweden)

n=124 Type 2 diabetes 6-mth RCT, mean age 60 yrs metformin (M) n=19 glyburide (G) n=19 M+G (GM Low) n=46 M → M+G n=12 G → G+M n=11 M+G (GM High) n=17

1-3g/day 3.5-14mg

5.38 5.66 5.46 4.84 5.25 6.05

5.03 5.78 5.36 4.96 5.48

5.40**

3.66 3.93 3.67 3.04 3.49 4.04

3.38 4.04 3.58 3.31 3.73 3.71*

0.81 0.89 0.91 0.81 0.84 0.76

0.77 0.92 0.95 0.81 0.89 0.80*

2.02 2.01 1.97 2.60 2.05 2.40

1.95 2.10 1.89 1.85 1.92

2.10**

6.9 6.7 6.8 7.8 7.8 8.4

5.8*** 5.3*** 5.6*** 5.4*** 5.7*** 6.2***

78.6 82.6 80.2 84.6 76.0 83.2

78.8 86.2*** 81.0 88.1 76.3 83.3

9.3 8.6 9.3 13.2 12.0 14.3

6.9*** 6.6*** 7.2*** 7.3*** 7.3*** 8.5***

FPG (mmol/L)

Hoffmann, 1997 (Germany)

n=94 Type 2 diabetes Age 35-70 yrs RCT 6-mth follow-up metformin n=31(M) acarbose n=31 (A) placebo n=32 (P)

1.7g/day

3 × 0.1g

5.74

6.30

5.90

5.83

5.41

5.83

3.59

4.08

3.62

3.64

3.19††

3.80

1.61

1.42

1.54

1.61

1.65†

1.39

1.41

1.68

1.60

1.28

1.23

1.46

9.7

9.6

9.4

8.7††††

8.5††††

9.8

79.0

73.9

74.9

78.5

73.1

75.1

8.8

9.1

8.7

7.8††††

7.6††††

9.2

Rains, 1988 (UK)

n=35 Type 2 diabetes 6-mth RCT age <70 yrs metformin glibenclamide

1-3g/d 5-15mg/d

6.13 5.95

5.74** 5.73

4.21 3.98

3.85** 3.86

1.06 1.03

1.03 0.97

1.70 1.73

1.68 1.67

↓ **** ↓ ****

80.3 78.9

79.9 81.6

****††††

- -


83

Metformin plus sulphonylureas There have been a number of studies that have assessed the lipid profile in people with Type 2 diabetes before and after the addition of metformin therapy to existing treatment with sulphonylureas. In most cases, there was persistent hyperglycaemia despite maximal dose sulphonylurea therapy. In 213 people with Type 2 diabetes and fasting blood glucose ≥7.8 mmol/L despite diet and maximal dose of glyburide, DeFronzo et al (1995) studied the effects of additional treatment with metformin 2.55g daily over 29 weeks. The combination therapy resulted in a fall in HbA1c of 1.6% compared to glyburide alone (n=209). Total cholesterol fell by 0.26 mmol/L, LDL cholesterol by 0.21 mmol/L and triglycerides by 0.23 mmol/L (all p<0.001). There was no significant change in HDL cholesterol. The combination therapy of metformin plus glyburide was superior to either drug alone both for reducing glycaemia and improving lipid levels. Hermann et al (1994) compared the hypoglycaemic and lipid modifying effects of metformin and glyburide alone and in combination. Combination therapy in 63 people with Type 2 diabetes previously treated with diet alone was titrated up to a maximum of metformin 3.0g daily and glyburide 14mg daily, then maintained for 6 months. People on high dose combination therapy (n=17) had a greater fall in mean HbA1c (from 8.4 to 6.2%, p<0.001) than people in other treatment groups. In the high dose combination therapy group, total cholesterol fell significantly from 6.1 to 5.4 mmol/L (p=0.006), LDL cholesterol from 4.0 to 3.7 mmol/L (p=0.019), and triglycerides from 2.4 to 2.1 mmol/L (p=0.010); while HDL cholesterol rose from 0.76 to 0.80 mmol/L (p=0.025). In a study of 828 people (mean age 55.7 years) with Type 2 diabetes (Dailey et al, 2002), metformin and glyburide were administrated 1.25 mg/250 mg b.i.d in people with HbA1c ≤9.0%, and 2.5 mg/500 mg b.i.d in people with HbA1c >9.0% for 52 weeks. At the end of the study HbA1c was reduced from 8.7% at baseline to 7.0% (no p value). The mean changes in total cholesterol was -0.21 mmol/L (CI -0.28, -0.13 mmol/L, p<0.05) and -0.07 mmol/L (CI -0.13, -0.01 mmol/L, p<0.05) in LDL cholesterol. People with initial HbA1c >9.0% had a greater reduction in total and LDL cholesterol, -0.60 mmlo/L (CI -0.78, -0.42 mmol/L, p<0.05), and -0.34 mmol/L (CI -0.48, -0.21 mmol/L, p<0.05), respectively. Similarly, triglycerides fell by 0.31 mmol/L (CI -0.48, -0.14 mmol/L, p<0.05), and 1.10 mmol/L (CI -1.72, -0.53 mmol/L, p<0.05), respectively. HDL cholesterol did not alter during the study. Metformin plus insulin Giugliano et al (1993) used a double blind, placebo controlled design to investigate the efficacy and safety of metformin in the treatment of obese people with Type 2 diabetes poorly controlled on insulin (mean daily dose of 90 units for at least 3 months) after secondary failure to maximum doses of sulphonylureas. With metformin therapy 1.7g daily (n=27) for 6 months there was a significant reduction in HbA1c from 11.7 to 9.8% (p<0.05), total cholesterol from 5.9 to 5.7 mmol/L (p<0.05), triglycerides from 2.9 to 2.6 mmol/L (p<0.05) and an increase in HDL cholesterol from 1.03 to 1.16 mmol/L (p<0.05). Metformin also significantly reduced mean insulin requirements from 90 to 68 units per day (p<0.05). In summary: • Metformin, whether used as monotherapy or added to sulphonylurea or insulin therapy

may result in modest improvements in the lipid profile, independent of a reduction in body weight

• Factors which predict an improvement in lipids include the absolute reduction in HbA1c (in the order of 1.5% or more) and higher doses of metformin

Sulphonylureas (Table 8) Sulphonylurea monotherapy The largest study of the effect of sulphonylurea therapy on lipids in Type 2 diabetes was the Diadem Study which examined the response to a mean dose of 160mg daily of gliclazide over a period of 2 years in 4,265 people from general practice (Cathelineau et al, 1997).

84

Accompanying a fall of HbA1c from 8.7 to 7.3% (p<0.001), mean total cholesterol fell from 5.9 to 5.7 mmol/L (p<0.001) and triglycerides levels fell from 1.7 to 1.5 mmol/L (p<0.001). The mean BMI decreased from 28.5±4.7 to 27.9±4.5 kg/m2 (p=0.001). However it should be noted that some subjects were treated with lipid lowering agents but the publication does not report separately results in the treated and untreated subjects. Rains et al (1988) randomised 35 people with Type 2 diabetes to metformin or gliblenclamide (upto 15mg daily) treatment for 3 months (the effect of metformin is discussed in Metformin section above). Glibenclamide reduced HbA1c by 2.0% (CI -2.80, -1.30%, p<0.0001). There were no significant changes in total (from 6.0 to 5.7 mmol/L), LDL (4.4 to 4.1 mmol/L) or HDL cholesterol (1.06 to 1.09 mmol/L) or in triglycerides (1.3 to 1.1 mmol/L). Body weight was significantly increased from 78.9 to 81.6 kg with glibenclamide therapy (p<0.001). A recently published 12-month randomised controlled trial (Derosa et al, 2003) compared glimepiride 1 mg/d (n=62) with repaglinide 1 mg/d (n=62) in people with Type 2 diabetes who were not on hypoglycaemic agents at study entry. The dose of both medications was titrated over the first 8 weeks. At 12 months, both groups had a significant reduction in FPG (p<0.01) and HbA1c (p<0.01). There were no significant changes in total, LDL and HDL cholesterol and triglycerides in either groups during the study period. However, Lp(a) level was significantly reduced from baseline in both the repaglinide group (15.4±7.2 to 11.1±6.8 mg/dl, p<0.05) and the glimepiride group (17.4±9.1 to 10.5±7.2 mg/dl, p<0.05). Sulphonylurea combination therapy Studies assessing lipid levels after adding metformin therapy to maximal dose sulphonylureas have been described earlier in this Section. There are no studies reporting the effects of adding sulphonylurea therapy to maximal doses of metformin, but there are studies on addition of sulphonylurea therapy to insulin therapy (see section on Insulin combination therapy). In summary: • sulphonylurea therapy may result in a modest improvement in lipids with a reduction of

HbA1c of 1.5% or more despite the potential to increase body weight

85

Table 8: The effects of sulphonylurea therapy on lipids in people with Type 2 diabetes

Effects of lipids

Reference Population studied Drug Dose

Mean total Cholesterol (mmol/L)



Mean Triglycerides

(mmol/L)

HbA1c (%)

Body Weight (kg) Notes

BMI(kg/m2) FBG (mmol/L)

Cathelineau, 1997 (France)

n=4,265 Type 2 diabetes Cohort study 2-yr follow-up mean age 58.5 yrs glipizide

80–320mg/day

5.90

5.74∗∗∗∗ -

-

-

-

1.66

1.46∗∗∗∗

8.7

7.3∗∗∗∗

28.5

27.9∗∗∗

10.11

7.61∗∗∗∗

FPG (mmol/L)

Derosa, 2003 (Italy)

n=124 Type 2 diabetes 12-mth follow-up RCT mean age 54 yrs glimepiride, n=62 repaglinide, n=62

1mg/d 1mg/d

5.70 5.57

5.21 5.10

3.68 3.60

3.52 3.41

1.14 1.11

1.11 1.17

1.92 1.73

1.75 1.53

7.8 8.0

6.7∗∗ 6.8∗∗

- -

9.1 8.8

6.9∗∗ 6.7∗∗

Hermann, 1994 (Sweden)

n=124 Type 2 diabetes 6-mth RCT age 34-74 yrs metformin n=19 glyburide n=19 M+G(GM Low) n=46 M→M+G n=12 G→G+M n=11 M+G(GM High) n=17

1-3g/d 3.5-14mg/d

5.38 5.66 5.46 4.84 5.25 6.05

5.03 5.78 5.36 4.96 5.48

5.40∗∗

3.66 3.93 3.67 3.04 3.49 4.04

3.38 4.04 3.58 3.31 3.73 3.71∗

0.81 0.89 0.91 0.81 0.84 0.76

0.77 0.92 0.95 0.81 0.89 0.80∗

2.02 2.01 1.97 2.60 2.05 2.40

1.95 2.10 1.89 1.85 1.92

2.10∗∗

6.9 6.7 6.8 7.8 7.8 8.4

5.8∗∗∗ 5.3∗∗∗ 5.6∗∗∗ 5.4∗∗∗ 5.7∗∗∗ 6.2∗∗∗

78.6 82.6 80.2 84.6 76.0 83.2

78.8 86.2∗∗∗ 81.0 88.1 76.3 83.3

- -

Rains, 1988 (UK)

n=35 Type 2 diabetes 3-mth RCT age <70 yrs metformin glibenclamide

1-3g/d

5-15mg/d

6.13

5.95

5.74∗∗

5.73

4.21

3.98

3.85∗∗

3.86

1.06

1.03

1.03

0.97

1.70

1.73

1.68

1.67

-1.53% (-2.23, -0.83) ∗∗∗∗

-2.05% (-2.80, -1.30) ∗∗∗∗

80.3

78.9

79.9

81.6∗∗∗∗ ††††

-

-


86

Insulin (Table 9) Insulin monotherapy The effect of insulin monotherapy on lipid levels in Type 2 diabetes has mostly involved non randomised studies in people with poor glycaemic control despite maximal oral hypoglycaemic agent therapy. A study by Rodier et al (1995) followed 18 people for 6 months on insulin therapy and included a control group which remained on maximum doses of glibenclamide plus metformin. Intensive therapy with pre-meal regular insulin plus 1 or 2 injections of long acting insulin reduced HbA1c from 10.7 to 8.5% (p<0.05). On insulin, total cholesterol did not change significantly, but HDL cholesterol rose from 0.98 to 1.37 mmol/L (p<0.01) and triglycerides levels fell from 1.5 to 1.0 mmol/L (p<0.05 compared to oral agent group). Wolffenbuttel et al (1996) studied 95 elderly people with diabetes poorly controlled on maximal doses of oral agents. Treatment with pre-mixed injections of regular and intermediate acting insulin twice daily for 6 months reduced HbA1c from 11.2 to 8.2% (p<0.05). Total cholesterol fell from 7.0 to 6.2 mmol/L (p<0.05), HDL cholesterol rose from 1.09 to 1.21 mmol/L (p<0.05) and triglycerides levels fell from 2.4 to 1.6 mmol/L (p<0.05). Two studies have followed larger numbers of people for 2 and 5 years. Kudlacek & Schernthaner (1992) followed 102 non-obese subjects with secondary failure to oral therapy during 5 years of insulin therapy. Almost all were treated with intermediate insulin twice daily and additional regular insulin as required. HbA1c fell from 8.7% at baseline to 7.1% at 5 years (p<0.0001). Total cholesterol fell from 6.2 to 5.4 mmol/L (p<0.0002) and triglycerides levels from 2.8 to 2.4 mmol/L (p<0.01). A significant weight gain associated with insulin treatment was observed at 5 years, with BMI change from 24.5 to 28.5 kg/m2 (p<0.0001). Another long-term study compared standard with intensive insulin therapy over 2 years. With standard treatment in 78 subjects HbA1c did not change significantly from the baseline level of 9.5% while in 75 subjects with intensive therapy HbA1c fell from 9.3% to about 2.1 % lower than that of standard treatment (p<0.001). With intensive therapy total cholesterol fell from 5.4 to 5.0 mmol/L (p=0.06) and LDL and HDL cholesterol did not change. With intensive insulin therapy triglycerides levels fell from 2.3 to 1.7 mmol/L at 2 years (p=0.02), but did not change with standard therapy (Emanuele et al, 1998). Insulin combination therapy Landstedt-Hallin et al (1995) compared the effect of bedtime NPH insulin (0.25 U/kg/day) (Group N) to that of regular preprandial insulin (same dose split among three injections per day) (Group D) both combined with glibenclamide 10.5 mg on lipids in 76 people with secondary failure to sulphonylurea therapy over a 4 month period. Both insulin regimes significantly improved FBG compared to baseline levels (p<0.0001). Both regimes equally and significantly (p<0.0001) reduced HbA1c. Both insulin regimes equally and significantly reduced plasma triglycerides (Group N: 2.9 to 1.9 mmol/L, p<0.001; Group D: 2.4 to 1.8 mmol/L, p<0.01) and total cholesterol (Group N: 6.0 to 5.5 mmol/L, p<0.0001; Group D: 6.0 to 5.7 mmol/L, p<0.01). There was a slight but significant increase in HDL cholesterol from 1.1 to 1.2 mmol/L (p<0.05) with bedtime insulin but no change with preprandial insulin. However, weight gain was more pronounced in subjects given regular preprandial insulin during the day (3.4±2.1 kg v 1.9±1.9 kg, p<0.001). In summary: • Insulin therapy in people with Type 2 diabetes who have failed oral hypoglycaemic

therapy has a modestly favourable effect on lipids

87

Table 9: Effects of insulin on lipids in people with Type 2 diabetes Effects on Lipids

Mean total Cholesterol (mmol/L)



Mean Triglycerides

(mmol/L)

HbA1c (%)

Body Weight (kg) Reference Population studied Drug

dose Before After Before After Before After Before After Before After Before After

2.25

1.74*

Emanuele, 1998 (US)

n=153 men Type 2 diabetes age 40-69 yrs; 2-yr follow-up; intensive insulin (n=75) standard insulin (n=78)

>2 doses 1 dose

5.35 5.35

5.04 5.04*

3.36 3.44

-

3.16

1.09 1.11

1.03 1.01** unchanged

9.3 9.5

<7.3**** similar

-

BMI (kg/m2)

Kudlacek, 1992 (Austria)

n=102 Type 2 diabetes 5-yr follow-up Cohort study mean age 64 yrs insulin therapy

-

6.2

5.4∗∗∗∗

- - - -

2.8

2.4∗∗

8.7

7.1∗∗∗∗

24.5

28.5∗∗∗∗

Landstedt-Hallin, 1995 (Sweden)

n=76 Type 2 diabetes 16-wk RCT age 40-80 yrs; glibenclamide: + bedtime NPH insulin + 3 times regular insulin

10.5 mg

6.0 6.0

5.5∗∗∗∗ 5.7∗∗

- -

- -

1.1 1.2

1.2∗ 1.3

2.9 2.4

1.9∗∗∗∗ 1.8∗∗

9.2 9.2

7.5∗∗∗∗ 7.1∗∗∗∗

78.4 77.8

80.3∗∗∗∗ 81.2∗∗∗∗

††

Rodier, 1995 (France)

n=18 Type 2 diabetes 6-mth RCT age 42-75 yrs max.OHA, n=9 insulin n=9

met. 1.7g/d & glib. 15mg/d

5.28 5.02

5.70 5.65

- -

- -

1.06 0.98

1.06 1.37*

1.30 1.52

2.14 0.97†

9.3 10.7

9.9 8.5∗

No sig. change ↑ 3.9kg∗

Wolffenbuttel, 1996 (Netherland)

n=95 Type 2 diabetes 6-mth follow-up Cohort study mean age 68 yrs insulin(30/70) n=34 glib+ bedtime NPH n=28 glib+ breakfast NPH n=33

glib. 15mg/d

7.0 6.4 6.1

6.2*

6.1∗

5.8∗

- - -

- - -

1.09 1.02 1.05

1.21∗

1.06 1.10∗

2.36 2.00 2.21

1.62∗

1.70∗

1.91∗

11.2 10.5 11.1

8.2∗

8.1∗

8.5∗

67.4 76.1 69.2

71.4∗

80.5∗

72.6∗ Before/ After comparison * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between groups comparison † p<0.05, †† p<0.01, ††† p<0.005, †††† p<0.001

88

Acarbose (Table 10) Acarbose, an alpha glucosidase inhibitor, is commonly used in Europe for improving glycaemic control in people with Type 2 diabetes but is not as widely used in Australia. Hanefeld et al (1991) in a randomised double-blind placebo controlled trial tested the effect of 3×100mg/day of acarbose on glycaemic control and lipids in 94 people with Type 2 diabetes inadequately controlled by diet alone (FBG ≥7.8 mmol/L or a postprandial blood glucose >10 mmol/L). Acarbose significantly improved glycaemic control compared with placebo (HbA1c: 9.3 to 8.7%, p<0.01 v 9.4 to 9.3%, p=NS; FBG: 9.8 to 8.4 mmol/L v 10.2 to 9.6 mmol/L, p=0.007 for acarbose v placebo). Despite the glycaemic improvement, arcabose had no effect on total cholesterol or fasting triglycerides. The effects on HDL, VLDL, and LDL levels were not studied. Acarbose had no effect on body weight but caused significant gastrointestinal side effects. Coniff et al (1995a) tested the efficacy and safety of 3 different doses of acarbose (100×3, 200×3 and 300×3mg/day) in a placebo controlled trial of 229 people with Type 2 diabetes treated with diet alone. After 16 weeks of treatment there was a significant reduction in HbA1c with all doses (relative to placebo: -0.78%, -0.73% and -1.10%, respectively, all p<0.05). Acarbose did not affect weight in any of the 3 doses and had no significant effect on cholesterol and triglycerides levels. Flatulence, diarrhoea and abdominal pain were significantly higher in the acarbose treated patients compared with placebo at all 3 doses. In a double blind-randomised control study of 89 poorly controlled people with Type 2 diabetes, Lam et al (1998) compared the effects of acarbose 50mg three times a day for 4 weeks and 100mg three times a day for another 20 weeks. Compared with placebo, acarbose improved HbA1c (-0.5% v +0.1%, p=0.038) and was accompanied by a significant reduction in weight (-0.54 kg v +0.42 kg, p<0.05). However there was no improvement in plasma lipid profiles (total and HDL cholesterol and triglycerides). Acarbose caused significant gastrointestinal side effects (p<0.05). Acarbose was found to be superior to placebo in reducing HbA1c (-0.54 v +0.04%, p<0.05) and 2h postprandial glucose (-3.2 v -0.8 mmol/L, p<0.05) in 67 poorly controlled people with Type 2 diabetes (FBG >7.8 mmol/L). However, acarbose caused no changes in total cholesterol, LDL cholesterol, HDL cholesterol or triglycerides (Coniff et al, 1995b). In contrast Hoffmann & Spengler (1997) found a significant reduction in LDL cholesterol by 21.8% and an increase in HDL cholesterol by 16.2% in 94 people treated with acarbose 300 mg per day compared with placebo (p=0.007 and p=0.016, respectively). A pronounced reduction in the LDL/HDL ratio of 26.7% was observed with acarbose therapy (p=0.013). Although triglycerides fell by 26.8% and total cholesterol fell by 14.1%, the changes were not statistically significant. After 24 weeks of treatment, HbA1c was 8.5% in the acarbose group compared with 9.8% in the placebo group (p<0.0001). In summary: • Acarbose therapy in people with Type 2 diabetes has little effect on lipid levels • This may reflect the more modest improvement in diabetes control achieved with

acarbose compared with other hypoglycaemic agents

89

Thiazolidinedione (Table 11) Thiazolidinediones, a new class of insulin sensitizing agents, have recently become available for use in Australia. Rosenblatt et al (2001) randomised 197 people with Type 2 diabetes (mean age 54.4 years) in whom all hypoglycaemic agents were discontinued for 6 weeks before study entry to receive either pioglitazone 30mg/d or placebo for 16 weeks. At baseline, there were no differences between the 2 groups in glycaemic control, lipid profiles and body weight. After 16 weeks of treatment, the pioglitazone group demonstrated a significant decrease in HbA1c compared with the placebo group (-0.60±0.165 v +0.76±0.171%, p=0.0001). Compared with placebo, pioglitazone therapy resulted in a significant reduction in triglycerides (-14.8% v +1.8%, p=0.02) and an increase in HDL cholesterol (+15.8% v +3.2%, p=0.007). The changes in total and LDL cholesterol did not differ between the groups. The mean change in body weight from baseline was +1.35 kg in the pioglitazone group and -1.87 kg in the placebo group (p<0.0001). In a multicentre, randomised double-blind, placebo control study, Freed et al (2002) compared the effects of rosiglitazone alone and in combination with atorvastatin on glycaemic control and lipid metabolism. 243 people with Type 2 diabetes were treated with rosiglitazone 4mg twice a day in an 8-week open-label period and then were randomised to a 16-week period to continued rosiglitazone plus placebo, or atorvastatin 10mg/day, or atorvastatin 20mg/day. Eight weeks of rosiglitazone alone treatment resulted in a 5.8% increase in HDL cholesterol (from 1.01 to 1.06mmol/L) and a 9.0% in LDL cholesterol (from 3.13 to 3.44mmol/L). Baseline HbA1c was similar (7.8±1.5, 7.9±1.2%) but after 8 weeks, a total of 75% of people achieved HbA1c of <8.0% and 38% achieved HbA1c of <7.0% in the rosiglitazone group. A total of 297 people with Type 2 diabetes (mean age 58.4 years) were randomised to receive pioglitazone 30mg/day, or 45mg/day or placebo for 16 weeks in a multicentre study (Herz et al, 2003). The reduction in HbA1c was 0.8% and 0.9% with pioglitazone (both p<0.001), and 0.2% with placebo (p=0.025), the difference between pioglitazone and placebo being significant (p<0.001). HDL cholesterol increased by 16% with pioglitazone 30mg/day (p<0.001) and 20% with pioglitazone 45mg/day (p<0.001), compared with a 9% increase with placebo (pioglitazone v placebo, p<0.001). For triglycerides, a fall of 16% with pioglitazone 45mg/day was significantly greater than placebo (p=0.007), whereas a 5% reduction with pioglitazone 30mg/day did not reach significance. Total cholesterol was reduced by 4% (p<0.05) and LDL cholesterol by 7% (p<0.05) with pioglitazone 30mg/day, but not with pioglitazone 45mg/day. Body weight increased slightly in people receiving pioglitazone (0.35kg, 0.82kg, respectively) compared with a reduction of 1.52kg in people receiving placebo (p<0.001). In summary: • Thiazolidinediones have a modestly favourable dose dependent effect in increasing HDL

cholesterol and lowering triglycerides despite an increase in weight

90

Table 10: Effects of acarbose therapy on lipids in people with Type 2 diabetes

Effects on Lipids Mean total cholesterol (mmol/L)



Mean Triglycerides

(mmol/L)

HbA1c (%)

Body Weight (kg) Other Factors Reference Population studied Drug


Lp(a) (mg/dl)

Coniff, 1995a (US)

n=229 Type 2 diabetes 22-wk RCT aged over 30 yrs acarbose, n=58 acarbose, n=54 acarbose, n=53 placebo, n=64

300mg/d 600mg/d 900mg/d

5.60 5.44 5.45 5.38

5.69 5.45 5.42 5.32

- - - -

2.31 2.14 2.60 2.27

2.42 2.04 2.74 2.58

8.69 8.96 9.54† 8.67

8.24† 8.56† 8.77† 9.00

85.9 87.9 84.5 91.3

90.93 87.51 83.80 90.85

19.9 11.8 36.4 25.6

16.75 11.14 35.12 23.52

Coniff, 1995b (US)

n=255 Type 2 diabetes 36-wk RCT mean age 56 yrs acarbose, n=67 tolbutamide, n=66 acar+tolb, n=60 placebo, n=62

600mg/d tolb 0.75-

1.5g/d

5.98 5.70 5.98 5.98

5.78 5.75 6.11 5.85

3.94 3.83 3.73 4.04

3.86 3.73 3.94 3.74

1.01 1.03 1.01 1.06

1.09 1.11 1.14 1.11

2.81 2.24 2.49 2.73

2.33 2.21 2.25 2.41

6.88 6.95 6.73 7.10

6.34† 6.02†

5.41†*** 7.14

- - - -

Hanefeld, 1991 (Germany)

n=94 Type 2 diabetes 24-wk RCT age 43-70 yrs acarbose, n=47 placebo, n=47

300mg/d

5.7 5.8

5.8 6.0

- - - -

2.2 2.1

1.8 1.9

9.30 9.40

8.65∗∗

9.32

76.2 78.2

74.7 76.7

- -

LDL/HDL ratio

Hoffmann, 1997 (Germany)

n=94 Type 2 diabetes 6-mth RCT age 35-70 yrs metformin, n=31 acarbose, n=31 placebo, n=32

1.7g/d 300mg/d

5.74 6.30 5.90

5.83 5.41 5.83

3.59 4.08 3.62

3.64 3.19†† 3.80

1.61 1.42 1.54

1.61 1.65† 1.39

1.41 1.68 1.60

1.28 1.23 1.46

9.7 9.6 9.4

8.7†††† 8.5††††

9.8

79.0 73.9 74.9

78.5 73.1 75.1

2.56 3.15 2.63

2.56 2.31† 3.01

Lam, 1998 (Hong Kong)

n=89 Type 2 diabetes 24-wk RCT age 35-70 yrs acarbose n=45 placebo n=44

300mg/d

- -

-0.09 -0.05

-

- -

-0.06 -0.06

- -

+0.16 -0.22

9.5 9.4

8.8† 9.4

- -

-0.54† +0.42

-


91

Table 11 Effects of thiazolidinedione therapy on lipids in people with Type 2 diabetes

Effects on Lipids Mean total cholesterol (mmol/L)



Mean Triglycerides

(mmol/L)

HbA1c (%)

Body Weight (kg) Other Factors Reference Population studied Drug


FPG (mmol/L)

Freed, 2002 (US)

n=243 Type 2 diabetes 24-wk RCT aged 35-80 yrs rosiglitazone, n=237, 8 wk rosiglitazone+atorvastatin, n=82, 16 wk rosiglitazone+atorvastatin, n=79, 16 wk rosiglitazone+placebo, n=76, 16 wk

8mg/d 10mg/d

20mg/d

- - - -

- - - -

-

3.34

3.44

3.52

↑ 9.0% 2.31††††

2.12††††

3.55

-

1.04

1.04

1.14

↑ 5.8% 1.06††

1.09††††

1.09

-

1.86

1.81

1.75

↓ 2.0% 1.51 ††††

1.32 ††††

1.79

7.9

7.6

7.8

7.2

7.1

7.0

- ↑ 1.4-1.7kg

8.7

8.5

8.7

7.1

7.5

7.1

Herz, 2003 (Canada, Spain)

n=297 Type 2 diabetes 16-wk RCT mean age 58.4 yrs pioglitazone, n=99 pioglitazone, n=99 placebo, n=99

30mg/d 45mg/d

-

↑ 4%* → -

-

↑ 7%* → -

1.14 1.13

1.20

↑ 16%† ↑ 20%

†††† ↑ 9%

1.91 1.99

1.72

↓ 5% ↓ 16% ****/††

↑

7.5 7.6

7.5

6.7**** 6.7****/

†††† 7.3*

86.6 84.1

86.3

↑ 0.35kg ↑ 0.82kg

††††

↓ 1.58kg

FPG (mmol/L)

Rosenblatt, 2001 (US)

n=197 Type 2 diabetes 16-wk RCT mean age 54.4 yrs pioglitazone, n=101 placebo, n=96

30mg/d

5.75

5.72

no sig.

change

3.33

3.46

no sig.

change

1.03

1.02

1.19***

* †† 1.05

4.02

3.16

3.43*** †

3.22

10.65

10.40

10.05†

11.16

↑ 1.35**** ††††

↓ 1.87

↓ 2.76†

↑ 0.43 Before/ After comparison * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between groups comparison † p<0.05, †† p<0.01, ††† p<0.005, †††† p<0.001

92

Summary - Improved blood glucose control and lipids • Metformin, whether used as monotherapy or added to sulphonylurea or insulin therapy

may result in modest improvements in lipids, independent of a reduction in body weight • Sulphonylurea therapy results in a modest improvement in lipid profile, despite the

potential to increase body weight • Insulin therapy in people with Type 2 diabetes who have failed oral hypoglycaemic

therapy has a modestly favourable effect on lipids • Acarbose therapy in people who have failed dietary therapy or maximum sulphonylurea

therapy has little effect on lipid levels which may reflect the more modest improvement in diabetes control achieved with acarbose compared with other hypoglycaemic agents

• Thiazolidinediones have a modestly favourable effect on increasing HDL cholesterol and

lowering triglycerides despite an increase in weight • A reduction in HbA1c of approximately 1.5% is required to have a beneficial effect on

lipids

93


Improved blood glucose control and lipids

Evidence

level of Evidence Author


Magnitude Rating

Relevance Rating

Cathelineau G (1997) (Adults – France) III-2 Cohort Medium HighC+ T+ High

Coniff RF (1995a) (Adults – US) II RCT High High High

Coniff RF (1995b) (Adults – US) II RCT High High High

Daileyl GE (2002) (Adults – US) III-2 Cohort High High C+L+T+ High

DeFronzo RA (1995) (Adults – US) II RCT High High C+L+T+ High

Derosa G (2003 (Adults – Italy) II RCT High Low High

Emanuele N (1998) (Adult men - US) II RCT Medium Medium C+T+ High

Fanghanel G (1996) (Adults – Mexico) II RCT High High C+L+ H+ T+ Low

Freed MI (2002) (Adults – US) II RCT High High L+ H+ T+ High

Giugliano D (1993) (Adults – Italy) II RCT High High C+ H+ T+ High

Hanefeld M (1991) (Adults – Germany) II RCT High High T+ High

Hermann LS (1994) (Adults – Sweden) II RCT High High C+ L+ H+T+ High

Herz M (2003) (Adults – Canada, Spain)

II RCT High High H+T+ High

Hoffmann J 1997 (Adults – Germany) II RCT High High H+ L+ High

Kudlacek S (1992) (Adults – Austria) III-2 Cohort Medium High C+ T+ High

Lam KSL (1998) (Adults – China) II RCT High High Medium

Landstedt-Hallin L (1995) (Adults – Sweden)

II RCT High High C+ H+ T+ High

Rains SGH (1988) (Adults – UK) II RCT Medium HighC+ L+ High

Rodier M (1995) (Adults – France) II RCT High High H+ T+ High

Rosenblatt S (2001) (Adults – US) II RCT High High H+ T+ High

Wolffenbuttel BHR (1996) (Adults – Netherland)

III-2 Cohort Medium High C+ H+ T+ High

For magnitude rating: + the lipids improved as the glycaemic control improved; High = clinically important & statistically significant; Medium = small clinical importance & statistically significant; Low = no statistically significant effect. Criteria for Quality and Relevance ratings are detailed in Appendix 9. C= total cholesterol; L= LDL-cholesterol; H= HDL-cholesterol; T= triglycerides; V= VLDL-Cholesterol.

94


What are the effects on lipids of treatment with lipid-modifying agents and hormone replacement therapy in Type 2 diabetes?

Recommendations

Statins should be used to lower LDL cholesterol when triglycerides are normal or only slightly elevated. For severe hypercholesterolaemia, a bile acid binding resin or low dose nicotinic acid may be added. Fibrates should be used as first line therapy in people with predominantly elevated triglycerides and low HDL cholesterol with normal to slightly elevated LDL cholesterol levels. If treatment with a fibrate is not tolerated or if additional triglycerides lowering effect is required, fish oil can be used but the effect on diabetes control should be monitored. Treatment with a statin and fibrate should be considered in people with moderate to marked elevation of both LDL cholesterol and triglycerides. Because of the increased risk of myositis, the person should be fully informed and carefully monitored.

Evidence Statements • Fibric acid derivatives (fibrates) are effective in reducing triglycerides and increasing

HDL cholesterol in people with Type 2 diabetes Evidence level II

• Statins are effective in the reducing total and LDL cholesterol in people with Type 2 diabetes Evidence level II

• Nicotinic acid (niacin) is effective in improving lipids in people with Type 2 diabetes but may have a small adverse effect on blood glucose control Evidence level II

• Bile acid sequestrants (resins) may be effective in lowering total and LDL cholesterol in

people with Type 2 diabetes but data are limited Evidence level II

• Omega –3 fatty acids (ω-3) are effective in lowering triglycerides in people with Type 2

diabetes but may cause a dose dependent deterioration in blod glucose control Evidence level II

95

• Oestrogen replacement therapy may have a modest beneficial effect on lipids in

postmenopausal women with Type 2 diabetes Evidence level II

• Some combination therapies are effective in reducing lipids in people with Type 2 diabetes but data are limited Evidence level III-2

96

Background - Effects of lipid-modifying agents and hormone replacement therapy on lipids in Type 2 diabetes In people with Type 2 diabetes, there is a cluster of metabolic disturbances that include lipid abnormalities. At the basis of these abnormalities are insulin resistance and central obesity, which are associated with abnormal concentrations of several classes of lipoproteins including high levels of very low density lipoprotein (VLDL) particles and low levels of high density lipoprotein (HDL) particles. Furthermore, there are often changes in the composition of lipoproteins. For example, there is a preponderance of small, dense low density lipoprotein (LDL) particles which are thought to have increased atherogenicity (Barakat et al, 1990) Lipid abnormalities in Type 2 diabetes are characterised by raised fasting triglycerides and lowered HDL cholesterol. These two factors are thought to contribute significantly to the increased risk of coronary heart disease in people with Type 2 diabetes (Laakso et al, 1993; Laakso, 1996). In addition, people with diabetes have the same prevalence of lipid abnormalities as the non diabetic population eg increased total cholesterol and increased LDL cholesterol. In diabetes, these lipid abnormalities are often exacerbated by poor blood glucose control. The management of lipid abnormalities in people with Type 2 diabetes is to attempt to improve blood glucose control with diet, exercise and hypoglycaemic agents (see Sections 2 and 3). However, even with good diabetes control lipid abnormalities often persists. Because of the specific metabolic abnormalities found in Type 2 diabetes, the results of lipid-lowering medication studies in people without diabetes may not be directly applicable to people with diabetes with lipid abnormalities. The review in this Section focuses on the lipid-lowering effects of commonly used therapeutic agents (statins, fibrates, niacin, resins, hormone replacement therapy (HRT) and ω-3 fatty acids) from well-designed, randomised controlled trials in people with Type 2 diabetes (Table 13). There are a number of reviews on the effects of lipid-lowering agents in the treatment of lipid abnormalities in Type 2 diabetes (Garg & Grundy, 1997; Haffner, 1998, Colagiuri & Best, 2002).

97

Table 13: Effects of lipid-modifying agents on lipids and lipoproteins in people with Type 2 diabetes

Effects on Lipids and Lipoproteins (%) Lipid Modifying Agents Dose TCHOL LDL HDL TG APO-A APO-B

Glycaemic control

Fibrates (see Table 14) Gemfibrozil 1200mg/day ↓6.6-11%

↓5.2-10% ↑6.4 -14% ↓28-50%

↑2-21% ↓4.1% No effect

Bezafibrate

400-600mg/day

↓8.6-14.2%

↓6-10.8%

↑11.4-20%

↓33-51%

↓5%-↑9.6%

↓30-↑5%

No effect

Fenofibrate

200mg/day

↓10-11%

↓7-11%

↑6-7%

↓24-28% No effect

Statins (see Table 15) Simvastatin

20-40 mg/day

↓24-30%

↓34-42%

↑4-9%

↓9-15% No effect

Pravastatin

40 mg/day

↓19-21.2%

↓27-31.3%

↑4-8%

↓6.3-16% No effect

Lovastatin

20-40 mg/day

↓18-20%

↓25-26%

↑6-14%

↓15%-↑2% No effect

Fluvastatin

40 mg/day

↓20%

↓25%

↑5%

↓17%

No effect

Atorvastatin

10 mg/day

↓29-32%

↓18-43.7%

↑4.2-16.7%

↓11-29.7% No effect

Second-line agents

Nicotinic acid (see Table 16)

1.5×3 g/day ↓4-8% ↓7-8% ↑13-29% ↓15-36% Raises HbA1c, FBG & plasma uric acid

Bile acid sequestrants

(cholestyramine)

8×2 g/day

↓18% ↓28% ↑5% ↑7% FBG ↓13%

ω-3 fatty acids (fish oil) (see Table 17)

1.8-3.0 g/day ↓5.9 - ↑7.9% ↓1.6% - ↑5% ↑1-8.8% ↓3.4-31% Mean rise in blood glucose 0.26 mmol/L and in HbA1c 0.15%

T Chol (total cholesterol), LDL (low density lipoprotein cholesterol), HDL (high density lipoprotein cholesterol), TG (total plasma triglycerides), Apo-A (Apo lipoprotein-A), Apo-B (Apo lipoprotein B), HbA1c (glycated haemoglobin), FBG (fasting blood glucose). (↓) decrease, (↑) increase

98

Evidence - Effects of lipid-modifying agents and hormone replacement therapy on lipids in Type 2 diabetes Many studies were identified through the literature search but only studies which included approximately 50 or more subjects are reviewed in this Section, unless the only relevant data available were from smaller studies. Fibric acid derivatives (fibrates) are effective in reducing triglycerides and increasing HDL cholesterol in people with Type 2 diabetes Fibrates stimulate the peroxisome proliferator activated receptor-α, changing the expression of a number of enzymes that regulate lipid metabolism including lipoprotein lipase. Fibrates decrease hepatic production of VLDL particles and enhance their clearance. The only fibrate currently available in Australia is gemfibrozil, but trials using fenofibrate and bezafibrate are also reviewed because these other fibrates are widely used throughout the world (see Table 14). Gemfibrozil in Type 2 diabetes There have been a number of randomised placebo controlled trials testing the efficacy and safety of gemfibrozil in people with diabetes. The largest of these included 214 people with diabetes randomised to gemfibrozil 600mg twice daily and 109 to placebo for 20 weeks (Vinik et al, 1993). Triglycerides fell by 28% from 3.0 to 2.0mmol/L with gemfibrozil, while triglycerides rose by 8% from 3.0 to 3.1 mmol/L in the placebo group (p<0.0001 gemfibrozil v placebo). HDL cholesterol increased significantly and peaked at 12 weeks by 12.2% in the gemfibrozil group compared with little change in the placebo group (p<0.001). The reduction in mean total cholesterol was significant in the gemfibrozil group compared with an increase in the placebo group (p<0.05). LDL cholesterol rose in both groups (p<0.05) but there was no difference between the groups. Frick et al (1987) recruited 4,081 middle-age men with primary dyslipidaemia (non-HDL cholesterol ≥5.2mmol/L) in the Helsinki Heart Study. Over the mean follow-up of 5 years, treatment with gemfibrozil 1200mg/day significantly lowered triglycerides by 43% (from 1.98 to 1.30mmol/L) and increased HDL cholesterol by 10% (from 1.22 to 1.32mmol/L). Total and LDL cholesterol were also reduced by 11% (6.99 to 6.39mmol/L) and 10% (4.90 to 4.49mmol/L), respectively. There were only minimal changes in lipid levels in the placebo group. Koskinen et al (1992) reported the lipid results of 135 people with Type 2 diabetes in the Helsinki Heart Study. Triglycerides level fell by 27% from a baseline of 2.4mmol/L in the 59 people on gemfibrozil and fell by 5% from a baseline of 2.9mmol/L in 76 people on placebo (no p value reported). HDL cholesterol rose by 6% from a baseline of 1.18mmol/L in the gemfibrozil group compared with a 1% increase in the placebo group. Total and LDL cholesterol were reduced to 6.48 mmol/L and 4.66 in the gemfibrozil group, to 7.10 mmol/L and 4.91 mmol/L, respectively in the placebo group. Avogaro et al (1999) randomised people with Type 2 diabetes and plasma triglycerides ≥2.0 mmol/L to gemfibrozil treatment (n=110) or to placebo (n=107). During the 20-week study period, gemfibrozil significantly decreased plasma triglycerides from 3.6 to 2.4mmol/L (p<0.001) compared with an increase from 3.6 to 4.3mmo/L (p<0.05) in the placebo group. HDL cholesterol increased significantly with both gemfibrozil and placebo (both p<0.05). No

99

significant changes in total and LDL cholesterol were observed. The mean HbA1c values were similar in both groups (7.7 to 8.1% in the gemfibrozil group; 7.7 to 7.7% in the placebo group, p=0.09 between groups). In a study of 96 people with Type 2 diabetes and dyslipidaemia (defined as LDL cholesterol >4.0mmol/L and triglycerides ≤4.5mmol/L) (Tikkanen et al, 1998), 49 were randomly assigned to take gemfibrozil (600 mg twice a day) and 47 to take simvastatin (10mg/day for the first 8 weeks, 20mg/day for the next 8 weeks and 40mg/day for the third 8-week period). After 24 weeks of gemfibrozil treatment, triglycerides fell by 45% from a baseline of 2.5mmol/L (p<0.01), ranging from about 40% in people with hypercholesterolaemia and initial triglycerides <2.3 mmol/L to 50% or more in people with combined hyperlipidaemia. HDL cholesterol increased by 14% from 1.19mmol/L at the end of study (p<0.01). Gemfibrozil was also effective in reducing total cholesterol by 10% from 7.0mmol/L (p<0.01) and LDL cholesterol by 6.5% from 4.6mmol/L (p<0.01). In contrast, simvastatin resulted in a reduction in total cholesterol by 30% from 6.9mmol/L (p<0.01) and LDL cholesterol by 42% from 4.5 mmol/L(p<0.01). Triglycerides were also reduced by 15% from 2.5mmol/L with simvastatin (p<0.01), but HDL cholesterol did not change significantly (+4%). In a 16-week randomised controlled trial of 136 people with Type 2 diabetes (Schweitzer et al, 2002), treatment with gemfibrozil 1200mg/d (n=66) resulted in a greater reduction in triglycerides levels compared with treatment with pravastatin 40mg/d (n=70) (-29.6% v -6.3%, p<0.001). In contrast, total and LDL cholesterol were significantly lower with pravastatin than with gemfibrozil (-21.2% v -6.6%, p<0.001; -31.3% v -5.2%, p<0.001, respectively). The increment in HDL cholesterol was 6.4% in the pravastatin group and 5.8% in the gemfibrozil group. During the study period, HbA1c did not change significantly in either group (7.5 to 7.8% with pravastatin; 7.6 to 8.1% with gemfibrozil, p=0.31). An increased level of LDL cholesterol with gemfibrozil treatment in some studies could have an adverse effect in people with Type 2 diabetes who are already at increased risk of macrovascular disease. However, gemfibrozil treatment has been shown to increase LDL particle size, potentially rendering these particles less atherogenic (Lahdenpera et al, 1993; O'Neal et al, 1998). Lahdenpera et al (1993) reported that LDL particle diameter increased from 244±7 to 251±5 Å (p<0.05) whereas it remained unchanged in the placebo group. O’Neal et al (1998) found no significant difference in LDL cholesterol level between gemfibrozil (from 3.8 to 4.3 mmol/L) and placebo (from 3.5 to 3.9 mmol/L), but a significant increase in LDL particle diameter was observed in the gemfibrozil group (p<0.02). Gemfibrozil has also been found to have no significant adverse effects on glycaemic control. Change in HbA1c was similar in the gemfibrozil group (from 6.8 to 7.2%) and the placebo group (from 6.5 to 6.9%), with no difference in the percentage changes, 8.6 and 7.2, respectively (Vinik et al, 1993). Similarly, Vuorinen-Markkola et al (1993) reported HbA1c increased slightly in both gemfibrozil (8.2±0.4%, p<0.05) and placebo group (8.0±0.3%, p=NS) during 12 weeks treatment period. There were no differences in mean 24h blood glucose concentration in the two groups (10.4±0.6 v 11.0±0.7 mmol/L; 10.0±0.8 v 9.8±0.7 mmol/L, respectively). In summary: • The most consistent effect of gemfibrozil is a significant reduction in triglycerides levels

(approx 30-50%) and an increase in HDL cholesterol (approx 10%).

100

Table 14: Effects of fibrates on lipids in Type 2 diabetes

Effects on Lipids

Total Cholesterol (mmol/L)

LDL Cholesterol (mmol/L)

HDL Cholesterol (mmol/L)

VLDL Cholesterol (mmol/L)

Total Triglycerides

(mmol/L)

Apo A1 (mg/dl)

Apo B (mg/dl)

Reference

Population studied Drug dose

Inclusion criteria (mmol/)


Avogaro, 1999 (Italy)

n=217 Type 2 diabetes 20-wk follow-up RCT gemfibrozil n=110 placebo n=107

1200mg/d TG ≥ 2.0

5.96 5.91

6.20 5.91

no sig.change no sig.change

0.85 0.80

1.04* 0.91*

-

3.57 3.59

2.42†††† 4.29*

- -

DAIS investigators, 2001 (Canada, Finland, Sweden, France)

n=418 Type 2 diabetes 3-yr follow-up RCT Fenofibrate n=207 Placebo n=211

200mg/d

T-CHO/HDL ≥ 4.0

LDL 3.5-4.5 TG≤ 5.2

5.56 5.58

5.0†††† 5.63

3.38 3.43

3.14†††† 3.41

1.01 1.05

1.09††† 1.07

- -

2.59 2.42

1.84†††† 2.47

- - - -

Elkeles, 1998 (UK) SENDCAPS

n=128 Type 2 diabetes 3-yr follow-up RCT age: 35-65 yrs Bezafibrate n=64 Placebo n=64

400mg/d

TG < 8.0 T-CHO

< 8.0 T-CHO/HDL

< 7.2

5.77 5.60

5.29††† 5.80

3.66 3.98

3.31 3.94

1.02 0.94

1.04† 0.92

-

-

2.24 2.09

1.44†††† 2.00

141 128

134 122

131 130

139 155

Kirchgassler, 1998 (Germany)

n=1,379 Type 2 diabetes 12-wk cohort study Fenofibrate 200mg/d TG ≥2.8

LDL ≥4.1 7.8 6.4 5.2 4.0 1.1 1.36 - 4.6 3.22 - -

Koskinen, (1992) (Finland)

n=135 Type 2 diabetes 5-yr follow-up RCT Gemfibrozil (n=59) Placebo (n=76)

1200mg/d non HDL-CHO >5.2

7.54 7.54

6.48 7.10

5.18 5.23

4.66 4.91

1.18 1.18

1.26 1.19

-

2.42 2.90

1.79 2.75

- -

Ogawa, 2000 (Japan)

n=342 Type 2 diabetes mean age 61 yrs 16-wk follow-up Bezafibrate n=174 Control n=168

400mg/d -

6.20 6.23

5.43†† 6.57

-

1.20 1.21

1.44†† 1.21

-

2.98 3.09

1.47†† 3.02

- -

Before/ After comparison* p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between groups comparison † p<0.05, †† p<0.01, ††† p<0.005, †††† p<0.001

101

Table 14: Effects of fibrates on lipids in Type 2 diabetes

Effects on Lipids





Total Triglycerides

(mmol/L)

Apo A1 (mg/dl)

Apo B (mg/dl)

Reference

Population studied Drug dose

Inclusion criteria (mmol/)


Rovellini, 1992 (Italy)

n=99 Type 2 diabetes 8-mth follow-up RCT mean age 65yrs Bezafibrate Control, no treatment

400mg/d -

7.12 6.76

6.11**** 6.73

-

-

1.14 1.14

1.27 1.11

-

-

3.22 2.85

1.73**** 2.89

-

-

-

-

Rustemeijer, 2000 (The Netherlands)

n=45 Type 2 diabetes aged 40-80 yrs 12-wk follow-up RCT, crossover Pravastatin, n=22 Bezafibrate, n=23

40mg/d 400mg/d

T-CHO 5.0-8.0

TG 1.8-5.0

6.6 6.7

5.06†††† 5.98

4.03 4.12

2.85†††† 3.87

1.15 1.15

1.25 1.33††

1.41 1.43

0.99 0.86

2.95 2.87

2.48 1.79††††

mmol/l

1.37 1.35

mmol/l

1.43†††† 1.48

-

Schweitzer, 2002 (US)

n=136 Type 2 diabetes mean age 57 yrs RCT 16-wk follow-up Pravastatin, n=70 Gemfibrozil, n=66

40mg/d 1200mg/d

LDL ≥3.4 to ≤5.2

TG ≤4.5

6.26 6.14

4.93†††† 5.73

4.10 3.96

2.82†††† 3.75

1.23 1.20

1.30 1.28

0.58 0.71

0.55 0.52

2.06 2.22

1.93 1.56††††

108.2 103

123.3 126.8

123.2 119.2

98.2†††† 112.7

Tikkanen, 1998 (Finland)

n=96 Type 2 diabetes age 35-70yr RCT 24-wk follow-up Gemfibrozil n=49, Simvastatin n=47

1200 mg/d 10 – 40 mg/d

LDL>4.0 TG <4.5

7.00 6.94

6.3**††

4.84**

4.57 4.53

4.27**†† 2.65**

1.19 1.26

1.35**††

1.31**††

- -

2.54 2.46

1.39**†† 2.08

-

-

-

-

Vinik, 1993 (US)

n=442 Type 2 diabetes 20-wk follow-up RCT age 36-84 yrs. Gemfibrozil n=214 Placebo n=109

1200mg/d TG

1.7-5.6

6.06

5.87

5.76*

††††

6.06*

3.76

3.66

3.78

3.68

0.96

0.96

1.09***

* ††††

0.97

-

3.00

3.03

2.02* ††††

3.08*

-

-


102

Bezafibrate in Type 2 diabetes Randomised controlled trials with the fibric acid derivative bezafibrate (not presently approved for use in Australia) have shown similar effects to gemfibrozil in reducing triglycerides and increasing HDL cholesterol, but a greater ability to reduce LDL cholesterol in people with Type 2 diabetes. The largest and longest study was the St Mary’s, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) study (Elkeles et al, 1998) in which lipid measurements were made in 128 people with Type 2 diabetes before and after 3 years of treatment with bezafibrate 400mg daily (n=64) or placebo (n=64). Median triglyceride levels fell by 33% from 2.2 to 1.4mmol/L on bezafibrate and by 5% from 2.1 to 2.0mmol/L on placebo (p=0.001 for bezafibrate compared with placebo). Median HDL cholesterol rose by 6% (1.02 to 1.04mmol/L) with bezafibrate and fell by 2% (0.94 to 0.92mmol/L) with placebo (p=0.02). Total cholesterol was lower after 3 years on bezafibrate compared with placebo (5.8 to 5.3 v 5.6 to 5.8mmol/L, p=0.004), but the change in LDL cholesterol between the groups did not reach significance (3.7 to 3.3 v 4.0 to 3.9mmol/L, p=0.06). Another study followed 45 people with Type 2 diabetes on bezafibrate 400mg daily for 8 months and compared the effects with a control group of 44 people, but there was no placebo treatment (Rovellini et al, 1992). Triglycerides levels fell by 51% from 3.2 to 1.7mmol/L in the treated group (p<0.001) and rose by 2% from 2.9mmol/L in the control group. HDL cholesterol showed a nonsignificant trend toward an increase from 1.14 to 1.27mmol/L in the bezafibrate group and did not change in the control group. The study by Ogawa et al (2000) randomised 342 people with Type 2 diabetes to treatment with bezafibrate (n=174) or to a control group (n=168). Compared with people in the control group, people on bezafibrate 400mg/d had significantly lower triglycerides (3.0 to 1.5 v 3.1 to 3.0mmol/L, p<0.01) and total cholesterol (6.2 to 5.4 v 6.2 to 6.6mmol/L, p<0.01) after 16 weeks of treatment. HDL cholesterol was increased significantly in the bezafibrate group compared with the control group (1.20 to 1.44 v 1.21 to 1.21mmol/L, p<0.01). In a 12-week randomised, crossover study of 45 people with insulin treated Type 2 diabetes, Rustemeijer et al (2000) reported that bezafibrate 400mg daily was more effective than pravastatin 40mg daily in increasing HDL cholesterol (+15.3 v +8.7%, p<0.01) and Apo A1 (+9.6 v +4.3%, p<0.001), and reducing triglycerides (-37.6 v -16.0%, p<0.001). Although total cholesterol also fell with bezafibrate (p<0.01), this reduction was smaller compared to that with pravastatin (-10.8 v -23.3%, p<0.01). No adverse effects of bezafibrate on glycaemic parameters of fasting glucose, HbA1c or fructosamine have been reported. In the SENDCAP study there was no difference in HbA1c between the groups treated with bezafibrate (from 9.6 to 10.3%) or placebo (from 9.4 to 10.1%) (p=0.4) (Elkeles et al, 1998). Glycaemic control improved during 8 months bezafibrate treatment in the study by Rovellini et al (1992) with blood glucose level decreasing from 9.0 to 7.9mmol/L (p<0.001) and HbA1c from 7.7% at baseline to 7.2% at 8 months (p<0.01), however this study was not blinded. In the study by Ogawa et al (2000), treatment with bezafibrate was associated with a reduction in HbA1c (7.2±0.1 to 6.9±0.1%, p<0.05) and FPG (8.4 to 7.1 mmol/L, p<0.01). In contrast, these values did not change in the control group. There was no change in body weight during the study. Fenofibrate in Type 2 diabetes The most useful data on the effect of fenofibrate (not presently approved for use in Australia) on lipid levels in Type 2 diabetes comes from clinical trials of CHD prevention. The Diabetes and Atherosclerosis Intervention Study (DAIS) followed 207 people on fenofibrate 200mg daily and 211 people on placebo for at least 3 years (DAIS Investigators, 2001). Triglycerides

103

fell by 28% from 2.6mmol/L with fenofibrate and rose by 1% from 2.4mmol/L with placebo (p<0.0001), while HDL cholesterol rose by 7% from 1.01mmol/L on fenofibrate and by 2% from 1.05mmol/L on placebo (p<0.0001). LDL cholesterol fell by 7% from 3.4mmol/L and total cholesterol by 10% from 5.6mmol/L on fenofibrate and was unchanged on placebo (both p<0.0001). These results are very similar to those from two large, open label, “before and after” studies. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study included a 6 week active run-in period, with 9,795 people with Type 2 diabetes on fenofibrate 200mg daily. Triglycerides fell by 24% and HDL cholesterol rose by 6% with fenofibrate. LDL cholesterol fell by 11% and total cholesterol also fell by 11% over 6 weeks. All changes were highly significant (personal communication from the FIELD study investigators, 2001). Another open label study with the same dose of fenofibrate for 3 months in 1,379 people with Type 2 diabetes demonstrated a 30% reduction of triglycerides from 4.6mmol/L and a 24% increase of HDL cholesterol from 1.1mmol/L. LDL cholesterol fell by 23% from 5.2mmol/L and total cholesterol by 18% from 7.8mmol/L (Kirchgassler et al, 1998). As with bezafibrate, fenofibrate seems to be more effective than gemfibrozil in lowering total and LDL cholesterol. Statins are effective in the reducing total and LDL cholesterol in people with Type 2 diabetes Statins inhibit the hepatic enzyme HMGCoA (3-hydroxy-3-methylglutaryl Coenzyme A) reductase which is rate limiting in the production of cholesterol. A lower cholesterol level within the hepatocyte causes upregulation of LDL receptors and enhanced clearance of LDL particles from plasma. Statins have become by far the most widely used class of lipid modifying agents, achieving substantial reductions in total and LDL cholesterol concentrations. Statins also have minor to moderate effects in reducing triglycerides and increasing HDL cholesterol, but are less effective than fibrates in this regard. Placebo controlled or comparative studies of the lipid modifying effects of statins have been performed in people with Type 2 diabetes using pravastatin, simvastatin, fluvastatin, lovastatin and atorvastatin (see Table 15). In addition, lipid changes with statin therapy in people with Type 2 diabetes have been reported from clinical trials and indicate that the effects are the same as in non-diabetic subjects. Pravastatin in Type 2 diabetes Major randomised controlled trials showing reduction of cardiovascular events with pravastatin have all used 40mg daily. Treatment with pravastatin 40mg daily over 5 years was tested in a subgroup analysis of the 586 people with clinically diagnosed Type 2 diabetes in the secondary prevention Cholesterol and Recurrent Events (CARE) trial. Pravastatin reduced baseline mean total cholesterol of 5.3mmol/L by 19% and mean LDL cholesterol of 3.5mmol/L by 27% compared with placebo (Goldberg et al, 1998). In the non-diabetic group total cholesterol was reduced by 20% and LDL cholesterol by 28%. Mean baseline triglyceride levels of 1.9mmol/L fell by 13% in the diabetic group and mean HDL cholesterol of 0.97mmol/L rose by 4%. In the non-diabetic group triglycerides levels fell by 14% and HDL cholesterol rose by 5%. A randomised, double-blind crossover study of 45 people with insulin treated Type 2 diabetes (Rustemeijer et al, 2000) showed that pravastatin 40mg/day was more effective in reducing total cholesterol (-23.3 v -10.8%, p<0.001), LDL cholesterol (-29.2 v -6.0%, p<0.001), and LDL-ApoB (-25.7 v -9.4%, p<0.001) compared with bezafibrate 400mg/day over a 12-week treatment period. In contrast, bezafibrate was superior in increasing HDL cholesterol (+15.3 v +8.7%, p<0.01) and Apo A1 (+9.6 v +4.3%, p<0.001), and reducing triglycerides (-37.6 v –16.0%, p<0.001). Pravastatin treatment was associated with a significant increase in HbA1c level (8.1 to 8.6%, p<0.001) while bezafibrate treatment was accompanied by a significant

104

decrease in HbA1c level (8.3 to 7.9%, p<0.01). No changes in body weight were observed in either treatment period. In a 16-week randomised controlled trial of 136 people with Type 2 diabetes (Schweitzer et al, 2002), total and LDL cholesterol were significantly lower with pravastatin 40mg/day (n=70) than with gemfibrozil 1200mg/day (n=66) (-21.2% v -6.6%, p<0.001; -31.3% v -5.2%, p<0.001, respectively). In contrast, gemfibrozil had a greater lowering effect on triglyceride levels (-29.6% v -6.3%, p<0.001). The increment in HDL cholesterol was 6.4% in the pravastatin group and 5.8% in the gemfibrozil group. In addition, pravastatin reduced Apo B concentration to a significantly greater extent than gemfibrozil (-19.3% v -4.1%, p<0.001). During the study period, HbA1c did not change significantly in either group (7.5 to 7.8% with pravastatin; 7.6 to 8.1% with gemfibrozil, p=0.31). Simvastatin in Type 2 diabetes The dose of simvastatin used in major clinical trials with cardiovascular events as outcomes has been 20 to 40mg daily. In a subgroup analysis of the 202 people with clinically diagnosed Type 2 diabetes in the secondary prevention Scandinavian Simvastatin Survival Study (4S), treatment with simvastatin 20 to 40mg daily over 5 years reduced baseline mean total cholesterol of 6.7mmol/L by 27% and mean LDL cholesterol of 4.8mmol/L by 36% compared with baseline (Pyorala et al, 1997). In the non-diabetic group total cholesterol was reduced by 24% and LDL cholesterol by 34%. Mean baseline triglycerides levels of 1.7 mmol/L fell by 11% in the diabetic group and mean HDL cholesterol of 1.12mmol/L rose by 7%. In the non-diabetic group triglycerides level fell by 9% and HDL cholesterol rose by 8%. In a subsequent analysis of data from the 4S trial which included an additional 281 people diagnosed with Type 2 diabetes on the basis of fasting blood glucose ≥7.0 mmol/L, lipid and lipoprotein changes were again not different between diabetic and non-diabetic groups (Haffner et al, 1999). In another placebo controlled trial 28 people were randomised to treatment with simvastatin for 24 weeks and 29 people to placebo (Farrer et al, 1994). Simvastatin dose was titrated from 10 up to 40mg daily (mean dose at completion was 29mg). On active treatment total cholesterol fell by 28% from 7.8 to 5.6mmol/L (p<0.001) and LDL cholesterol by 38% from 5.5 to 3.4mmol/L (p<0.001). Triglycerides levels fell by 15% from 2.5 to 2.2mmol/L (p<0.05), while HDL cholesterol rose by 9% from 1.16 to 1.23mmol/L (p<0.05). Between group differences for total, LDL cholesterol and triglycerides were significant (p<0.001-0.01). No changes in HbA1c, FPG were observed with simvastatin treatment.

105

Table 15: Effects of statins on lipids in Type 2 diabetes

Effects on Lipids and Lipoproteins Total

Cholesterrol (mmol/L)




Total Triglycerides

(mmol/L)

Apo A1 (mg/dl)

Apo B (mg/dl)

Reference Population Drug Dose

(mg/d)

Inclusion Criteria

(mmol/L) Before After Before After Before After Before After Before After Before After Before After

Athyros, 2002a (Greece)

n=120 Type 2 diabetes age 44-69 yrs, RCT 24-wk follow-up Atorvastatin, n=40 Fenofibrate, n=40 In combination, n=40

20

200

T-CHO >5.7

LDL >3.4 TG

2.3-4.5

6.53

6.55

6.60

4.51**

** 5.52**

** 4.12**

** †

4.17

4.22

4.22

2.51**

** 3.62**

** 3.31**

** †

0.90

0.90

0.91

0.98**

** 1.04**

** 1.11**

**

-

3.14

3.18

3.14

2.20**

** 1.89**

** 1.57**

** †

124

124

124

127

132

138

-

Downs, 1998 (US) AFCAPS TexCAPS

n=6,605 age 45-73 yrs, RCT Placebo Lovastatin

20-40

T-CHO 4.65-6.82 TG ≥4.52

5.85 5.71

5.90 4.75**

††††

3.98 3.89

4.04 2.96**

††††

0.96 0.96

0.97 1.02**

††††

-

1.88 1.78

1.84 1.61**

††††

- -

Farrer, 1994 (UK)

n=57; Type 2 diabetes age 25-70 yrs RCT 9-mth follow-up Placebo Simvastatin

10-40

T-CHO >6.5

TG <5.0

8.1 7.8

8.0 5.6****

††

5.6 5.5

5.5 3.4****

††

1.18 1.16

1.17 1.23*

-

2.9 2.5

3.5 2.2**

135 130

140 149.5

** ††

180 180

178 129.6

** ††

Freed, 2002 (US)

n=243 Type 2 diabetes 24-wk RCT aged 35-80 yrs rosiglitazone+atorvastatin, n=82, 16 wk rosiglitazone+atorvastatin, n=79, 16 wk rosiglitazone+placebo n=76, 16 wk

8mg/d 10mg/d 20mg/d

-

- - -

- - -

3.34

3.44

3.52

2.31†††

† 2.12†††

† 3.55

1.04

1.04

1.04

1.06††

1.09†††

† 1.09

1.86

1.81

1.75

1.51†††

† 1.32†††

† 1.79

- -

Before/ After comparison * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between group comparison † p<0.05, †† p<0.01, ††† p<0.005, †††† p<0.001 T-CHO = Total cholesterol; LDL = LDL cholesterol; TG = Triglycerides; IFG = Impaired fasting glucose

106







Total Triglycerides

(mmol/L)

Apo A1 (mg/dl)

Apo B (mg/dl)


(mg/d)

Inclusion Criteria


Gavish, 2000 (Israel)

n=148 Type 2 diabetes age 49-70 yrs 21-mth follow-up first 6 mths Simvastatin, n=100 Bezafibrate, n=48 then 12 mths in combination, n=148

20 40

6.9 7.0

7.0

5.4** 6.7**

5.4**††

4.5 4.6

4.5

3.1** 4.4**

3.2**††

0.9 0.8

0.8

0.9 1.0**

1.0**††

-

3.8 5.2

4.3

3.5 3.2**

2.5**††

- -

Gentile, 2000 (Italy)

n=409 Type 2 diabetes age 50-65 yrs 24-wk follow-up RCT Atorvastatin, n=84 Simvastatin, n=78 Pravastatin, n=81 Lovastatin n=80 Placebo, n=86

10 10 20 20

LDL >4.6 TG ≤4.5

↓ 29% ↓ 21% ↓ 16% ↓ 18% ↑ 1%

↓ 37% ↓ 26% ↓ 23% ↓ 21% ↓ 1%

↑ 7.4% ↑ 7.1% ↑ 3.2% ↑ 7.2% ↓ 0.5%

-

↓ 24% ↓ 14% ↓ 12% ↓ 11% ↓ 1%

- -

Goldberg, 1990 (US)

n=102, Type 2 diabetes age 18-70 yrs 24-wk follow-up RCT Lovastatin n=50 Gemfibrozil n=52

20-40 2×600

LDL ≥ 4.14 TG <4.52

7.04 7.10

5.61**†† 6.61**

5.02 4.97

3.67**†† 4.88

1.09 1.08

1.22** 1.28**

0.93 1.02

0.64** 0.55**

2.29 2.45

2.15† 1.46**

- -

Goldberg, 1998 (US) CARE

n=586, age 21-75 yrs Type 2 diabetes 5-yr follow-up RCT Pravastatin v Placebo

40

T-CHO <6.22 LDL

2.98-4.51 TG <3.96

5.33 5.33

4.32 5.33

3.52 3.52

2.57 3.52

0.97 0.97

1.01 0.97

-

1.85 1.85

1.61 1.85

- -

Haffner, 1999 (Scandinavia)

n=1,161 age 35-70 yrs Type 2 diabetes+IFG 5.4-yr follow-up RCT Simvastatin Placebo

up to 40

T-CHO 5.5-8.0

TG ≤2.5

6.74 6.74

4.90† 6.87

4.86 4.86

3.10† 5.05

1.13 1.13

1.21† 1.10

-

1.65 1.65

1.54† 1.72

- -


107







Total Triglycerides

(mmol/L)

Apo A1 (mg/dl)

Apo B (mg/dl)


(mg/d)

Inclusion Criteria


Knopp, 1994b (US & Canada)

n=66 Type 2 diabetes age 40-70 yrs, RCT 20-wk follow-up Placebo at 6 wk Fluvastatin at 6 wk Placebo at 12 wk Fluvastatin at 12 wk

20

2×20

after 8wk diet therapy

T-CHO >5.2 LDL

3.4-7.8 TG >

2.3-11.3

7.33 6.16††††

7.38 5.93††††

4.38 3.60††††

4.53 3.42††††

0.98 1.06†† 1.04 1.09

1.94 1.40†† 1.81

1.40††

4.14 3.18† 3.66

3.27††

- -

Pyorala, 1997 (Scandinavia)

4S

n=202 Type 2 diabetes aged 35-70 yrs 5.4-yr follow-up RCT Placebo Simvastatin

20-40

T-CHO 5.5-8.0

TG ≤2.5

6.72 6.71

-

4.90

4.80 4.81

-

3.08

1.13 1.12

-

1.20

- -

1.78 1.69

-

1.50

- - - -

Rustemeijer, 2000 (The Netherlands)

n=45 Type 2 diabetes aged 40-80 yrs 12-wk follow-up RCT, crossover Pravastatin, n=22 Bezafibrate, n=23

40

400

T-CHO 5.0-8.0

TG 1.8-5.0

6.6

6.7

5.06†††

† 5.98

4.03

4.12

2.85†††

† 3.87

1.15

1.15

1.25

1.33††

1.41

1.43

0.99

0.86

2.95

2.87

2.48

1.79†††

†

mmol/l

1.37

1.35

mmol/l

1.43†††

† 1.48

-

Schweitzer, 2002 (US)

n=136 Type 2 diabetes mean age 57 yrs Pravastatin Gemfibrozil

40

1200

LDL ≥3.4 to ≤5.2

TG ≤4.5

6.26

6.14

4.93†††

† 5.73

4.10

3.96

2.82†††

† 3.75

1.23

1.20

1.30

1.28

0.58

0.71

0.55

0.52

2.06

2.22

1.93

1.56

108.2

103

123.3

126.8

Soedamah-Muthu, 2003 (UK)

n=122 Type 2 diabetes aged 40-75 yrs 6-mth RCT Atorvastatin Placebo

10 LDL ≤3.9 TG ≤5.0

5.49

5.22

3.61**

** 5.22

3.48

3.16

1.85**

** 2.95

1.20

1.23

1.39

1.22

-

1.85

1.65

1.50**

** 1.70

- -


108







Total Triglycerides

(mmol/L)

Apo A1 (mg/dl)

Apo B (mg/dl)


(mg/d)

Inclusion Criteria


The DALI Study Group, 2001 (The Netherlands)

n=217 Type 2 diabetes aged 45-75 yrs 30-wk RCT Atorvastatin, n=73 Atorvastatin, n=72 Placebo, n=72

10 80

T-CHO 4.0-8.0

TG 1.5-6.0

5.9 6.0 6.0

4.1 3.6

6.0††††

3.7 3.7 3.8

2.2 1.7

3.6††††

1.05 1.03 1.05

1.10 1.09 1.04†

-

2.54 2.85 2.62

1.84 1.78

2.88††††

-

122 124 127

84 74

125††††

Tikkanen, 1998 (Finland)

n=96 Type 2 diabetes age 35-70 yrs 24-wk follow-up Simvastatin Gemfibrozil

10-40 2×600

LDL >4.0 TG <4.5

6.94 7.00

4.84**

6.30**††

4.53 4.57

2.65** 4.27**††

1.26 1.19

1.31** 1.35**††

- -

2.46 2.54

2.08** 1.39***

†††

- - - -

Wagner, 2003 (Spain)

n=44 Type 2 diabetes age 35-70 yrs 24-wk follow-up Atorvastatin 12 wk Gemfibrozil 12 wk in combination 12wk

10-20 900-1200

LDL >2.6 TG <4.5 - -

3.94 3.81 3.83

2.56****

3.68** 2.75****

1.19 1.19 1.19

1.24** 1.24* 1.24*

- -

1.83 1.89 2.14

1.62**** 1.28**** 1.32****

135 134 137

138 134 139

124 122 125

93**** 115**** 95****


109

The effects of simvastatin on the lipid profile in people with Type 2 diabetes have been compared directly with those of gemfibrozil in a double blind trial over 24 weeks (Tikkanen et al, 1998). Simvastatin was started at 10mg daily in 47 people and increased to 20mg after 8 weeks and 40mg after 16 weeks, whereas gemfibrozil was given as 600mg twice daily to 49 people for 24 weeks. After 24 weeks simvastatin reduced total cholesterol by 30% from the baseline level of 6.9mmol/L compared with a 10% reduction with gemfibrozil (both p<0.01). The reduction of LDL cholesterol from 4.5mmol/L was 42% with simvastatin compared with 7% with gemfibrozil (both p<0.01). The statin effects on total and LDL cholesterol were significantly greater than the fibrate effects (both p<0.01). In contrast reduction of triglyceride levels from 2.5mmol/L with simvastatin was 15% and with gemfibrozil 45% (both p<0.01), while the rise in HDL cholesterol from 1.26mmol/L was 4% with simvastatin (p=NS) and 14% with gemfibrozil (p<0.01). The fibrate effects on triglycerides and HDL cholesterol were significantly greater than the statin effects (both p<0.01). Lovostatin in Type 2 diabetes Lovastatin (not presently approved for use in Australia) was used in the AFCAPS/TexCAPS primary prevention trial (Downs et al, 1998). Among 6,605 participants aged 45 to 73 years (diabetes not specified) who were randomly assigned to lovastatin 20-40mg/day (n=3,304) or placeob (n=3,301), the mean total cholesterol was 5.7mmol/L, LDL cholesterol 3.9mmol/L, and HDL cholesterol 0.94mmol/L for men and 1.03mmol/L for women and triglycerides were 1.8mmol/L at baseline. At one year, lovastatin significantly reduced total and LDL cholesterol compared with placebo (-18 v +0.9%, p<0.001; -25 v +1.5%, p<0.001, respectively). Triglycerides fell by 15% with lovastatin and rose by 1.7% with placebo (p<0.001). Lovastatin resulted in a 6% increase in HDL cholesterol comparing with a 2% increase with placebo(p<0.001). A double blind placebo controlled trial has compared lovastatin 20 to 40 mg daily with gemfibrozil 600mg twice daily over 24 weeks in 102 people with Type 2 diabetes (Goldberg et al, 1990). From a mean baseline level of 7.1mmol/L total cholesterol fell by 20% on lovastatin (n=50; p<0.01) and by 7% on gemfibrozil (n=52; p<0.01), while LDL cholesterol fell from 5.0mmol/L by 26% on lovastatin (p<0.01) and by 1% on gemfibrozil (p=NS). Triglycerides fell from 2.3mmol/L by 36% on gemfibrozil (p<0.05), but rose by 2% on lovastatin (p=NS), while HDL cholesterol rose from 1.08mmol/L by 21% on gemfibrozil and 14% on lovastatin (p<0.01). Lovastatin was more effective in reducing total and LDL cholesterol than gemfibrozil (both p<0.01), whereas gemfibrozil lowered triglycerides more than lovastatin (p<0.05). Fluvastatin in Type 2 diabetes A relatively large double blind placebo controlled trial in people with Type 2 diabetes and significantly elevated levels of both cholesterol and triglycerides has shown significant changes in lipid and lipoprotein levels with fluvastatin 20mg daily for 6 weeks, then 40mg daily for 6 weeks (Knopp et al, 1994b). Baseline total cholesterol of 7.3mmol/L fell by 20% (p<0.001) at the end of the study on fluvastatin (n=30) compared with placebo (n=29). Baseline LDL cholesterol of 4.5mmol/L fell by 25% (p<0.001) and baseline triglycerides of 3.9mmol/L by 17% (p<0.01). HDL cholesterol was 1.02mmol/L at baseline and rose by 5% with fluvastatin (p<0.10). Atorvastatin in Type 2 diabetes In a 6-month study, Soedamah-Muthu et al (2003) compared the effect of atorvastatin 10 mg/day with placebo among 122 people with Type 2 diabetes, who had a history of previous myocardial infarction and modestly increased lipids (mean LDL 3.2mmol/L and median triglycerides 1.8mmol/L). Over 6 months, the median changes in total cholesterol and LDL

110

cholesterol were significantly greater in the atorvastatin group than in the placebo group (-1.8 v -0.2mmol/L, p<0.001; -1.5 v -0.3mmol/L, p<0.001, respectively). Triglycerides were also reduced significantly with atovastatin treatment (-0.55 v -0.05mmol/L, p<0.001). There were no significant differences in HbA1c (p=0.4) and BMI (p=0.4) between the two groups during the study period. In the DALI study (The Diabetes Atorvastatin Lipid Intervention Study) (The DALI Study Group, 2001), 217 people aged 45-75 years with Type 2 diabetes were randomised to receive atorvastatin 10mg/day (n=73), atorvastatin 80mg/d (n=72), or placebo (n=72) for 30 weeks. Treatment with atorvastatin 10 and 80mg produced a significant reduction in triglycerides levels (-25%, -35%, respectively, both p<0.001), while both had a similar effect on HDL cholesterol (+6.0% v +5.2%, respectively), but without difference between the two groups. Atorvastatin 80mg was more effective than atorvastatin 10mg in lowering total cholesterol (-39%, p<0.001 v -30%, p<0.001), LDL cholesterol (-52%, p<0.001 v -41%, p<0.001), and Apo B (-40%, p<0.001 v -31%, p<0.001) (all p<0.005). During the 30 weeks of treatment, atorvastatin 80mg was associated with a slight increase in HbA1c (from 8.4 to 8.6%, p=0.06), whereas a slight decrease in HbA1c was observed in both atorvastatin 10mg and placebo group (p<0.05 at week 30). In an open-label, randomised trial, Gentile et al (2000) compared once daily atorvastatin 10 mg with simvastatin 10mg, pravastatin 20mg, lovastatin 10mg, and placebo in 409 people with Type 2 diabetes and moderate elevated LDL cholesterol (>4.2mmol/L). During 24 weeks of treatment, atorvastatin produced greater reduction in total cholesterol (-29%) and LDL cholesterol (-37%) than simvastatin (-21%, p<0.05; -26%, p<0.05, respectively), pravastatin (-16%, p<0.01; -23%, p<0.01), lovastatin (-18%, p<0.05; -21%, p<0.01), and placebo (+1%, p<0.01; -1%, p<0.01). Similarly, atorvastatin was more effective in reducing triglyceride levels (-24%) than simvastatin (-14%, p<0.05), pravastatin (-12%, p<0.05), lovastatin (-11%, p<0.05), and placebo (-1%, p<0.01). However, with regard to the effect of increasing HDL cholesterol, atorvastatin did not differ from other statins, except for pravastatin which had a smaller increment in HDL cholesterol than atorvastatin (+3.2% v +7.4%, p<0.05). These results could reflect the medication doses used in the study and their equivalence. Wagner et al (2003) compared atorvastatin 10-20mg/day with gemfibrozil 900-1200mg/day in 44 people with Type 2 diabetes and elevated lipids (LDL cholesterol >2.6mmol/L and triglycerides <4.5mmol/L) in a randomised control trial. After 12 weeks of treatment, LDL cholesterol was significantly lower with atorvastatin (3.9 to 2.6mmol/L, p<0.0001 v 3.8 to 3.7 mmol/L, p<0.01), whereas gemfibrozil lowered triglycerides more effectively (1.8 to 1.6 mmol/L v 1.9 to 1.3mmol/L, p<0.001). HDL cholesterol increased from 1.19 to 1.24mmol/L on both treatments (p<0.05). Mean LDL particle size increased only after treatment with gemfibrozil (from 25.59±0.06 to 25.69±0.06 nm, p<0.05). Apo B was reduced from 124 to 93 mg/dl with atorvastatin and from 122 to 115 mg/dl with gemfibrozil (both p<0.0001). Glycaemic control remained stable with gemfibrozil (HbA1c from 7.2 to 7.3%), while HbA1c rose from 7.0 to 7.4% (p<0.05) after treatment with atorvastatin. In a multicentre, randomised double-blind, placebo control study, Freed et al (2002) compared the effects of rosiglitazone alone and in combination with atorvastatin on glycaemic control and lipids. 243 people with Type 2 diabetes were treated with rosiglitazone 4mg twice a day during the first 8 weeks. During the 8 weeks of rosiglitazone treatment there was 5.8% increase in total HDL cholesterol whereas LDL cholesterol increased by 9.0%. All subjects were then randomised to a 16-week period of combined rosiglitazone with atorvastatin 10mg/day, 20mg/day, or placebo. With atorvastain added, there was a significant reduction in LDL cholesterol (-31.5%, -38.8%, respectively) compared with rosiglitazone plus placebo (p<0.0001). Triglycerides fell by 18.5% (p<0.001) and 27.2% (p<0.0001), respectively. Total HDL cholesterol further increased by 4.8%, and HDL3 cholesterol by 5.2% with the combination therapy (p<0.001). Over the 24-week, glycaemic control

111

improved with HbA1c decreasing from 7.9 to 7.2%, 7.6 to 7.1%, and 7.8 to 7.0%, respectively. Body weight increases ranged from 1.4 to 1.7kg during this period. Nicotinic acid (niacin) is effective in improving lipids in people with Type 2 diabetes but may have a small adverse effect on blood glucose control Studies which have examined the effect of nicotinic acid (niacin) on lipid levels in people with Type 2 diabetes are shown in Table 16. The effect of niacin on lipid and lipoprotein levels was studied in a prospective, randomised placebo-controlled trial which involved 468 subjects, including 125 with diabetes (type not specified) (Elam et al, 2000). After a 12 week run-in period with niacin 100mg, 500mg, and then 1000mg daily, 64 people with diabetes were randomly assigned to niacin 3000mg/d and 61 to placebo for a further 48 weeks. Treatment with niacin significantly reduced LDL cholesterol by 8% and triglycerides by 23%, while HDL cholesterol increased significantly by 29% (p<0.001 for all compared with placebo). With regard to glycaemic control, HbA1c was unchanged in the niacin group compared with a reduction in HbA1c of 0.3% in the placebo group (p=0.04). Grundy et al (2002) assessed the effect of extended-release (ER) niacin 1000-1500mg/day in 146 people with Type 2 diabetes, including 69 people who were also treated with statins, in a randomised, placebo controlled trial. The dose of ER niacin was gradually titrated to 1000-1500mg in the first 4 weeks. During 16 weeks, HDL cholesterol increased in a dose-dependent manner, with a 13-19% increase in the 1000mg niacin group and 22-24% increase in the 1500mg niacin group compared with little change in the placebo group (both p<0.05). There was also a dose-related reduction in triglycerides levels with a 15-20% decrease in the 1000mg niacin group and a 28-36% decrease in the 1500mg niacin group, but only the latter was significantly different from the decrease of 5-8% in the placebo group (p<0.05). The reduction in total and LDL cholesterol was only observed in the 1500mg niacin group (compared with placebo, p<0.05). Changes in HbA1c over the study period were small in all treatment groups, with -0.02% in the placebo group, +0.07% in the 1000mg niacin group, and +0.29% in the 1500mg niacin group, but the difference between placebo and the 1500mg niacin group was significant (p=0.048). The effects on the lipid profile of lower doses of nicotinic acid have been studied in combination with pravastatin and are reported in the section below on combination therapy in people with Type 2 diabetes.

112

Table 16: Effects of nicotonic acid (niacin) on lipids in Type 2 diabetes

Effects on Lipids

Reference Population studied Drug dose

Inclusion

criteria (mmol/

L)





Total Triglycerides

(mmol/L)

Apo A 1 (mg/dl)

Apo B (mg/dl)

Elam, 2000 (US)

n=125 Type 2 diabetes mean age 67 yrs 48-wk follow-up RCT Niacin n=64 Placebo n=61

3000mg/d

-

5.36

5.62

5.13***

* 5.70

3.44

3.57

3.16***

* 3.60

0.98

1.01

1.27

1.01

-

1.99

2.27

1.54****

2.37

- -

Grundy, 2002 (US)

n=146 Type 2 diabetes aged ≥21 yrs 16-wk follow-up ER niacin n=45 ER niacin n=52 Placebo, n=49

1000mg/d 1500mg/d

LDL ≥3.36 HDL ≤1.03

or TG ≥2.20

- - -

_4% -6% +4%

2.72 2.75 2.51

2.86 2.59 2.74

1.01 1.06 1.09

1.21 1.34 1.13

-

3.14 2.93 3.03

2.26 1.88 2.79

- -

Before/ After comparison * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between group comparison † p<0.05, †† p<0.01, ††† p<0.005, †††† p<0.001; TG = Triglycerides; T-CHO = Total cholesterol; HDL = HDL cholesterol

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Bile acid sequestrants (resins) may be effective in lowering total and LDL cholesterol in people with Type 2 diabetes but data are limited Studies which have examined the effect of bile acid sequestrants (resins) on lipid levels in people with Type 2 diabetes are shown in Table 17. Bile acid sequestrants (resins) bind bile acids in the intestinal tract and interrupt the enterohepatic pathway. Increased hepatic synthesis of bile acids reduces intracellular cholesterol levels and upregulates LDL receptor expression, increasing plasma clearance of LDL cholesterol. Bile acid sequestrants are effective in lowering LDL cholesterol levels in people without diabetes and have additive effects to statins, which prevent the compensatory increase in hepatic cholesterol synthesis that occurs with resins. Only one well controlled study of resin therapy has been reported in people with Type 2 diabetes. In a randomised, double blind, placebo controlled, crossover study 21 people with Type 2 diabetes took 8g cholestyramine twice daily for 6 weeks (Garg & Grundy, 1994b). All participants had fasting triglyceride levels below 3.4mmol/L. Compared with placebo, total cholesterol was 18% lower on cholestyramine (5.9 v 4.9mmol/L, p<0.001) and LDL cholesterol was 28% lower (4.1 v 3.0mmol/L, p<0.001). However, triglycerides levels rose by 7% on cholestyramine (from 1.9 to 2.1mmol/L) compared with placebo (p=0.02). There was no significant change in HDL cholesterol which was 1.02mmol/L on placebo and 5% higher on cholestyramine (p=NS). There was also a 13% reduction in mean plasma glucose compared with placebo (6.5 v 7.6mmol/L, p=0.003), but no difference in HbA1c (8.3 v 8.8%, p=0.17) was observed. Constipation was the main side effect and two subjects discontinued the study because of cholestyramine intolerance. Since cholestyramine may increase triglycerides, its use should be restricted to people with normal triglycerides. Also since it is not absorbed from the intestinal tract into the systemic circulation, cholestyramine can be used in people with moderate to severe renal failure or hepatic dysfunction or who are intolerant of statin therapy Omega–3 fatty acids (ω-3) are effective in lowering triglycerides in people with Type 2 diabetes but may cause a dose dependent deterioration in blood glucose control There is considerable epidemiological evidence that eating fish is associated with lower risk of coronary heart disease (CHD). A recent secondary prevention trial has also shown that ω-3 polyunsaturated fatty acids in the form of fish oil capsules reduce CHD risk, although a subgroup analysis of people with diabetes (15% of the 11,324 participants) has not been reported (GISSI, 1999). The two main polyunsaturated long-chain ω-3 fatty acids in fish oil are eicosapentaenoic acid (EPA; n-3, C20:5) and docosahexaenoic acid (DHA; n-3, C22:6). Protection from CHD is thought to be mediated through the effects these fatty acids have on lipid metabolism, platelet aggregation and coagulation factors There have been at least 15 controlled trials and many uncontrolled trials of fish oil therapy in Type 2 diabetes and two systematic reviews have been reported (Friedberg et al, 1998; Montori et al, 2000). The meta-analysis by Friedberg et al (1998) analysed data from 7 controlled trials and 7 uncontrolled trials of people with Type 2 diabetes. Total cholesterol fell by 1% from the mean baseline level of 5.8mmol/L (p=NS), while LDL cholesterol rose by 5% from 3.7mmol/L (p<0.05). Mean triglycerides levels at baseline were 2.6mmol/L and fell by 31% on fish oil (p<0.05). HDL cholesterol fell by 1% from the mean baseline level of 1.01mmol/L (p=NS). Fasting blood glucose rose by 5% from the mean baseline level of 9.1 mmol/L (p=0.06) and HbA1c rose by a relative change of 2% from 8.8% (p=NS). The dose of

114

fish oil varied between studies, but the controlled trials generally used about 1.8g of EPA and 1.2g of DHA. There was a direct relationship between dose and effects on triglycerides and blood glucose control. For every 1g per day increase in EPA or DHA, triglycerides levels fell by 0.36 and 0.47mmol/L (both p<0.05) and HbA1c rose by absolute levels of 0.38 and 0.6% respectively (both p<0.05). The meta-analysis by Montori et al (2000) considered only randomised controlled trials and included data from 18 studies. Doses of fish oil ranged from 3 to 18g daily (1.08-5.2g EPA and 0.3-4.8g DHA). There was a significant effect of fish oil in lowering triglycerides (-0.56 mmol/L [95% CI -0.71 to -0.41]) and the effect was more evident (-0.73mmol/L [CI -0.95 to -0.51]) in trials that recruited only hypertriglyceridaemic subjects. LDL cholesterol rose significantly with fish oil (0.21mmol/L [CI 0.02 to 0.41]) and this increase was greater in trials that used the highest doses of fish oil (0.51mmol/L [CI 0.18 to 0.84]) and that recruited subjects with baseline hypertriglyceridaemia (0.60mmol/L [CI 0.16 to 1.04]). Fish oil had no significant effects on total cholesterol (0.007mmol/L [CI -0.13 to 0.15]) and HDL cholesterol (0.02mmol/L [CI 0.01 to 0.05]). There was no significant difference in fasting glucose or HbA1c. Mean weighted difference for fasting glucose was 0.26 mmol/L (CI -0.08 to 0.60) and for HbA1c 0.15% (CI -0.08 to 0.37). A randomised crossover study has compared the lipid and lipoprotein effects of fish oil (2.89g EPA and 1.78g DHA daily) with gemfibrozil (900mg daily) over 2 week treatment periods (Fasching et al, 1996). In 10 people with Type 2 diabetes, total cholesterol fell by 13% with gemfibrozil (from 6.5 to 5.6mmol/L, p<0.01) and fell by 6% with fish oil (from 6.6 to 6.2mmol/L, p<0.05). LDL cholesterol also fell from 4.7 to 4.0mmol/L, and from 4.9 to 4.8 mmol/L, respectively. Triglycerides fell by 39% on gemfibrozil (from 2.2 to 1.4mmol/L, p<0.001) and by 18% on fish oil (from 2.3 to 1.9mmol/L, p<0.01). The effects of gemfibrozil on cholesterol and triglycerides were greater than fish oil (both p<0.05). Oestrogen replacement therapy may have a modest beneficial effect on lipids in postmenopausal women with Type 2 diabetes Since many women with diabetes take HRT for a variety of reasons, the effects of HRT on lipid and lipoprotein levels in postmenopausal women with Type 2 diabetes are relevant to their cardiovascular risk management (Table 18). The Heart and Estrogen/progestin Replacement Study (HERS) (Hulley et al, 1998) randomised 2,763 women with coronary disease, including 18% with diabetes, aged less than 80 years to be treated with 0.625mg conjugated equine oestrogen plus 2.5mg medroxyprogesterone acetate (n=1,380) or placebo (n=1,383). At the end of the first year, LDL cholesterol decreased by 14% (3.8 to 3.2mmol/L) in the hormone group and by 3% (3.8 to 3.6mmol/L) in the placebo group (p<0.001). HDL cholesterol increased from 1.29 to 1.40 mmol/L in the hormone group but decreased from 1.29 to 1.27mmol/L in the placebo group (p<0.001). Mean triglycerdies rose by 10% and 2%, respectively in the hormone group and placebo group. In the Women’s Health Initiative study (Manson et al, 2003), 16,608 postmenopausal women aged 50-79years including 2.4% with previous CHD (number with diabetes not specified), were randomly assigned to conjugated equine estrogen 0.625mg/day plus medroxyprogesterone acetate 2.5mg/day (n=8,506) or to placebo (n=8,102). The 2 groups were comparable at baseline except that more women in the placebo group had a history of coronary revascularisation (1.5 v 1.1%, p=0.04). At one year, women in the hormone group had lower levels of total and LDL cholesterol (-5.4%, -12.7%, respectively), and higher levels

115

of HDL cholesterol (+7.3%) and triglycerides (+6%) than women in the placebo group (all p<0.05). There have been a number of studies specifically in women with Type 2 diabetes. Forty postmenopausal women with Type 2 diabetes were randomised to treatment with unopposed oestrogen therapy, given as 17-β-oestradiol 2mg daily for 6 weeks, or to placebo (Brussaard et al, 1997). Compared with placebo, 17–β–oestradiol significantly reduced total cholesterol (-5% v 1%, p=0.04) and LDL cholesterol (-14% v 2%, p=0.0001) over the 6 week treatment period. HDL cholesterol significantly increased in the oestradiol group compared with the placebo group (23% v 3%, p=0.0002). Triglycerides levels did not change significantly with oestradiol (1.74 to 1.79mmol/L, p=NS). HbA1c at baseline was 8.7% and fell by 7% on oestrogen (p=0.03). Manning et al (2001) used a crossover design to compare combined HRT (oestrogen 0.625 mg plus medroxyprogesterone 2.5mg daily) with placebo among 61 women with Type 2 diabetes (mean age 64 years). After 6 months, total cholesterol was 7% lower and LDL cholesterol was 12% lower with HRT therapy than with placebo (5.8 v 6.3mmol/L, p<0.05; 3.6 v 4.1mmol/L, p<0.05, respectively). Lp(a) decreased significantly during HRT treatment (149.4 v 173.4U/L, p<0.05). There was a nonsignificant trend of an increase in HDL cholesterol with HRT therapy (1.19 v 1.09mmol/L). HbA1c remained stable in both treatment periods. Perera et al (2001) in a randomised placebo-controlled trial in 43 women with Type 2 diabetes were treated with 80μg estreadiol patches in combination with oral norethisterone 1mg daily or identical placebos for 6 months. Total cholesterol and triglycerides were reduced by 8% and 22%, respectively in those receiving HRT compared with placebos (both p<0.05). There was also a trend to reduced HDL cholesterol in the HRT group (-8% v +1%, p=0.06). No changes in LDL and VLDL cholesterol were observed. HbA1c was unchanged in the HRT group, whereas HbA1c increased slightly in the placebo group (from 6.4 to 6.8%), but this did not differ between the two groups. Data from the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial showed raloxifene, an oestrogen-receptor modulator, improved lipid profiles in women with Type 2 diabetes (Barrett-Connor et al, 2003). 202 women were randomised to receive raloxifene 60 mg/day (n=108) or placebo (n=94) in this 3-year study. At 36 months, raloxifene treatment significantly reduced total cholesterol and LDL cholesterol compared with placebo (both p<0.004). The median change in triglycerides (+0.8% v -3.6%, p=NS) and HDL cholesterol (+3.5% v +4.4%, p=NS) did not differ among women treated with raloxifene or placebo. Glycaemic control was comparable in both groups (median change in HbA1c: -0.54% v -4.03%, p=NS) over the study period. These results show that oestrogen therapy in postmenopausal women with Type 2 diabetes has a modest effect in reducing total and LDL cholesterol and, overall, little effect on HDL cholesterol and triglycerides.

116

Table 17: Effects of ω-3 fatty acid (fish oils) on lipids in Type 2 diabetes

Effects on lipids Total

Cholesterol (mmol/L)




Total Triglycerides

(mmol/L)

Apo A1 (mg/dl)

Apo B (mg/dl)

Reference Population studied Drug dose (g/d)

Inclusion Criteria

Before After Before After Before After Before After Before After Before After Before Afterr

Fasching, 1996 (Austria)

n=10 Type 2 diabetes mean age 61yrs 12-wk follow-up RCT crossover Fish oil for 2 wk Gemfibrozil for 2 wk with 8 wk wash-out

4.6 900mg

Type 2b Type 4 Hyper-

lipidaemia

6.60 6.49

6.21∗ 5.64∗∗

4.86 4.68

4.78†

3.98∗∗

- -

0.75 0.93

0.49∗∗∗∗ 0.47∗∗∗∗

2.30 2.22

1.89∗∗† 1.35∗∗

141 139

136 136

155 151

139∗ 128∗∗

Friedberg, 1998

n=14 studies of Type 2 diabetes Systematic Review Fish oil supplements

1.8-21.6 -

5.8

5.73

3.70

3.90∗

1.01

1.00

- -

2.60

1.79∗

- - - -

GISSI, 1999

n=11,324 42-mth follow-up 14.8% Type 2 diabetes Fish oil, n=2,836 Vitamin E, n=2,830 Fish oil+Vit E, n=2,830 Control, n=2,828

1.0 300mg

change from baseline to 6 mths

↑ 7.9% ↑ 7.1% ↑ 8.9% ↑ 7.1%


↑ 9.9% ↑ 7.2% ↑ 10.8% ↑ 7.4%


↑ 8.8% ↑ 9.4% ↑ 8.9% ↑ 9.2%


↓ 3.4% ↑ 2.9% ↓ 0.9% ↑ 1.4%

fish oil v control†

- - -

Montori, 2000

n=18 studies Systematic review Type 2 diabetes Fish oil supplements

3-18 -

mean change from baseline

0.007 CI (-0.13, 0.15)


0.21* CI (0.02-0.41)


0.02 CI (0.01-0.05)

-


-0.56* CI(-0.71, -0.41)

- -

Before/ After comparison * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between group comparison † p<0.05, †† p<0.01, ††† p<0.005, †††† p<0.001;

117

Table 18: Effects of hormone replacement therapy on lipids in Type 2 diabetes

Effects on lipids





Total Triglyceride

(mmol/L)

HbA1c (%)

Reference Population studied

Drug dose

(mg/day)

Inclusion criteria

(mmol/L) Before After Before After Before After Before After Before After Before After

Barrett-Connor, 2003 (US)

n=202 Type 2 diabetes mean age 68 yrs 3-yr follow-up RCT raloxifene,n=108 placebo,n=94

60 -


-12.5%†††

-3%


-16%†††

-4%


+3.5% +4.4%

-


+0.8% -3.6%


-0.54% -4.03%

Brussaard, 1997 (Belgium)

n=40 Type 2 diabetes mean age 60 yrs RCT 6-wk follow-up 17 β-estradiol n=20 placebo n=20

2

-

5.25 5.28

4.97* 5.32†

3.30 3.36

2.86**** 3.42††††

1.20 1.20

1.46**** 1.24††††

0.69 0.64

0.62 0.60

1.74 1.53

1.79 1.61

8.7 8.1

8.0* 7.8

Hulley, 1998 (US)

n=2,763 18% Type 2 diabetes 4.1-yr follow-up estrogen +medroyprogesterone v placebo

0.625 2.5

TG >3.4 -

3.75

3.75

3.23 ††††

3.62

1.29

1.29

1.40 ††††

1.27

-

1.90

1.86

2.04

1.93

-

Manning, 2001 (New Zealand)

n=61 Type 2 diabetes mean age 64 yrs 12-mth crossover RCT estrogen +medroyprogesterone v placebo

0.625 2.5

-

5.80†

6.29

3.60†

4.09

1.19

1.09

0.70

0.70

2.40

2.31

7.6

7.6

Manson, 2003 (multicentres)

n=16,608 aged 50-79 yrs 5.2-yr follow-up estrogen +medroyprogesterone v placebo

0.625 2.5

-

difference in mean % change from

baseline to year 1 between gps

-5.4%†



-12.7%†



+7.3%† -



+6.9%† -

Before/ After comparison * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between group comparison † p<0.05, †† p<0.01, ††† p<0.005, †††† p<0.001

118

Table 18: Effects of hormone replacement therapy on lipids in Type 2 diabetes

Effects on lipids





Total Triglyceride

(mmol/L)

HbA1c (%)

Reference Population studied

Drug dose

(mg/day)

Inclusion criteria

(mmol/L) Before After Before After Before After Before After Before After Before After

Perera, 2001 (UK)

n=43 Type 2 diabetes mean age 62 yrs 6-mth RCT estradiol patches + norethisterone v. identical placebos

80μg 1

-

5.60

5.23

5.13*

5.12

3.66

3.46

3.37

3.26

1.26

1.14

1.16

1.15

0.70

0.60

0.70

0.53

1.78

1.42

1.38*

1.42

6.6

6.4

6.6

6.8 Before/ After comparison * p<0.05, ** p<0.01, *** p<0.005, **** p<0.001; Between group comparison † p<0.05, †† p<0.01, ††† p<0.005, †††† p<0.001

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Some combination therapies are effective in reducing lipids in people with Type 2 diabetes but data are limited The specific lipid abnormality of Type 2 diabetes (elevated triglycerides and low HDL cholesterol) is often combined with elevated total and LDL cholesterol, which has the same prevalence in people with Type 2 diabetes as in the overall population. Correction of these multiple lipid abnormalities is often not possible with a single lipid modifying agent and in clinical practice combination therapy with more than one agent may be used. Despite the potential benefit, only a few studies have been carried out using combination therapy in people with Type 2 diabetes. Combination therapy with statin plus fibrate Gavish et al (2000) performed an open 21-month trial in which 48 people with Type 2 diabetes received slow release bezafibrate 400mg/day and 100 received simvastatin 20mg/day for 6 months following which all subjects received both medications for one year. All subjects received only diet and oral hypoglycaemic agents in the first 3 months. The effects of the combination therapy were significantly greater than either simvastatin or bezafibrate alone, with a 42% reduction in plasma triglycerides (4.3 to 2.5mmol/L, p<0.01), 23% reduction in total cholesterol (7.0 to 5.4mmol/L, p<0.01) and 29% reduction in LDL cholesterol (4.5 to 3.2mmol/L, p<0.01), whilst HDL cholesterol increased by 25% (0.8 to 1.0 mmol/L, p<0.01). Lp(a) was also reduced by 19% from 32±28 to 26±24mg/dl (p<0.01). More importantly, cardiovascular events were significantly reduced from 6% with statin and 12% with fibrate to less than 2% during the combination treatment (p values not stated). The change in plasma creatinine phosphokinase (CPK) was greater with combination therapy from 74±33 to 113±87IU/L compared with 88±48IU/L with simvastatin alone and 76±24 IU/L with bezafibrate alone, but all changes were within the acceptable normal range for CPK. The effect of a combination of atorvastatin 20mg/day and micronised fenofibrate 200mg/day (n=40) on lipids was compared to each drug alone (n=40 for each group) in 120 people with Type 2 diabetes who were free of coronary artery disease at study entry (Athyros et al, 2002a). The combination therapy reduced total cholesterol by 37%, LDL cholesterol by 46%, and triglycerides by 50%; whereas it increased HDL cholesterol by 22% (p<0.0001 for all compared with baseline). All these changes were significantly greater than those of monotherapies (all p<0.05), and more people on combined therapy reached the ADA (2001) recommended LDL cholesterol goal of <2.6mmol/L (97.5% for combination therapy, 80% with atorvastatin, 5% with fenofibrate, p<0.05), the desirable triglyceride levels of <2.26 mmol/L (100% v 75%, 92.5%, respectively, p<0.05), and the optimal HDL cholesterol goal of >1.2mmol/L (60% v 7.5%, 30%, respectively, p<0.05). Moreover, the combined therapy reduced the 10-year probability for myocardial infarction from 21.6% to 4.2% (p<0.0001) compared with 7.5% with atorvastatin and 10.9% with fenofibrate (combined compared with monotherapies, p<0.05). No significant adverse events were recorded. CPK was increased with combined therapy at a higher level than with both monotherapies, but it still remained within the normal range. One component of the study by Wagner et al (2003) reported that the low dose combination of atorvastatin 10mg and gemfibrozil 900mg in 44 people with Type 2 diabetes significantly reduced LDL cholesterol by 26.5% (from 3.8 to 2.8mmol/L, p<0.0001), triglycerides by 24.1% (from 2.1 to 1.3 mmol/L, p<0.0001) and Apo B by 21.8% (125 to 95mg/dl, p<0.0001) during 12 weeks of treatment. HDL cholesterol increased from 1.19 to 1.24mmol/L (p<0.05). Mean LDL particle size was also decreased with combined treatment (from 25.51±0.06 to 25.68±0.06nm, p<0.05). Glycaemic control improved, with a reduction in HbA1c from 7.4 to 7.3% (p<0.05) and no change in body weight occurred after treatment. There was no an

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elevation in liver enzymes greater than 3 times the upper normal limit and in CPK greater than 10 times the upper normal limit during the study period. Combination therapy with statin plus low-dose nicotinic acid Because of its potential beneficial effect on HDL cholesterol, nicotinic acid is potentially useful in Type 2 diabetes. However, high doses can worsen blood glucose control and can cause significant side effects. Flushing with nicotinic acid occurs so frequently that a double blind trial is not feasible. There have been two randomised trials of combination therapy with pravastatin and nicotinic acid. In the first study 11 people with Type 2 diabetes were included in a trial of pravastatin 40mg daily (n=6) or nicotinic acid 1,500mg daily (n=5) for 12 weeks, followed by combination therapy with pravastatin 20mg daily plus nicotinic acid 1,000mg daily in all participants (Tsalamandris et al, 1994). Baseline total cholesterol in people taking nicotinic acid first was 8.1mmol/L and in people taking pravastatin first 7.3mmol/L, LDL cholesterol was 5.7 and 5.2mmol/L, triglycerides were 6.7 and 5.5mmol/L and HDL cholesterol was 0.97 and 0.83mmol/L. On combination therapy total cholesterol fell by 26%, LDL cholesterol by 32%, triglycerides by 38% and HDL cholesterol rose by 33% (p values not given). HbA1c rose from 7.4 to 7.9% (p=NS), but there was no effect on fasting glucose. Another open label study included 14 people with Type 2 diabetes and 2 with Type 1 diabetes, using pravastatin 20mg daily as sole therapy for 4 weeks. Nicotinic acid was then added, titrating up to 1,500mg daily over 2 weeks and continuing both pravastatin and nicotinic acid for another 4 weeks (Gardner et al, 1997). Baseline total cholesterol was 7.7 mmol/L and fell by 21% with pravastatin (p<0.05) and by 27% with combination therapy (p<0.05). LDL cholesterol was 5.3mmol/L at baseline and fell by 23% (p<0.05) and by 33% (p<0.05 compared with both baseline and pravastatin alone). Triglycerides levels at baseline were 2.1mmol/L and fell by 13% and 22% (both p=NS). HDL cholesterol was 1.14mmol/L at baseline, did not change with pravastatin, but rose by 14% with combination therapy (p=NS). Fasting glucose was 11.8 mmol/L at baseline, rose by 3% with pravastatin and fell by 11% with combination therapy. The following study demonstrated that combined intensive lipid lowering therapy improved overall lipid profile in people with diabetes (Kanters et al, 1999). In order to reach the NCEP II recommended lipid targets (triglycerides <1.7mmol/L, LDL cholesterol <2.6mmol/L, and HDL cholesterol >0.9 mmol/L for men and >1.1 mmol/L for women), a stepped medication strategy was used, in which simvastatin 20 mg daily or gemfibrozil 600mg twice daily was given first, then followed by the combination of the two and finally the combination plus acipimox 500-1500mg daily. During 30 weeks, the lipid targets were reached in 42 out of 59 people (71%) with Type 2 diabetes, with total cholesterol decreasing by 1.7mmol/L, LDL cholesterol by 1.3mmol/L, and triglycerides by 1.1mmol/L. Mean HbA1c did not change during the study. Five people dropped out because of side effects including flushing and headache, myalgia and gastrointestinal disturbance. The LDL particle size before and after lipid-lowering treatment with the same stepped medication strategy described above was examined in 50 people with Type 2 diabetes (Niemeijer-Kanters et al, 2001). At baseline, 24 people were characterised by the more atherogenic LDL subclass pattern B. After 30 weeks of treatment, a shift towards normal LDL particle size (pattern A) was observed in 17 people, with an increase in LDL particle diameter (from 253±5 to 266±6Å, p<0.001) observed only in this group, while 7 people still showed LDL subclass pattern B. Overall, reductions in total cholesterol of 1.4 to 1.5mmol/L (p<0.001), LDL cholesterol of 0.6 to 0.8mmol/L (p<0.001), and triglycerides of 0.6 to 1.6mmol/L (p<0.001) were observed in people with LDL subclass pattern A or B at the end of study, whereas HDL cholesterol rose by 0.3 to 0.4mmol/L (p<0.001), with a significant increase in HDL3 cholesterol (p<0.001).

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Summary – Effects of lipid-modifying agents and hormone replacement therapy on lipids • Fibrates reduce plasma triglycerides by approximately 30-50% in people with Type 2

diabetes • Fibrates generally increase HDL cholesterol by approximately 10% in people with Type

2 diabetes • The effect of gemfibrozil on LDL cholesterol in people with Type 2 diabetes is variable.

Fibrates have no adverse effects on glycaemic parameters • The primary effect of statins in people with Type 2 diabetes is to lower LDL cholesterol • Statins reduce total cholesterol by between 20 and 30% and the LDL cholesterol by

between 25 and 45% in people with Type 2 diabetes • The triglyceride-lowering effect of statins varies between 6 and 30% and the HDL

raising effect between 4 and 17% • Statins do not affect glycaemic control in people with Type 2 diabetes • Nicotinic acid improves the lipid profile in people with Type 2 diabetes by lowering

total and LDL cholesterol and triglycerides and increases HDL cholesterol • Nicotinic acid in high doses may cause a modest deterioration in blood glucose control • There are limited data on the effectiveness of bile acid sequestrants in Type 2 diabetes • ω-3 fatty acids given as fish oil supplements lower triglycerides by between 5 and 30%,

increase LDL cholesterol levels by 5% and HDL cholesterol by 1-9% and have little effect on total cholesterol levels

• ω-3 fatty acids (fish oil) may cause a dose dependent deterioration in blood glucose control increase fasting

• Oestrogen therapy in postmenopausal women with Type 2 diabetes increases HDL cholesterol by 5 to 20%, reduces LDL cholesterol by about 10% and increases triglyceride levels by about 5%

• Combined therapy with a statin and a fibrate is effective in people with Type 2 diabetes, although data are limited

• Care must be taken with combination therapy to fully inform and monitor patients because of the increased risk of myositis in people treated with a statin plus a fibrate

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Effects of lipid-lowering agents and hormone replacement therapy on lipids in Type 2 diabetes

Evidence

Level of Evidence Author


Magnitude Rating

Relevance Rating

Athyros VG (2002a) (Adults – Greece) II RCT High High C+L+ H+ T+ High

Avogaro A (1999) (Adults – Italy) II RCT High High H+ T+ High

Barrett-Connor E (2003) (Adult women – US) II RCT High High C+L+ High

Brussard HE (1997a) (Adult women – The Netherlands)

II RCT High High C+L+ H+ High

DAIS Investigators (2001) (Adults – Canada, Finland, Sweden, France)

II RCT High High C+L+ H+ T+ High

Down JR (1998) (Adults – US) II RCT High High C+L+ H+ T+ High

Elam MB (2000) (Adults – US) II RCT High High L+ H+ T+ High

Elkeles RS (1998) (Adults – UK) II RCT High High C+ H+ T+ High

Farrer M (1994) (Adults – UK) II RCT High High C+L+ H+ T+ High

Fasching P (1996) (Adults – Austria) II RCT Medium High L+ T+ High

Freed MI (2002) (Adults – US) II RCT High High L+ H+ T+ High

Frick MH (1987) (Adult men – Finland) II RCT Medium High + Low

Friedberg CE (1998) I Meta-analysis High High L- T+ High

Gardner SF (1997) (Adults – US) III-2 Cohort Medium High L+ High

Garg A (1994b) (Adults – US) II RCT High High C+L+ T- High

Gavish D (2000) (Adults – Israel) III-2 Cohort High High C+L+ T+ H+ Medium

Gentile S (2000) (Adults – Italy) II RCT High High C+L+ H+ T+ High

GISSI (1999) (Adults – Italy) II RCT High High+ High

Goldberg R (1990) (Adults – US) II RCT High High+ High

Goldberg R (1998) (Adults – US) II RCT High High+ High

Grundy SM (2002) (Adults – US) II RCT High High H+ T+ High

Haffner SM (1999) (Adults – Danmark, Finland, Iceland, Norway, Sweden)

II RCT Medium High+ High

Hulley S (1998) (Adult women – US) II RCT High Low Low

Kanters SDJM (1999) (Adults – The Netherlands) III-2 Cohort High High+ High

Kirchgassler KU (1998) (Adults – Germany) III-2 Cohort Medium High+ High

Knopp RH (1994b) (Adults – US) II RCT High High C+L+ H+ T+ High

Koskinen P (1992) (Adult men – Finland) II RCT High High+ High

Lahdenpera S (1993) (Adults – Finland) II RCT High High L- H+ T+ High

For magnitude rating: + lipid modifying agents improve lipid levels; High = clinically important & statistically significant; Medium = small clinical importance & statistically significant; Low = no statistically significant effect. Criteria for Quality and Relevance ratings are detailed in Appendix 9. C= total cholesterol; L= LDL-cholesterol; H= HDL-cholesterol; T= triglycerides.

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Author

Level Type Quality Rating

Magnitude Rating

Relevance Rating

Manning PJ (2001) (Adult women – New Zealand) II RCT High High C+L+ High

Manson JE (2003) (Women – multicentres) II RCT High Low High

Montori VM (2000) I Meta-analysis High High L- T+ High

Niemeijer-Kanters SDJM (2001) (Adults – The Netherlands)

III-2 Cohort High High C+L+ H+ T+ High

Ogawa S (2000) (Adults – Japan) II RCT Medium High C+ H+ T+ Low

O’Neal DN (1998) (Adults – Australia) II RCT High High C+ T+ High

Perera M (2001) (Adults – UK) II RCT High High C+ T+ High

Petersen M (2002) (Adults – Denmark) II RCT High High FO+ High

Pyorala K (1997) (Adults – Scandinavia) II RCT High High+ High

Rovellini A (1992) (Adults – Italy) III-2 Cohort Medium High C+ T+ High

Rustemeijer C (2000) (Adults – The Netherlands) II RCT High High C+ L+ T+ H+ High

Schweitzer M (2002) (Adults – US) II RCT High High C+ L+ T+ High

Soedamah-Muthu SS (2003) (Adults – UK) II RCT High High C+ L+ T+ High

The DALI Study Group (2001) (Adults – The Netherlands)

II RCT High High C+ L+ H+ T+ High

Tikkanen MJ (1998) (Adults – Finland) II RCT High High C+ L+ H+ T+ High

Tsalamandris C (1994) (Adults – Australia) III-2 Cohort High High C+L+ H+ T+ High

Vinik AI (1993) (Adults – US) II RCT High High C+ H+ T+ High

Vuorinen-Markkola H (1993) (Adults – Finland) II RCT Medium High H+ T+ High

Wagner AM (2003) (Adults – Spain) II RCT High High L+ H+ T+ High

For magnitude rating: lipid modifying agents improve lipid levels; High = clinically important & statistically significant; Medium = small clinical importance & statistically significant; Low = no statistically significant effect. Criteria for Quality and Relevance ratings are detailed in Appendix 9. C= total cholesterol; L= LDL-cholesterol; H= HDL-cholesterol; T= triglycerides.

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Does treatment with lipid modifying agents or hormone replacement therapy improve outcomes in Type 2 diabetes?

Recommendations People with Type 2 diabetes who have an LDL cholesterol >2.5mmol/L after interventions to modify lifestyle and improve blood glucose control, should be considered for statin therapy People with Type 2 diabetes who have triglycerides >2.0mmol/L after interventions to modify lifestyle and improve blood glucose control, should be considered for fibrate therapy

Evidence Statements

• Statins can prevent coronary heart disease in people with Type 2 diabetes

Evidence level II

• Statins can prevent coronary heart disease in people with impaired fasting glucose (IFG) Evidence level II

• Statins can prevent stroke in people with Type 2 diabetes Evidence level II

• Fibrates may prevent coronary heart disease in people with Type 2 diabetes

Evidence level II

• There are no data on the effect of ϖ-3 polyunsaturated fatty acids (fish oil) and the risk of cardiovascular disease specifically in people with Type 2 diabetes Evidence level II

• There is no evidence that hormone replacement therapy reduces the risk of coronary

heart disease in postmenopausal women with Type 2 diabetes Evidence level II

• Lipid modifying therapy in Type 2 diabetes is considered to be cost effective

Evidence level III

• The primary target in people with Type 2 diabetes is an LDL cholesterol of 2.5mmol/L Evidence level II

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Background - Effects of lipid modifying agents on outcomes in Type 2 diabetes Cardiovascular disease, particularly coronary heart disease (CHD), is the most common cause of morbidity and mortality in Type 2 diabetes (Laakso, 1997). For men with Type 2 diabetes the mortality from CHD is 2-4 times higher than in non-diabetic men and the relative risk is even greater for women with Type 2 diabetes (Stamler et al, 1993). This increased prevalence of CVD is addressed in detail in the “Prevention and Detection of Macrovascular Disease in Type 2 Diabetes” guideline. The common CVD risk factors (lipids, blood pressure, smoking and increasing age) are also operative in people with Type 2 diabetes (Turner et al, 1998). LDL cholesterol level remains an important predictor of CVD risk in Type 2 diabetes, but levels are similar to the non-diabetic population and therefore LDL cholesterol alone does not explain the excessive CVD in this group (see Section 1 of this guideline). The increase in CHD is also associated with elevated triglycerides and reduced HDL cholesterol levels, the specific form of lipid abnormality frequently found in Type 2 diabetes. These lipid abnormalities are also associated with qualitative changes in LDL cholesterol, particularly particle size and composition, which is thought to render the particles more atherogenic (Barakat et al, 1990). Many studies in Type 2 diabetes have shown that lipid abnormalities can be corrected by lipid modifying interventions, but data on altering outcomes are more limited. The earlier large prospective studies included only small cohorts of people with Type 2 diabetes and these were mainly secondary prevention studies in people with pre-existing CHD. However recent data have become available on prevention studies (primary or secondary) with statins involving significant numbers of people with diabetes (Steiner, 2000; Colagiuri & Best, 2002). The results of similar studies with fibric acid derivatives or fibrates will become available in 2005. Implications for Clinical Practice With the convincing data of benefit of statin therapy from the Heart Protection Study in people with diabetes (Heart Protection Study Collaborative Group, 2003), a central issue considered in this Section is how should lipid modifying agents be used in people with Type 2 diabetes. The aim of the management of people with Type 2 diabetes is to prevent or reduce morbidity and premature mortality from macrovascular and microvascular complications. In addition to treatment of the diabetes, this requires treatment of other modifiable risk factors such as blood pressure, lipids and smoking. It is widely accepted that blood pressure and lipid lowering therapy should be used (unless contraindicated) in the management of all people with Type 2 diabetes who have had a previous cardiac or cerebrovascular event. However the use of these therapies in people who have not had a previous macrovascular event (ie primary prevention) is not universally agreed. Published guidelines have used the following approaches to lipid lowering therapy for primary prevention of CVD in people with diabetes: • intervention based on blood lipid levels alone (NCEP 2001, NCEP 2002; ADA 2004;

NHF 2001) • intervention based on blood lipid levels and assessment of overall cardiovascular risk

(UK NICE guidelines 2002, European Guidelines on Cardiovascular Disease Prevention

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in Clinical Practice, 2003). However it should be noted that the European Guidelines on Cardiovascular Disease Prevention in Clinical Practice classify all people with Type 2 diabetes as being at high risk and suggest blood lipid lowering therapy in those with lipid levels above target.

Absolute risk assessment and the prediction of future vascular events The concept of risk factors for vascular disease is universally accepted based on epidemiological studies showing an association of particular risk factors and cardiovascular events and intervention studies demonstrating that reducing risk factors results in a reduction in CVD events. In recent years there has been an increasing focus on using a combination of risk factors rather than single risk factors to predict the likelihood of a future vascular event. The concept of using absolute risk assessment to inform clinical decision making in the primary prevention of vascular disease is widely accepted (Jackson, 2000a). Absolute risk assessment allows identification of individuals in whom the largest number of vascular events will occur. Most methods for calculating absolute risk are based on data derived from the Framingham study (Anderson et al, 1991). However the applicability of the Framingham equations to predict CHD in people with diabetes has been questioned because of the low prevalence of diabetes in the Framingham study. Yeo and Yeo (2001) compared mean values for age, sex, systolic blood pressure, smoking habit, diabetes status, total cholesterol and HDL cholesterol to estimate predicted CHD events and mortality using the Framingham equations for subjects participating in the UKPDS (UKPDS 33) with actual event rates observed during the study. The Framingham estimate for annual CHD events was 1.6% and 0.2% for mortality compared with UKPDS observed event rates of 2.7% and 1.0% respectively, a 40% and 80% respectively underestimate by the Framingham equations. By comparison the Framingham estimates correlated closely with observed event rates in the non-diabetic WOSCOPS population. Recently a specific risk assessment tool has been developed based on the UKPDS which may more accurately define risk in people with diabetes (Stevens et al, 2001). There is no universal agreement on the level of risk for intervening, a decision which is not only influenced by the risk level but also by available resources (British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, British Diabetic Association, 2000). In Australia, the National Vascular Disease Prevention Alliance (an alliance of the National Heart Foundation, Diabetes Australia, National Stroke Foundation and the Australian Kidney Foundation) is working with the Department of Health and Ageing to develop a policy and tool for absolute risk assessment for Australia on which to base interventions to reduce CVD risk factors. Approach to use of Lipid Lowering Therapy Two approaches have been used in clinical studies of lipid lowering therapy: • fixed dose of a medication • adjusting the dose of medication to achieve a target lipid level Most outcomes studies have used a fixed dose of medication whereas most guidelines advocate adjusting therapy to achieve a target lipid level (mostly LDL cholesterol). Until the absolute risk work described above is completed, the position adopted in both the Lipid Control and Blood Pressure Control Guidelines is that interventions with lipid and blood pressure lowering therapy in people with Type 2 diabetes who have not had a previous macrovascular event should be based on lipid and blood pressure levels exceeding target levels.

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Evidence - Effects of lipid modifying agents and hormone replacement therapy on outcomes in Type 2 diabetes A recent meta-analysis has examined the cardiovascular benefit of lowering cholesterol, blood pressure and blood glucose in people with Type 2 diabetes. This study was reported before the release of the Heart Protection Study (HPS Collaborative Group, 2002a) findings and combined primary and secondary prevention studies and treatment with statins and fibrates (Huang, 2001). The lipid lowering studies showed significantly reduced combined cardiac events (risk rate 0.77, 95% CI 0.62-0.96) for secondary prevention (3 studies) but no significant effect in primary prevention studies (2 studies). Of individual cardiac events only the reduction in myocardial infarction in secondary prevention studies was significant. The benefit was comparable to blood pressure lowering and greater than for blood glucose lowering. Statins can prevent coronary heart disease in people with Type 2 diabetes There is evidence from well designed studies that reducing LDL cholesterol with statins decreases the risk of CHD (Table 19). These large double blind, placebo controlled trials have been performed predominantly in non-diabetic populations but some have included substantial numbers of people with diabetes. Those studies which included subgroup analyses of people with diabetes are reviewed below. Where there is no information in people with diabetes, studies in the non-diabetic population are described. Secondary Prevention Improvement in clinical outcomes The 4S (Scandinavian Simvastatin Survival Study) included 4,444 people aged 35-70 years with total cholesterol between 5.5 and 8.0mmol/L (mean 6.75mmol/L) and triglycerides ≤2.5 mmol/L who were randomised to treatment with simvastatin or placebo and were followed for an average period of 5.4 years (Scandinavian Simvastatin Survival Study Group (4S), 1994). Simvastatin was commenced at a dose of 20mg daily and was titrated to 40mg to achieve a target total cholesterol of 3.0-5.2mmol/l. At 1 year 72% achieved the target cholesterol with 37% of participants taking simvastatin 40mg. Over the course of the study, the mean changes from baseline in the simvastatin group were reductions of 25% for total cholesterol, 35% for LDL cholesterol and 10% for triglycerides, with an increase of 8% for HDL cholesterol. The risk of major coronary events in the simvastatin treated group was reduced by 34% (p<0.00001). There have been two published analyses of the diabetic subgroup in the 4S study (Pyorala et al, 1997; Haffner et al, 1999). Of the 4,444 subjects, 202 had a clinical history of diabetes. Over the 5.4-year follow-up, simvastatin treatment significantly reduced the risk of major CHD events (RR 0.45 [0.27-0.74], p=0.002) and of any atherosclerotic event (RR 0.63 [0.43-0.92], p=0.018). Total mortality was decreased by 43% (RR 0.57 [0.30-1.08]), but this did not achieve statistical significance (p=0.087) (Pyorala et al, 1997). A subgroup analysis of people with diabetes in the 4S study by Haffner et al (1999) included a further 281 subjects who were defined as having diabetes on the basis of fasting glucose ≥7.0mmol/L (total with diabetes 483). Lipid and lipoprotein changes with treatment in the diabetic subgroup were similar to the non-diabetic group. Treatment with simvastatin reduced major CHD events by 42% (RR 0.58 [CI 0.41-0.80], p=0.001) and revascularisation by 48% (RR 0.52 [CI 0.32-0.82], p=0.005). These were not significantly different from a 32% reduction (RR 0.68 [CI 0.59-0.79], p<0.001) and a 33% reduction (RR 0.67 [CI 0.55-0.80], p<0.001) in the cohort with normal glucose tolerance. Total mortality was reduced by 21% with simvastatin, but this

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was not significant (RR 0.79 [CI 0.49-1.27], p=0.34). The corresponding figure in nondiabetic cohort was 28% (RR 0.72 [CI 0.57-0.90], p=0.005). The CARE study (Cholesterol And Recurrent Events) (Sacks et al, 1996) included 4,159 people with mean cholesterol levels of 5.4mmol/L and LDL cholesterol 3.0 to 4.5mmol/L. Participants were randomised to placebo or pravastatin 40mg/day and had a median follow-up period of 5.0 years. Pravastatin lowered total cholesterol by 20%, LDL cholesterol by 32%, triglycerides by 14% and raised HDL cholesterol by 5% (p<0.001 for all comparisons). Myocardial infarction or CHD death was reduced by 24% (p<0.003) in the group on pravastatin and there was also a 31% reduction (p<0.03) in the risk of stroke. The CARE study included 586 people with a clinical history of diabetes (Goldberg et al, 1998). Average cholesterol levels, response to pravastatin and risk reduction of end points were similar to the non-diabetic group. In people with diabetes there was a significant reduction in total coronary events (CHD death, nonfatal MI, revascularisation procedures) (25%, p=0.05) and in revascularisation procedures (32%, p=0.04). However because of the higher event rates, people with diabetes experienced a greater absolute risk reduction in total coronary events compared with people without diabetes (8.1% v 5.2%). The LIPID study (Long-term Intervention with Pravastatin in Ischaemic Disease) (LIPID Study Group, 1998) followed 9,014 subjects for an average of 6.1 years. Initial cholesterol levels, the response to pravastatin 40mg daily and the reduction of cardiovascular events were similar to CARE. Overall, there was a 22% reduction in total mortality (CI 13-31%, p<0.001) and a 24% reduction in CHD death (CI 12-35%, p<0.001). The risk of myocardial infarction decreased by 29% (CI 18-38%, p<0.001) and the risk of stroke by 19% (CI 0-34%, p=0.048) in the pravastatin group. In the LIPID study there were 1,077 subjects with diabetes (Keech et al, 2003). The risk of a major CHD event in these 1,077 subjects with diabetes was 61% higher than the non-diabetic group. There was a 19% reduction in myocardial infarction or CHD death in the group with diabetes (absolute risk reduced from 23.4 to 19.6%, p=0.11) compared with a 24% reduction among all patients (absolute risk reduced from 15.9 to 12.3%, p<0.001). The Heart Protection Study (HPS) was a primary and secondary prevention study of simvastatin 40mg daily and anti-oxidant vitamin therapy (vitamin E 600mg, vitamin C 250 mg, beta-carotene 20mg daily) in a 2×2 factorial design (HPS Collaborative Group, 2002a; HPS Collaborative Group, 2002b). HPS included 20,536 people aged 40-80 years with total cholesterol >3.5mmol/L and a substantial 5 year risk of death because of a past history of coronary disease or occlusive disease of non-coronary arteries, or diabetes or treated hypertension (Heart Protection Study Collaborative Group, 2002a). In the 10,269 people assigned to treatment with simvastatin 40mg daily, the risk of a major vascular event (CHD, stroke or revascularisation) was 19.8% compared with 25.2% in the 10,267 people on placebo (24% relative risk reduction, p<0.00001). The study failed to show any effect of antioxidant vitamin therapy for the whole cohort or any subcategory (Heart Protection Study Collaborative Group, 2002b). The Heart Protection Study included 5,963 people with diabetes of whom 1,981 had had a previous CHD event. Overall there was a highly significant 13% reduction in all cause mortality (14.9 v 12.9%, p< 0.0003) due to an 18% reduction in coronary death (p<0.0005). The incidence of a first major vascular event was reduced by 22% in people with diabetes treated with simvastatin compared with placebo (p <0.0001). Simvastatin therapy reduced the incidence of a first major vascular event by 11% (325/972 v 381/1009) compared with placebo (OR 0.89 [CI 0.75-1.05]), however this was not significant (HPS Collaborative

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Group, 2002a). In the 2,912 people with diabetes and no diagnosed vascular disease at baseline, there was a 33% reduction in first major vascular event (p=0.0003) (HPS Collaborative Group, 2003). In the PROSPER study (Shepherd et al, 2002), 5,804 elderly people (aged 70-82 years, 623 with diabetes) with previous cardiovascular disease were randomised to pravastatin 40 mg/day or placebo for an average of 3.2 years. LDL cholesterol was 34% lower in the pravastatin group than in the placebo group. Pravastatin resulted in a 15% reduction in the incidence of the combined primary endpoint (HR 0.85, CI 0.74-0.97; p=0.014), 19% reduction in CHD death or nonfatal myocardial infarction (HR 0.81, CI 0.69-0.94, p=0.006) and 24% reduction in mortality from CHD (HR 0.76, CI 0.58-0.99, p=0.043). Fatal or nonfatal stroke was not affected (HR 1.03, CI 0.81-1.31, p=0.8). With regard to baseline LDL cholesterol levels, the incidence of primary endpoint was significantly reduced in people with LDL >4.11mmol/L (HR 0.77, CI 0.60-0.98) compared with people with LDL <3.41mmol/L (HR 0.88, CI 0.80-1.10) and LDL 3.41-4.11mmol/L (HR 0.88, CI 0.70-1.10). Among people with diabetes (n=623) the incidence of primary endpoint was higher (HR 1.27, CI 0.90-1.80) compared with people without diabetes (HR 0.79, CI 0.59-0.91) (between groups p=0.015). In the GREACE study (Athyros et al, 2002b), 1,600 people (19.6% with diabetes) with a prior myocardial infarction or stenosis of >70% of at least one coronary artery were randomly assigned to treatment with atorvastatin (10-80mg/day) group or to usual care. The mean atorvastatin dosage was 24mg/day and 14% of people in the usual care group received lipid-lowering treatment during the entire study (statins 12%, fibrates 2%). Treatment with atorvastatin lowered total cholesterol by 36% (6.66 to 4.27mmol/L), LDL cholesterol by 46% (4.66 to 2.57mmol/L) and increased HDL cholesterol by 7% (1.01 to 1.09mmol/L) compared with the changes in the usual care group (-4% [6.60 to 6.35mmol/L], p<0.0001; -5% [4.63 to 4.38mmol/L], p<0.0001; and +2% [1.01 to 1.04mmol/L], p=0.003, respectively). After 3 years, 97% people in the atorvastatin group compared with only 3% people in the usual group achieved the NCEP recommended LDL cholesterol target of <2.6 mmol/L. Overall, atorvastatin significantly reduced risk of total mortality (RR 0.57, CI 0.39-0.78; p=0.0021), CHD mortality (RR 0.53, CI 0.29-0.74, p=0.0017), coronary morbidity (RR 0.46, CI 0.25-0.71; p<0.0001) and stroke (RR 0.53, CI 0.30-0.82; p=0.034). People with diabetes also benefited from atorvastatin therapy with a 58% reduction in all cardiac events (p<0.0001). Hoogwerf et al (1999) reported the effects of aggressive and moderate lipid lowering therapy on the clinical outcomes in the subset of people with Type 2 diabetes who had had a CABG procedure 1 to 11 years previously in he Post CABG Trial. Of the 116 people with diabetes, 63 were randomly assigned to aggressive lipid lowering using lovastatin (dosage not stated) to achieve an LDL cholesterol of 1.55-2.20mmol/L, while 53 were assigned to moderate lipid lowering using lovastatin to achieve an LDL cholesterol goal of 3.36-3.62mmol/L. Overall the outcomes in people with and without diabetes were similar. Over the 4-year period, there was a general reduction in RR for clinical events associated with aggressive lipid lowering therapy, with a 47% reduction in combined endpoint (14.9 v 26.2%, RR 0.53 [CI 0.18-1.60]), a 33% reduction in death (6.5 v 9.6%, RR 0.67 [CI 0.12-3.75]) and a 60% reduction in MI (4.8 v 11.6%, RR 0.40 [CI 0.07-2.47]), but none of these reached statistical significance. Also fewer people treated with aggressive lipid lowering therapy had a PTCA during the study period (4.9 v 7.9%, RR 0.61 [CI 0.09-4.39]), but again this did not reach significance. In a 24-month multicentre, randomised controlled trial, Cannon et al (2004) compared the effects of pravastatin 40mg/day with atorvastatin 80mg/day in 4,162 people (mean age 58 years, 17.6% with diabetes) who had experienced an acute myocardial infarction or unstable angina within the proceeding 10 days. At baseline, the lipid levels were comparable between

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the two groups. During the follow-up, the median LDL cholesterol level achieved was 2.46mmol/L (interquartile rage 2.04-2.92mmol/L) in the pravastatin group and 1.60mmol/L (interquartile range 1.29-2.04mmol/L) in the atorvastatin group (atorvastatin v pravastatin, p<0.001). The median HDL cholesterol level rose by 8.1% in the pravastatin group and 6.5% in the atorvastatin group (p<0.001). Overall, high-dose atorvastatin therapy resulted in a 16% reduction (CI 5-26) in the rate of primary endpoint compared with standard-dose pravastatin therapy (22.4 v 26.3%, p<0.001). The benefit appeared to be greater among people with a baseline LDL cholesterol of ≥3.24mmol/L, with a 34% reduction, compared with a 7% reduction in the event rate among those with a baseline LDL cholesterol of <3.24mmol/L (p<0.02). Among 734 people with diabetes, the 2-year event rates were reduced from 34.6% in the pravastatin group to 28.8% in the atorvastatin group (no p value reported but not significant from Figure 5) compared with a significant reduction from 24.6% with pravastatin to 21.0% with atorvastatin in the 3,428 people without diabetes. The following 2 studies specifically examined statin treatment in people with hypertension and included a mix of people with and without a previous CVD event. The ALLHAT study was primarily designed to compare the effectiveness of different blood pressure lowering medications - chlorthalidone, amlodipine, lisinopril and doxazocin in people aged 55 years and older with hypertension and at least one additional CHD risk factor (ALLHAT Collaborative Research Group, 2002a). ALLHAT-LLT was a substudy of ALLHAT which included 10,355 people (mean age 66 years), of whom 3,638 had Type 2 diabetes, with LDL cholesterol of 3.1-4.9mmol/L in those without CHD and 2.6-3.3mmol/L in those with CHD and fasting triglycerides less than 3.9mmol/L not receiving lipid lowering medication at the beginning of the study. People in ALLHAT-LLT were randomised to open-label treatment with pravastatin 40mg/day (n=5,170) or to receive usual care (n=5,185). Over a mean 4.8 year follow-up, the study failed to show a difference in all-cause mortality or CHD events between pravastatin and controls, a result which was observed for the total cohort and for the diabetic population (ALLHAT Collaborative Research Group, 2002b). The 6-year mortality rate was 14.9% for pravastatin and 15.3% for usual care, with a RR of 0.99 (CI 0.89-1.11, p=0.88) and the numbers of CVD deaths were similar in both groups (295 v 300) (RR 0.99, CI 0.84-1.16, p=0.91). CHD events (fatal CHD plus nonfatal MI) were somewhat lower in the pravastatin group than in the usual care group (380 v 421), but this did not reach significance (RR 0.91, CI 0.79-1.04, p=0.16). Possible explanations for this lack of difference include the modest differential reduction in LDL cholesterol (approximately 17%), the open-label study design, or the decreased benefit of lipid lowering therapy in people with well controlled hypertension. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) is a randomised CHD primary prevention study comparing conventional (β-blocker ± diuretic) and more contemporary (CCB ± ACEI) blood pressure lowering therapy in 10,305 adults aged 40-79 years with hypertension. In addition, the study population was required to have at least 3 other risk factors for cardiovascular disease. The study included a 2×2 factorial design comparing additional treatment with atorvastatin 10mg/day in people with a total cholesterol of ≤6.5 mmol/L. The study population included 2,532 people with diabetes (24.3% in the atorvastatin treatment group and 24.8% in the placebo group) (Sever et al, 2003). The lipid lowering part of the study was discontinued after 3.3 years follow-up because cardiovascular outcomes were significantly higher in the placebo group although the blood pressure was 138/80 mg/Hg for both groups. The hazard ratios were 0.73 (0.56-0.96, p=0.02) for fatal and non-fatal stroke, 0.79 (0.69-0.90, p=0.0005) for CVD and 0.71 (0.59-0.86, p=0.0005) for coronary events. However analysis of the diabetic subgroup did not show a significant difference in the primary endpoint of non-fatal MI plus fatal CHD. The authors speculate that this might be the result of the low number of absolute events among people with diabetes resulting in inadequate power to demonstrate a difference and the increased usage of statins in the diabetes placebo group (14%) compared with the non-diabetic placebo group (8%). However

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the possibility remains that lipid lowering therapy is not as effective in people with diabetes who have well controlled blood pressure. Improvement in angiographic outcomes Hoogwerf et al (1999) reported the effects of aggressive and moderate lipid lowering therapy on the angiographic outcomes in the subgroup of people with Type 2 diabetes who had had a CABG procedure 1 to 11 years previously in the Post CABG Trial. Of the 116 people with diabetes, 63 were randomly assigned to aggressive lipid lowering using lovastatin (dosage not stated) to achieve an LDL cholesterol of 1.55-2.20mmol/L, while 53 were assigned to moderate lipid lowering using lovastatin to achieve an LDL cholesterol goal of 3.36-3.62mmol/L. Among people with diabetes, the RRs for substantial progression and occlusion in saphenous vein grafts were lower with aggressive lipid lowering compared with moderate lipid lowering (RR 0.49 [CI 0.20-1.19], RR 0.54 [CI 0.15-2.02], respectively), although these were not significant. The corresponding figures in people without diabetes were 0.60 (CI 0.46-0.79) and 0.61 (CI 0.41-0.92), respectively. The mean change in minimum lumen diameter was -0.277 mm with aggressive therapy and -0.315 mm with moderate therapy in the diabetic group, -0.194 mm and -0.389 mm, respectively in the non-diabetic group. There were no statistically significant differences for all angiographic outcomes between people with and without diabetes. As reviewed earlier in this Section clinical outcomes were similar in the 2 groups. The SCAT Study (Teo et al, 2000) randomised 460 subjects, 70% with a previous myocardial infarction, to simvastatin 10mg/day or to placebo during an average follow-up of 47.8 months. Changes in coronary angiographic measurement between simvastatain and placebo were as follows: mean diameter -0.07±0.20 v -0.14±0.20 mm (p=0.004), minimum diameter -0.097±0.17 v -0.16±0.20 mm (p=0.0001), and percent diameter stenosis 1.67 v 3.83% (p=0.0003). Among 11% subjects with diabetes, the differences for the above measurements were also significant between simvastatin and placebo - p=0.031; p=0.025; and p=0.02, respectively. With regard to clinical events, there were no differences between the two groups in cardiac death, myocardial infarction, stroke, and the combined endpoint (all p>0.05). However, fewer subjects in the simvastatin group needed revascularisation procedures compared with the placebo group (13 v 28, p=0.02). The Canadian Coronary Atherosclerosis Intervention Trial (Waters et al, 1994) examined the effect of lovastatin 20-80mg/day on the progression of coronary atherosclerosis. LDL cholesterol was decreased by 21% from 6.47 to 5.08mmol/L in the lovastatin group (n=165) compared with a reduction of 1.4% in the placebo group (n=166) (between groups p<0.001). The mean lovastatin dose was 36mg/day during the 2-year study period. Lovastatin treatment was significantly associated with less worsening of all coronary lesions measured by the minimum lumen diameter (MLD) (0.05±0.13 v 0.09±0.16mm, p=0.010) and less new coronary lesions developed (23 v 49, p=0.001). Progression of lesions (worsening in MLD ≥0.04 mm) occurred in 33% of people in the lovastatin group compared with 50% in the placebo group (p=0.003). However, among 14% people with diabetes, the worsening in MLD of coronary lesions was not significant between the two treatment groups (0.08 v 0.11 mm, p=0.43). Primary Prevention Prior to the Heart Protection Study there were little data on statin therapy for primary prevention of CVD in diabetes. Of the 20,536 participants in the Heart Protection Study, 3,982 had diabetes and no previous CHD event. There was a significant 26% reduction in first major vascular event in the simvastatin treated group (p<0.001) (HPS Collaborative

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Group, 2002a). In the 2,912 people with diabetes and no diagnosed vascular disease at baseline, there was a 33% reduction in first major vascular event (p=0.0003) (HPS Collaborative Group, 2003). There was no effect with anti-oxidant vitamin supplements (HPS Collaborative Group, 2002b). The CARDS (Collaborative Atorvastatin Diabetes Study) (www.cardstrial.org, 2004) randomised 2,838 people (mean age 61 years) with Type 2 diabetes but no history of coronary, cerebrovascular or severe peripheral vascular disease to atorvastatin (10 mg/day) (n=1,428) or placebo (n=1,410). At baseline the median LDL cholesterol level in both groups was 3.1 mmol/L. After a mean follow-up of 4.5 years, LDL cholesterol was reduced by 40% to 1.9 mmol/L (p<0.0001) and total cholesterol by 26% (from 5.4 to 4.0 mmol/L, p<0.0001) in the atorvastatin group ccompared with little changes in the placebo group. 80% of subjects in the atorvastatin group achieved LDL cholesterol target level of <2.6 mmol/L, while the corresponding figure in the placebo group was only about 25%. Atorvastatin treatment resulted in a 37% risk reduction in combined primary endpoint (CI 17-52, p=0.001), a 32% risk reduction in any CVD endpoint (CI 15-45, p=0.001), and a 48% risk reduction in stroke (CI 11-69). All cause mortality was also reduced by 27% (CI -1, 48) with atorvastatin but this was not significant (p=0.059). WOSCOPS (West of Scotland Coronary Prevention Study) was a primary prevention study in 6,595 men with mean cholesterol 7.0mmol/L (Shepherd et al, 1995). After an average follow-up period of 4.9 years there was a 31% reduction (p<0.001) of nonfatal myocardial infarction or death from CHD in the group randomised to pravastatin 40mg daily compared with placebo. Another primary prevention study, the AFCAPS/TexCAPS (Airforce/Texas Coronary Atherosclerosis Prevention Study) recruited 5,608 men and 997 women with mean cholesterol 5.71mmol/L, mean LDL cholesterol 3.89mmol/L and mean HDL cholesterol 0.94 mmol/L in men and 1.03mmol/L in women. Participants were randomised to either lovastatin 20-40mg daily or placebo. After an average follow-up period of 5.2 years there was a 37% reduction (p<0.001) of acute major coronary events in the lovastatin treated group (Downs et al, 1998). These two primary prevention studies provide only limited data relevant to diabetes because of the small numbers of people with Type 2 diabetes included. In WOSCOPS only about 1% of people had diabetes (76 in total) and a separate analysis of the subgroup with diabetes was not performed (Shepherd et al, 1995). Of the AFCAPS/TexCAPS study participants, 2.3% had a clinical history of diabetes (155 in total). The 43% risk reduction of acute major coronary events in the diabetic group was not significantly different from the 36% reduction for the total cohort (Downs et al, 1998).

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Table 19: Effects of lipid modifying agents on risk of cardiovascular disease

Blood lipid effects Study No. Proportion with diabetes

Description Follow-up Before After

Main results

AFCAPS/ TexCAPS Downs, 1998

6,605 2.3% RCT Age 45-73 yr Lovastatin 40mg/day v placebo T-CHO 4.65-6.82mmol/L LDL 3.36-4.91mmol/L HDL ≤1.16mmol/L for men ≤1.22mmol/Lfor women TG ≤4.52 mmol/L

5.2 yrs All subjects Lovastatin gp: T-CHO 5.71 LDL 3.89 HDL 0.94 (men) 1.03 (women) TG 1.78

All subjects Lovastatin gp: T-CHO 4.75 LDL 2.96 HDL 1.00 (men) 1.11 (women) TG 1.61

RR Lovastatin v placebo First acute major coronary event 0.63 (0.50-0.79), p<0.001 MI 0.60 (0.43-0.83), p=0.002 Unstable angina 0.68 (0.49-0.95), p=0.02 Revascularization 0.67 (0.52-0.85), p=0.001 Coronary events 0.75 (0.61-0.92), p=0.006 CVD events 0.75 (0.62-0.91), p=0.003

ALLHAT-LLT The ALLHAT Collaborative Research Group, 2002b

10,355 35% RCT - 2×2 factorial design 14% history of CHD, 100% hypertension, mean age 66 yrs randomised to: pravastatin or usual care pravastatin started at 20mg/day and increased to 40mg/day to achieve a 25% decrease in LDL cholesterol After first 1,000 subjects recruited everyone randomised to pravastatin received 40mg/day

4.8 yrs All subjects Pravastatin gp T-CHO 5.77 LDL 3.77 HDL 1.23 TG 1.70

All subjects Pravastatin gp T-CHO 4.77 LDL 2.70 HDL 1.26 TG 1.64

RR Pravastatin v usual care: Overall: All-cause mortality: 14.9 v 15.3%, p=NS CVD deaths: 6.9 v 7.1%, p=NS CHD events: 9.3 v 10.4%, p=NS RRs in people with diabetes: All-cause mortality: 1.03, p=NS CHD death & MI: 0.89, p=NS

ASCOT Sever, 2003

10,305 24.6% RCT - 2×2 factorial design 9.7% with a previous stroke or TIA 5% with PVD 100% with hypertension Age 40-79 yr T-CHO ≥6.5mmol/L TG <4.5mmol/L Atorvastatin 10mg/day v Placebo

3.3 yrs All subjects Atorvastatin gp: T-CHO 5.48 LDL 3.44 HDL 1.31 TG 1.66

All subjects Atorvastatin gp: T-CHO 4.18 LDL 2.28 HDL 1.30 TG 1.32

HR Atorvastatin v placebo: Nonfatal MI plus fatal CHD: 0.64 (0.50-0.83), p=0.0005 Total coronary events: 0.71 (0.59-0.86), p=0.0005 Total CVD events: 0.79 (0.69-0.90), p=0.0005 Fatal or nonfatal stroke: 0.73 (0.56-0.96), p=0.024 In people with diabetes, no significant benefits for above endpoints

T-CHO = Total cholesterol; HDL = HDL cholesterol; LDL = LDL cholesterol; TG = Triglycerides. MLD = minimum lumen diameter. IMT = intima-media thickness

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Main results

BIP Study The BIP Study Group, 2000

3,090 10% RCT Previous MI or stable angina, Age 45-74 yr T-CHO 4.7-6.5mmol/L LDL≤4.7mmol/L HDL ≤1.17mmol/L TG <3.9mmol/L Bezafibrate 400mg/day v placebo

6.2 yrs All subjects Bezafibrate gp: T-CHO 5.49 LDL 3.83 HDL 0.90 TG 1.64

All subjects Bezafibrate gp: T-CHO (no data) LDL (no data) HDL 1.06 TG 1.30

RRR Bezafibrate v placebo: Primary endpoint, 9.4%, p=NS Non-fatal MI, 12.8%, p=NS Secondary endpoint, 4.9%, p=NS All endpoints combined, 6.6%, p=NS TG ≥2.2mmol/L 39% reduction in primaryendpoint (p<0.02) No separate analysis for diabetic group

CARE Trial Sacks, 1996

4,159 14.5% RCT 100% previous MI Age 21-75 yr T-CHO <6.21mmol/L TG <4.0mmol/L Pravastatin 40mg/day v placebo

5 yrs All subjects Pravastatin gp: T-CHO 5.41 LDL 3.60 HDL 1.00 TG 1.76

All subjects Pravastatin gp: T-CHO 4.33 LDL 2.59 HDL 1.05 TG 1.51

RRR in pravastatin group Death from CHD: 20% (-5, 39), p=NS Nonfatal MI: 23% (4-39), p=0.02 Fatal MI: 37% (-5, 62), p=NS Risk reduction of coronary events with diabetes: 25% (0-43), p=0.05 without diabetes: 23% (11-33), p<0.001

CARE Trial Goldberg, 1998 Subgroup analysis of people with diabetes

4,159 14% in pravastatin 15% in placebo group

RCT 100% previous MI Age 21-75 yr T-CHO <6.21mmol/L TG <4.0mmol/L pravastatin 40mg/day v placebo

5 yrs Diabetic cohort Pravastatin gp: T-CHO 5.33 LDL 3.52 HDL 0.97 TG 1.85

Diabetic cohort Pravastatin gp: T-CHO 4.32 LDL 2.57 HDL 1.01 TG 1.61

RRRs in people with diabetes inpravastatin group Coronary events: 25% (p=0.05) Revascularisation: 32% (p=0.04) CHD death: 3% (p=NS) Fatal MI: 46% (p=NS) Nonfatal MI: 18% (p=NS) Total MI: 23% (p=NS) Stroke: 14% (p=NS)

CARDS Study 2004

2,838 100% RCT Mean age 61 yr LDL≤4.14mmol/L TG≤6.78mmol/L atorvastatin 10mg/day v placebo

4.5 yrs Atorvastatin gp: T-CHO 5.40 LDL 3.10 HDL 1.30 TG 1.70

Atorvastatin gp: T-CHO 4.00 LDL 1.90 HDL 1.32 TG 1.30

RRRs in atorvastatin group combined primary endpoint: 37%(p=0.001) any CVD endpoint: 32% (p=0.001) acute coronary events: 36% stroke: 48% all-cause mortality: 27% (p=NS)


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Main results

CCAIT Canadian Coronary Atherosclerosis Intervention Trial Waters, 1994

331 14% RCT Mean age 53 yr 54% had a previous MI 18% had a previous angioplasty T-CHO 5.70-7.78mmol/L All received intensive dietary counselling Lovastatin 20mg/day, up to 80mg/day to achieve LDL of <3.36mmol/L v placebo

2 yrs All subjects Lovastatin gp: T-CHO 6.47 LDL 4.48 HDL 1.07 TG 2.19

All subjects Lovastatin gp: T-CHO 5.08 LDL 3.16 HDL 1.12 TG 1.95

Lovastatin v placebo worsening in MLD of all lesions: 0.05±0.13 v 0.09±0.16 mm, p=0.01 progression of worsening in lumen diameter ≥0.04mm: 33 v 50%, p=0.003 new coronary lesions developed: 23 v 49, p=0.001 In people with diabetes: worsening in MLD of all lesions: 0.08 v 0.11 mm, p=NS

DAIS Investigators, 2001

418 100%

RCT Type 2 diabetes, half had a history of CAD Age 40-65 yr T-CHO/HDL ≥4mmol/L LDL 3.5-4.5mmol/L TG ≤5.2mmol/L Fenofibrate 200mg/day v placebo

4 yrs All had diabetes Fenofibrate gp: T-CHO 5.56 LDL 3.38 HDL 1.01 TG 2.59

All had diabetes Fenofibrate gp: T-CHO 5.00 LDL 3.14 HDL 1.09 TG 1.84 (estimated from bar chart)

Fenofibrate v placebo: 40% less progression in MLD ,p=0.029; 42% less percentage diameter stenosis p=0.02; No difference in clinical outcomes

DART Burr, 1989

2,033 men Nil RCT All had previous MI Age <70 yr Given dietary advice to reduce fat intake, increase fibre and increase fish consumption v no dietary advice

2 yrs All subjects Adjusted fat advice v none T-CHO 6.29 v 6.55mmol/L, p=NS HDL 1.04 v 1.05mmol/L, p=NS

RRs in different groups: adjusted fat 1.0 (0.77-1.30) all deaths 0.91 (0.71-1.15) IHD events adjusted fish 0.71 (0.54-0.93, p<0.05) alldeaths 0.84 (0.66-1.07) IHD events adjusted fibre 1.27 (0.99-1.65) all deaths 1.23 (0.95-1.53) IHD events


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Main results

GISSI Prevenzione Trial 1999

11,324 14.8% RCT Gruppo Italiano per lo Studio della Supravvivenza nell’Infarto Miocardico – Prevenzione Trial Age limits not defined 4 groups: ω-3 PUFA (850mg/day) vitamin E (300mg/day) n-3 PUFA + vitamin E control

42 months All subjects % change from baseline to 6 months: n-3; Vit E; both; control T-CHO: ↑7.9; ↑7.1; ↑8.9; ↑7.1%; p=0.039 LDL: ↑9.9; ↑7.2; ↑10.8; ↑7.4%; p=0.002 HDL: ↑8.8; ↑9.4; ↑8.9; ↑9.2%; p=0.0001 TG: ↓3.4; ↑2.9; ↓0.9; ↑1.4%; p=0.0001

RR of ω-3 PUFA Death, MI or stroke: 0.85 (0.74-0.98); CVD death, MI or stroke: 0.80 (0.68-0.95) All fatal events: 0.80 (0.67-0.94) RR of vitamin E Death, MI or stroke: 0.89 (0.77-1.03); CVD death, MI or stroke: 0.88 (0.75-1.04) All fatal events: 0.86 (0.72-1.02) RR of ω-3 PUFA+Vitamin E Death, MI or stroke: 0.86 (0.74-0.99); CVD death, MI or stroke: 0.88 (0.75-1.03) All fatal events:0.80 (0.67-0.95) No separate results for people with diabetes

GREACE The GREek Atorvastatin and Coronary-heart-disease Evaluation Athyros, 2002b

1,600 19.6% Randomised, open-label All prior MI or >70% occlusion of ≥ one coronary artery Age <75 yr LDL >2.6mmol/L TG <4.5mmol/L Atorvastatin 10mg/d, up to 80mg/d to achieve LDL of 2.6mmol/L v Usual care

3 yrs All subjects Atorvastatin gp: T-CHO 6.66 LDL 4.66 HDL 1.01 TG 2.08

All subjects Atorvastatin gp: T-CHO 4.27 LDL 2.57 HDL 1.09 TG 1.45

RRs Atorvastatin v usual care: Total death: 0.57 (0.39-0.78), p=0.002 CHD death: 0.53 (0.29-0.74), p=0.0017 Coronary morbidity: 0.46 (0.25-0.71),p=0.0001 Stroke: 0.53 (0.30-0.82), p=0.034 In people with diabetes: All cardiac events: RR 0.42, p<0.0001


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Main results

Heart Protection Study, 2002a

20,536 19.4% RCT 2x2 factorial design Age 40-80 yr T-CHO ≥3.5mmol/L simvastatin 40mg/day v placebo

5 yrs All subjects Simvastatin gp: T-CHO 5.9 LDL 3.4 HDL 1.06 TG 2.1

All subjects Simvastatin gp: T-CHO 5.1 LDL 2.7 HDL 1.08 TG 1.9

With simvastatin: RRs in mortality: Vascular 0.83 (0.75-0.91), p<0.0001 Non-vascular 0.95 (0.85-1.07), p=NS All-cause 0.87 (0.81-0.94), p=0.0003 RRs of major event Coronary events 0.73 (0.67-0.79),p<0.0001 Stroke 0.75 (0.66-0.85), p<0.0001 Revascularisation 0.76 (0.70-0.83), p<0.0001 Any major vascular events 0.76 (0.72-0.81), p<0.0001 In people with diabetes & prior MI: RR for first major vascular event 0.76(0.71-0.82), p<0.0001

Heart Protection Study, 2002b

20,536 19.4% RCT 2x2 factorial design Age 40-80 yrs T-CHO ≥3.5mmol/L Vitamin E 600mg/day Vitamin C 250mg/day β-carotene 20mg/day v placebo

5 yrs All subjects Average lipids levels during follow-up (supplement v placebo; difference) T-CHO: 4.89 v 4.74, 0.15 mmol/L (p=0.024) LDL: 2.82 v 2.74, 0.08 mmol/L(p=0.019) HDL: 1.10 v 1.13, -0.03 mmol/L(p=0.007) TG: 2.13 v 1.92, 0.21 mmol/L(p=0.027)

RRs in mortality: Vascular 1.05 (0.95-1.15), p=NS Non-vascular 1.04 (0.92-1.17), p= NS All-cause 1.04 (0.97-1.12), p= NS RRs in major event Coronary 1.02 (0.94-1.11), p=NS Stroke 0.99 (0.87-1.12), p=NS Revascularisation 0.98 (0.90-1.06), p=NS Any major vascular event 1.00 (0.94-1.06),p=NS In people with diabetes & prior MI: RR for first major vascular event 1.01(0.95-1.08), p=NS


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Main results

Heart Protection Study, 2003

5,963 100% RCT 2x2 factorial design 19% with previous MI 14% with other CHD 18% other vascular disease Age 40-80 yr T-CHO ≥3.5mmol/L simvastatin 40mg/day v placebo

5 yrs Diabetic cohort Simvastatin gp: T-CHO 5.7 LDL 3.2 HDL 1.06 TG 2.3

Diabetic cohort Simvastatin gp: T-CHO 4.6 LDL 2.3 HDL 1.07 TG 2.0

For simvastatin group: Major coronary events: RR 0.73 (0.67-0.79), p<0.0001 Stroke: RR 0.75 (0.66-0.85), p<0.0001Revascularisation: RR 0.76 (0.70-0.83),p<0.0001 Any major vascular event: RR 0.76 (0.72-0.81), p<0.0001 In people with prior CHD: OR 0.89 (0.75-1.05), p=NS In people with other CVD: OR 0.78 (0.60-1.00), p=NS In people without CVD: OR 0.69 (0.55-0.87), p<0.01

Helsinki Heart Study Frick, 1987

4,081 men 2.6%

RCT Age 40-55 yr non-HDL ≥5.2mmol/L Gemfibrozil 1200mg/day v placebo

5 yrs All subjects Gemfibrozil gp: T-CHO 6.99 LDL 4.90 HDL 1.22 TG 1.98

All subjects Gemfibrozil gp: T-CHO 6.39 LDL 4.49 HDL 1.32 TG 1.30

Gemfibrozil v placebo: Cardiac endpoints: 27.3 v 41.4 per 1000, Overall reduction in cardiac endpoints inGemfibrozil gp: 34.0% (8.2-52.6), p<0.02 Nonfatal MI: 21.9 v 35.0 per 1000, 37%reduction, p<0.02 Total mortality: 21.9 v 20.7 per 1000,p=NS No separate results for people with diabetes

Helsinki Heart Study Koskinen, 1992

4,081 men 3.3% known diabetes & FPG ≥7mmol/L

RCT Age 40-55 yr Gemfibrozil 1200mg/day v placebo Lifestyle changes were recommended to both groups.

5 yrs Diabetic cohort Gemfibrozil gp: T-CHO 7.54 LDL 5.18 HDL 1.18 TG 2.42

Diabetic cohort Gemfibrozil gp: T-CHO 6.48 LDL 4.66 HDL 1.26 TG 1.79

Diabetes v without diabetes: MI or cardiac death: 7.4 v 3.3%, p<0.02 Gemfibrizol v placebo in diabetes: CHD events 3.4 v 10.5%, p=NS


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Main results

HERS Hulley, 1998

2,763 women

18.5% RCT Heart and Oestrogen/progestin Replacement Study 17% had a Q-wave MI 45% had PTCA & 41.5% had CABG Age ≥55 yr TG <3.4mmol/L Oestrogen 0.625mg/day + progesterone 2.5mg/day v placebo

4.1 yrs All subjects Estrogen-progestin gp: T-CHO - LDL 3.75 HDL 1.29 TG 1.90

All subjects at 1 year T-CHO - LDL 3.23 HDL 1.40 TG 2.04

Relative hazard (RH) treatment group primary CHD events: 0.99 (0.80-1.22), p=NS CHD death: 1.24 (0.87-1.75), p=NS nonfatal MI: 0.91 (0.71-1.17), p=NS RH at Year 4-5 compared to Year 1 primary CHD events: 0.67 (0.43-1.04), p=0.009 CHD death: 0.95 (0.49-1.84), p=NS nonfatal MI: 0.58 (0.34-1.02), p=0.01 No separate results for people with diabetes

LIPID Study Group, 1998

9,014 9% RCT All had previous MI or unstable angina Age 31-75 yr T-CHO 4.0-7.0mmol/L TG <5.0mmol/L Pravastatin 40mg/day v placebo

6.1 yrs All subjects Pravastatin gp: T-CHO 5.64 LDL 3.88 HDL 0.93 TG 1.60


RRR in pravastatin group Mortality 22% (13-31), p<0.001 Death from CHD 24% (12-35), p<0.001 Death from CVD 25% (13-35), p<0.001 MI 29% (18-38), p<0.001 Any stroke 19% (0-34), p=0.048 In combined coronary endpoint: Diabetes 19% (-10, 41), p= NS Nondiabetes 25% (15-33), p<0.001

LIPID White, 2000

9,014 9% All with a previous MI or unstable angina Age 31-75 yrs T-CHO 4.0-7.0mmol/L RCT Pravastatin 40mg/day v placebo



RRRs in pravastatin group: Stroke from any cause: 19% (0-34), p=0.05 Nonhaemorrhagic stroke: 23% (5-38), p=0.02 Haemorrhagic stroke: 0.2 v 0.4%, p=NS In people with diabetes: overall risk of stroke: 27% (-17, 54), p=NS


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Main results

LIPID Keech, 2003

9,014 8.7% known diabetes 3.3% undiagnosed diabetes 10.4% IFG

RCT All with a previous MI or unstable angina Age 31-75 yr T-CHO 4.0-7.0mmol/L TG <5.0 mmol/L Pravastatin 40mg/day v placebo

6.1 yrs Diabetic cohort: Pravastatin gp: T-CHO 5.56 LDL 3.70 HDL 0.86 TG 1.90 IFG cohort: T-CHO 5.62 LDL 3.80 HDL 0.90 TG 1.72

Diabetic cohort: Pravastatin gp: T-CHO 4.45 LDL 2.66 HDL 0.90 TG 1.54 IFG cohort: T-CHO 4.66 LDL 2.85 HDL 0.95 TG 1.56

RRRs Pravastatin v placebo: in people with diabetes: major CHD event: 24%, p<0.001 any CVD event: 21%, p<0.008 stroke: 39%, p=0.02 in people with IFG: major CHD event: 19%, p=NS any CVD event: 26%, p=0.003 stroke: 42%, p=NS

Post-CABG Trial Hoogwerf, 1999

1,351 8.6% Age 21-74 yr All had CABG No lipid inclusion criteria RCT 2×2 factorial design • aggressive v moderate lipid

lowering with lovastatin aggressive: to achieve LDL 1.55-2.20 moderate: to achieve LDL 3.36-3.62 • warfarin v placebo

4 yrs Diabetic cohort T-CHO 5.82 LDL 3.93 HDL 0.93 TG 2.09

Diabetic cohort Aggressive treatment LDL 2.49 Moderate treatment LDL 3.49

Aggressive v moderate treatment RRs in people with diabetes: Combined endpoint: 0.53 (0.18-1.60) Death: 0.67 (0.12-3.75) MI: 0.40 (0.07-2.47) CABG: 1.14 (0.16-8.19) PTCA: 0.61 (0.09-4.39)

Post-CABG Trial Knatterud, 2000

1,351 8.6% Mean age 60.9 yr All had previous CABG LDL 3.4-3.6mmol/L TG≤3.4 mmol/L RCT 2×2 factorial design • aggressive v moderate lipid-

lowering with lovastatin (40-80 mg/d v 2.5-5 mg/d)

aggressive: to achieve LDL 1.6-2.2 moderate: to achieve LDL 3.4-3.6 • warfarin v placebo

7.5 yrs All subjects: T-CHO 5.83 LDL 4.01 HDL 1.01 TG 1.79

All subjects: Aggressive treatment LDL 2.41 Moderate treatment LDL 3.49

Aggressive v moderate treatment CVD death or nonfatal MI: 15.1 v 20.3%, p=0.03 Composite clinical endpoint: 30.6 v 40.2%, p=0.001


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Main results

PPP The Prospective Pravastatin Pooling Project Byington, 2001

19,768 7.3% Data from CARE, LIPID, & WOSCOPS Mean age 58 yr Pravachol 40mg/day v placebo

≈5 yrs All subjects Pravastatin gp T-CHO 5.83 LDL 4.01 HDL 1.01 TG 1.79

All subjects Pravastatin gp T-CHO no data LDL no data HDL no data TG no data

HRs Pravastatin v placebo: across all 3 trials Total stroke: 0.80 (0.68-0.93), p=0.01 Nonfatal stroke: 0.76 (0.64-0.90) CARE & LIPID: Total stroke: 0.78 (0.65-0.93), p=0.01 Nonfatal stroke: 0.75 (0.62-0.90) In people with diabetes Total stroke: HR approximately 0.74 (not significant)

PROSPER Shepherd, 2002

5,804 10.7% RCT Aged 70-82 yr with previous vascular disease (CHD, cerebrovascular disease, or PVD) T-CHO 4.0-9.0mmol/L TG <6.0mmol/L Pravastatin 40mg/day v placebo

3.2 yrs All subjects T-CHO 5.7 LDL 3.8 HDL 1.30 TG 1.5

All subjects T-CHO - LDL 2.5 HDL 1.37 TG 1.3

HRs Pravastatin v placebo: Primary endpoints: 0.85 (0.74-0.97), p=0.014 CHD death or nonfatal MI: 0.81 (0.69-0.94), p=0.006 Nonfatal MI: 0.86 (0.72-1.03), p=NS CHD death: 0.76 (0.58-0.99), p=0.043 Fatal or nonfatal stroke: 1.03 (0.81-1.31), p=NS TIA: 0.75 (0.55-1.00), p=0.051 Primary endpoint: 0.78 (0.66-0.93) for CVD+; 0.94 (0.77-1.15) for CVD- In people with diabetes: Primary endpoint: 1.27 (0.90-1.80), p=NS


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Main results

Scandinavian Simvastatin Survival Study (4S), 1994

4,444 4.8% RCT All with angina or previous MI Age 35-70 yr T-CHO 5.5-8.0mmol/L TG <2.5mmol/L Simvastatin 20-40mg/day v placebo

5.4 yrs All subjects Simvastatin T-CHO 6.74 LDL 4.87 HDL 1.19 TG 1.49

All subjects Simvastatin T-CHO 5.06 LDL 3.17 HDL 1.29 TG 1.34

RRs in simvastatin-treated group mortality 0.70 (0.58-0.85), p=0.0003 all coronary deaths 0.58 (0.46-0.73), no p value all cardiovascular deaths 0.65 (0.52-0.80), no p value major coronary events 0.66 (0.59-0.75), p<0.00001 any coronary events 0.73 (0.67-0.81), p<0.00001 37% reduction (p<0.00001) in risk of needing myocardial revascularisation. No separate data for people with diabetes

Scandinavian Simvastatin Survival Study (4S) Pyorala, 1997

4,444 4.8% RCT Type 2 diabetes (n=202) & nondiabetic (n=4,242) Age 35-70 yr T-CHO 5.5-8.0mmol/L TG <2.5mmol/L Simvastatin 20-40mg/day v placebo

5.4 yrs Simvastatin-treated diabetic cohort T-CHO 6.72 LDL 4.80 HDL 1.13 TG 1.69

Simvastatin-treated diabetic cohort T-CHO 4.90 LDL 3.10 HDL 1.21 TG 1.54

RR in simvastatin-treated diabetic cohort: Total mortality 0.57, p=0.087 CHD mortality 0.64, p=0.24 Major CHD events (CHD death or nonfatalMI) 0.45, p=0.002 any CHD events 0.61, p=0.015 any atherosclerotic events 0.63, p=0.018

Scandinavian Simvastatin Survival Study (4S) Haffner, 1999

4,398 11% diabetes -4.6% known diabetes (202) -6.4% newly diagnosed (281) 15.4% IFG

RCT All with angina pectoris or previous MI Age 35-70 yr T-CHO 5.5-8.0mmol/L TG <2.5mmol/L Simvastatin 20-40mg/day v placebo

5.4 yrs Diabetic cohort Simvastatin gp: T-CHO 6.74 LDL 4.86 HDL 1.13 TG 1.65

Diabetic cohort Reductions similar to Pyorala study

RRs in simvastatin-treated diabeticcohort: major coronary events 0.58, p=0.001 total mortality 0.79, p=NS coronary mortality 0.72, p=NS revascularizations 0.52, p=0.005 RRs in IFG subjects: major coronary events 0.62, p=0.003 total mortality 0.57, p=0.02 coronary mortality 0.45, p=0.007 revascularizations 0.57, p=0.009


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Main results

SCAT Simvastatin/Enalapril Coronary Atherosclerosis Trial Teo, 2000

460 11% RCT, 2×2 factorial design Mean age 61 yr 54% had an angina 70% had a previous MI T-CHO 4.1-6.2mmol/L HDL <2.2mmol/L TG <4.0mmol/L Simvastatin 10mg/day v placebo Enalapril 5mg/day v placebo

47.8 months



Simvastatin v placebo: reduction in mean diameter: -0.07±0.20 v -0.14±0.20 mm, p=0.004 reduction in minimum diameter: -0.09±0.17 v -0.16±0.20 mm, p=0.0001 increase in % diameter stenosis: 1.67 v 3.83%, p=0.0003 In people with diabetes, the above three measurements were significant for simvastatin v placebo, with p=0.031; p=0.025; and p=0.02, respectively for clinical events: cardiac death: 3 v 2%, p=NS MI: 5 v 4%, p=NS stroke: 2 v 3%, p=NS combined endpoints: 11 v 9%, p=NS any revascularisation: 6 v 12%, p=0.021

SENDCAPS Elkeles, 1998

164 100% RCT Age 35-65 yr At least one of the following: T-CHO ≥5.2mmol/L or T-CHO/HDL ≥4.7 or TG ≥1.8mmol/L or HDL ≤1.1mmol/L Bezafibrate 400mg/day v placebo

3 yrs All had diabetes Bezafibrate gp: T-CHO 5.77 LDL 3.66 HDL 1.02 TG 2.24

All had diabetes Bezafibrate gp: T-CHO 5.29 LDL 3.31 HDL 1.04 TG 1.44

Bezafibrate v placebo: confirmed MI: 1.5 v 4.0%, p=NS probable ischaemia: 6.5 v 19.5%, p=0.03 definite CHD events: 7.4 v 22.6%, p=0.01

TIMI Thrombolysis in Myocardial Infarction Study Cannon, 2004

4,162 18% RCT 2x2 factorial desig n Mean age 58 yr 50.2% had hypertension 18.5% had a prior MI T-CHO ≤6.21mmol/L Pravastatin 40 mg/d Atorvastatin 80 mg/d

24 months All subjects Pravastatin gp: T-CHO 4.66 LDL 2.75 HDL 1.01 TG 1.74 Atorvastatin gp: T-CHO 4.69 LDL 2.75 HDL 0.98 TG 1.79

All subjects Pravastatin gp: T-CHO no data LDL 2.46 HDL 1.09 TG no data Atorvastatin gp: T-CHO no data LDL 1.60 HDL 1.04 TG no data

Atorvastatin v pravastatin: combined primary endpoint: ↓16% (5-26), p=0.005 need for revascularisation: ↓14%, p=0.04 recurrent unstable angina: ↓29%, p=0.02 in people with diabetes: the 2-yr event rate: 28.8 v 34.6%, no p value reported


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Main results

VA-HIT Rubins, 1999

2,531 25% RCT All with CHD Mean age 64 yr LDL ≤3.6mmol/L HDL ≤1.0mmol/L TG ≤3.4mmol/L Gemfibrozil 1200mg/day v placebo

5.1 yrs All subjects Gemfibrizol gp: T-CHO 4.5 LDL 2.9 HDL 0.82 TG 1.8

All subjects Gemfibrozil gp: T-CHO 4.4 LDL 2.9 HDL 0.89 TG 1.3

RRRs Gemfibrozil v placebo: Primary event: 22% (7-35), p=0.006 Combined outcome (death from CHD, nonfatal MI & stroke: 24% (11-36), p<0.001 Nonfatal MI: 23% (4-38), p=0.02 Death from CHD: 22% (-2, 41), p=NS Death from any cause: 11% (-8, 27), p=NS Confirmed stroke: 25% (-6, 47), p=NS In people with diabetes: Combined outcome: 24% (-0.1, 43), p=0.05

VA-HIT Rubins, 2002

2,531 24.8% known DM 5.6% undiagnosed DM 12.8% IFG

RCT All with CHD Mean age 64 yr LDL ≤3.6 mmol/L HDL ≤1.0 mmol/L TG ≤3.4 mmol/L Gemfibrozil 1200 mg/day v placebo

5.1 yrs Diabetic cohort Gemfibrizol gp: T-CHO 4.45 LDL 2.81 HDL 0.80 TG 1.88

Diabetic cohort Gemfibrizol gp: T-CHO no data LDL 2.81 HDL 0.84 TG 1.54

HRs Gemfibrozil v placebo in diabetic cohort: Composite endpoint: 0.68 (0.53-0.88), p=0.004 CHD death: 0.59 (0.39-0.91), p=0.02 Stroke: 0.60 (0.37-0.99), p=0.046

WOSCOPS Shepherd, 1995

6,595 1.15%

RCT Age 45-64 yr T-CHO ≥6.5mmol/L LDL ≥4.0mmol/L Pravastatin 40mg/day v placebo



RRRs Pravastatin v placebo: Coronary events 31% (17-43), p<0.001 Nonfatal MI 31% (15-45), p<0.001 Death from CHD 28% (-10, 52), p=NS Death from all cardiovascular causes 32% (3-53), p=0.033 Total mortality 22% (0-40), p=0.051 No data for people with diabetes


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Statins can prevent coronary heart disease in people with impaired fasting glucose (IFG) Impaired Fasting Glucose (IFG) is a relatively new category of glucose intolerance where FPG is ≥6.1mmol/L but <7.0mmol/L (The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 1997). The glucose level of 6.1mmol/L was chosen because above this level the first phase insulin secretory response to intravenous glucose is lost and there is increased risk of microvascular and macrovascular complications. This category is in addition to Impaired Glucose Tolerance (IGT) as defined by the oral glucose tolerance test and the correlation between these two groups of abnormal glucose metabolism short of diabetes is imperfect (Gomez-Perez et al, 1998). The new category of IFG identifies a population with impaired glucose metabolism at increased CHD risk (Goldberg, 1998). Data from the 4S, CARE and LIPID studies show increased risk of CHD event occurrence in this category (Haffner et al, 1999, Goldberg et al, 1998, Keech et al, 2003). A post hoc analysis of data from 4S on CHD risk in 678 people with IFG at study entry has been performed (Haffner et al, 1999). The relative reduction in risk for major coronary events with simvastatin treatment in this group was 38% (p<0.003) compared with 32% reduction (p<0.001) in the 1631 people with normal fasting glucose (≤6.0mmol/L). Because the relative risk of major coronary events for the IFG group was 1.15 (based on the placebo group data), the potential benefit from treatment is greater for the IFG group. A similar outcome was observed in people with IFG treated with pravastatin in the CARE study (Goldberg et al, 1998). In the 3,553 people who did not have diabetes, 342 had IFG. The reduction of nonfatal myocardial infarction and CHD death in this group was 23% compared with a 28% reduction in the 3,104 subjects with normal fasting glucose (p=NS). Again, the relative risk for CHD events was greater in the IFG group at 1.41, indicating potentially greater benefit from treatment in this group. In the LIPID study, people with IFG had a 23% higher risk of a major CHD event than people with normal fasting glucose (Keech et al, 2003). In this group pravastatin reduced the risk of CHD death or nonfatal myocardial infarction by 36% from an absolute risk of 17.8 to 11.8% (p<0.009). There has not been any analysis of subjects with IFG to indicate a benefit from treatment with statins for primary prevention or with fibrates for either primary or secondary prevention. Similarly there have been no published data on the use of statins to prevent coronary heart disease in people with IGT. Statins can prevent stroke in people with Type 2 diabetes Blauw et al (1997) performed a meta-analysis to evaluate the effect of statins including simvastatin, pravastatin and lovastatin in preventing stroke. Thirteen randomised controlled trials of statins which had reported data of cerebrovascular accidents were identified. A total of 20,438 subjects aged 55-68 years were included in this analysis, with 0.1 to 15% of individual study populations having diabetes in 10 trials. During a mean of 2.8 years follow-up, 181 strokes were observed in people randomised to treatment with statins and 261 strokes in people randomised to placebo. The overall risk reduction of 31% (OR 0.69, CI 0.57-0.83) was significant (p<0.001). No separate analysis was performed for people with diabetes. A meta-analysis by Law et al (2003) showed lowering LDL cholesterol reduced the risk of stroke. Results from 58 randomised controlled trials of cholesterol lowering by fibrates,

146

statin, niacin, or resins showed that stroke risk was reduced by 20% (CI 14-26) (p<0.001), mainly due to a 28% reduction (CI 20-35) (p<0.001) in thromboembolic stroke, while haemorrhagic stroke was only reduced by 3% (CI -35, 47). Moreover, the reduction was more apparent in people with known vascular disease at study entry (22% reduction [CI 16-28]; p<0.001) than in people without known vascular disease (6% reduction [CI -22 to 14]). Overall, a 1mmol/L reduction in LDL cholesterol level decreased all stroke by 10% and a 1.8mmol/L reduction decreased all stroke by 17%. Of 20,356 participants in the Heart Protection Study (HPS Collaborative Group, 2004), 3,280 had pre-existing cerebrovascular disease. Over the 5-year treatment period, simvastatin resulted in a 25% reduction in the incidence rate of first nonfatal or fatal stroke (4.3% in simvastatin group v 5.7% in placebo group, RR 0.75 [CI 0.66-0.85], p<0.0001), mainly due to a 30% reduction in ischaemic stroke (2.8% v 4.0%, RR 0.70 [CI 0.60-0.81], p<0.0001) with no apparent effect on haemorrhagic stroke (0.5% v 0.5%, RR 0.95 [CI 0.65-1.40], p=0.8). Among people with preexisting cerebrovascular disease there was no reduction in the stroke rate (RR 0.95 [CI 0.65-1.40], p=0.8). In contrast, a significant 34% reduction was observed among those without previous cerebrovascular disease (RR 0.66 [CI 0.57-0.76], p<0.0001). In the diabetic subgroup (n=5,963), the incidence of first stroke was 5.0% in people treated with simvastatin compared with 6.5% in people treated with placebo (RR 0.76 [CI 0.61-0.93], p=0.01). The 24% risk reduction (CI 6-39) was similar to a 26% reduction (CI 14-36) in people without diabetes (4.0% v 5.4%, RR 0.74 [CI 0.64-0.86], p=0.0002). White et al (2000) reported that treatment with pravastatin 40mg/day reduced the risk of stroke from any cause by 19% (CI 0-34%, p=0.05) and the risk of nonhaemorrhagic stroke by 23% (CI 5-38%, p=0.02) among participants in the LIPID Study. There was no difference in haemorrhagic stroke between people treated with pravastatin and placebo (0.2 v 0.4%, p=NS). In people with diabetes the risk of stroke was reduced from 9.9 to 6.3% (relative risk reduction 39%, CI 7-61%, p=0.02) (Keech et al 2003). Byington et al (2001) performed a combined analysis of data from the WOSCOPS, CARE and LIPID studies in which 19,768 people including 7.3% with diabetes (mean age 58 years), were randomly assigned to pravastatin 40mg/day or placebo. Overall 598 people had a stroke during 5 years of follow-up. The beneficial effect of pravastatin on total stroke and nonfatal stroke was observed across all 3 trials, with a 20% (HR 0.80, CI 0.68-0.93; p=0.01) and a 24% redution (HR 0.76, CI 0.64-0.90), respectively. When the 2 secondary prevention trials (CARE, LIPID) were combined, there was a 22% reduction in total stroke (HR 0.78, CI 0.65-0.93; p=0.001) and a 25% reduction in nonfatal stroke (HR 0.75, CI 0.62-0.90). The risk reduction was similar in people with diabetes (HR approximately 0.74 extrapolated from Figure 3) but this was not significant. Fibrates may prevent coronary heart disease in people with Type 2 diabetes The main medications used for lowering triglycerides and increasing HDL cholesterol are fibric acid derivatives or fibrates and placebo-controlled studies have provided some evidence of benefit. Secondary Prevention The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) (Rubins et al, 1999) studied 2,531 men with established CHD, HDL cholesterol ≤1.0mmol/L and LDL cholesterol ≤3.6mmol/L. The mean LDL cholesterol level was 2.9mmol/L and mean triglycerides 1.8mmol/L. People randomised to treatment with gemfibrozil 600mg twice daily had a 31% reduction in triglycerides (1.3mmol/L v 1.9mmol/L, p<0.001), a 6% increase in HDL cholesterol (0.9mmol/L v 0.8mmol/L, p<0.001), but no change in LDL cholesterol at one year (2.9mmol/L for both groups) compared with those on placebo. After follow up for a median of 5.1 years, the group assigned to gemfibrozil (71% in each treatment group were still taking their assigned medication) had shown a 22% decrease in the primary endpoint of

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nonfatal myocardial infarction or CHD death (p<0.006). Gemfibrozil treatment was also associated with a 25% reduction in the risk of stroke (p=0.10). Rubins et al (2002) conducted a subgroup analysis of people with diabetes from the VA-HIT study and showed that people with known diabetes (n=627) and people with newly diagnosed diabetes (n=142) had a significantly higher risk of CVD (known diabetes HR 1.87 [CI 1.44-2.43], p=0.001; new diabetes HR 1.72 [CI 1.10-2.68], p=0.02) compared with people with normal fasting glucose. People with diabetes benefited more from treatment with gemfibrozil than those without diabetes, with a 32% reduction in composite clinical endpoint (HR 0.68 [CI 0.53-0.88], p=0.004) compared with an 18% reduction (HR 0.82 [CI 0.67-1.02], p=0.07) in people without diabetes. There was also a 41% reduction in CHD death (HR 0.59 [CI 0.39-0.91], p=0.02) and a 40% reduction in the risk of stroke (HR 0.60 [CI 0.37-0.99], p=0.046) in the diabetic population. A multivariable analysis of the entire VA-HIT cohort by Robins et al (2001) showed concentrations of HDL cholesterol were inversely related to CHD events. Of the 3 major lipids (HDL cholesterol, LDL cholesterol and triglycerides) measured at baseline and during treatment, only the increase in HDL cholesterol predicted a lower risk of CHD events. With every 0.13 mmol/L increase in HDL cholesterol the risk of a CHD events was reduced by 11% (RR 0.89, CI 0.81-0.98, p=0.02). Neither triglycerides nor LDL cholesterol levels predicted CHD events. Conducted in Canada, Finland, France and Sweden, the Diabetes Atherosclerosis Intervention Study (DAIS) randomised 418 people with diabetes (27% women), aged 40 to 65 years, to treatment with fenofibrate 200mg daily or placebo for an average of 4 years (DAIS, 2001). At baseline, mean HbA1c was 7.5%, LDL cholesterol was 3.43mmol/L, HDL cholesterol was 1.03mmol/L, triglycerides were 2.42mmol/L and 48% had prior clinical evidence of CHD. There was a significant improvement in total, LDL and HDL cholesterol and triglycerides (p for all < 0.001) in those treated with fenofibrate compared with placebo. Primarily an angiographic study, the DAIS results showed that compared with placebo, fenofibrate treatment was associated with 40% less progression in MLD [(mean (standard error) (-0.06 (0.016) v -0.10 (0.016), p=0.029)], 42% less progression in percentage diameter stenosis (2.11 (0.594) v 3.65 (0.608)%, p=0.02). There was also a 23% reduction in combined clinical endpoints, however this was not significant. The Bezafibrate Infarction Prevention (BIP) study randomised 3,090 people with established CHD, HDL cholesterol ≤1.17mmol/L, triglycerides ≤3.3mmol/L and LDL cholesterol ≤4.7 mmol/L to bezafibrate 400mg daily or placebo (BIP Study, 2000). On treatment, HDL cholesterol increased by 18% and triglycerides decreased by 21%. After a mean period of 6.2 years (76% were still taking study medication) there was a non significant 7.3% (p=0.26) reduction in the primary endpoint of nonfatal myocardial infarction or CHD death. However, in a post hoc analysis of the subgroup with triglycerides ≥2.2mmol/L, the reduction in the primary endpoint was 39% (p<0.02). In the BIP study 309 subjects (10% of the total cohort) had diabetes, but a separate analysis of the diabetic subgroup has not yet been reported. Primary Prevention The largest study using fibric acid derivatives to date is the Helsinki Heart Study (Frick et al, 1987). This double blind, primary prevention study randomised 4,081 asymptomatic men aged 40 to 55 years, with non-HDL cholesterol level ≥5.2mmol/L, to treatment with gemfibrozil 600mg twice daily or placebo. Despite a total dropout rate of 30% over the 5 year follow–up period, there was a reduction of 34% (p<0.02) in the principal endpoints of nonfatal myocardial infarction and cardiac death in the group assigned to active treatment.

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Although there was a 26% lower mortality from CHD in the group on gemfibrozil, there were slightly more deaths overall in the gemfibrozil than the placebo group (45 v 42). A post hoc analysis of the Helsinki Heart Study (Manninen et al, 1989) showed that the reduction of CHD from gemfibrozil treatment was greatest in subjects with HDL cholesterol in the lower tertile (<1.08mmol/L) or triglycerides in the upper tertile (>2.08mmol/L). The 34% reduction of CHD was greater than expected from the 10% reduction of total cholesterol and in the subgroup of 1,131 people with LDL cholesterol ≥4.5mmol/L and triglycerides >2.0mmol/L there was a 43% reduction in CHD events (p<0.02) with only a 7.5% reduction in LDL cholesterol level for gemfibrozil compared with placebo treatment. Some of the benefit from gemfibrozil treatment was attributed to the 15% increase of HDL cholesterol and 38% reduction of triglycerides compared with placebo. The Helsinki Heart Study included 135 people with diabetes who had lower HDL cholesterol (1.18 v 1.26mmol/L; p<0.001) and higher triglycerides (2.69 v 2.05mmol/L; p<0001) compared with non-diabetic subjects (Koskinen et al, 1992). Gemfibrozil treatment compared with placebo was associated with a non significant 67% reduction of nonfatal myocardial infarction and CHD death (p=0.19). The St Mary’s, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) study was a primary prevention, double blind study which examined the effect of bezafibrate 400mg daily on cardiovascular outcome in 164 people with Type 2 diabetes (Elkeles et al, 1998), with follow up for 3 to 5 years. Inclusion criteria were one of - cholesterol ≥5.2mmol/L, triglycerides ≥1.8mmol/L, HDL cholesterol ≤1.1mmol/L or total to HDL cholesterol ratio ≥4.7. Median LDL cholesterol was 3.82mmol/L, median HDL cholesterol 0.98mmol/L and median triglycerides 2.17mmol/L. Over 3 years, bezafibrate treatment compared with placebo was associated with a 37% reduction of triglycerides (p=0.001), 8% increase of HDL cholesterol (p=0.02) and 10% reduction of LDL cholesterol (p=NS). Bezafibrate treatment had no effect on progression of carotid or femoral arterial disease measured by ultrasound, but there was a 67% reduction (p=0.01) in the incidence of definite CHD events, defined as documented myocardial infarction or ECG change of probable ischaemia on Minnesota coding. Studies of fibrates currently in progress in Type 2 diabetes The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study has recruited over 8,000 people with Type 2 diabetes aged 50 to 75 years in Australia, New Zealand and Finland. Entry criteria are total cholesterol between 3.0 and 6.5mmol/L, and either triglycerides >1.0mmol/L or total cholesterol to HDL cholesterol ratio ≥4.0. Randomised to treatment with fenofibrate 200mg or placebo, participants will be followed for at least 5 years, with the primary endpoint being CHD mortality. Although mainly a primary prevention study, about 20% of subjects have evidence of pre-existing CVD. The study will conclude in 2005. There are no data on the effect of ϖ-3 polyunsaturated fatty acids (fish oil) and the risk of cardiovascular disease specifically in people with Type 2 diabetes The ϖ-3 polyunsaturated fatty acids of fish oil have anti-atherogenic, anti-thrombotic and anti-arrhythmic effects (Simopoulos, 1997). A benefit for dietary supplementation with fish and/or fish oil capsules in survivors of a myocardial infarct has been found in two studies (Burr et al, 1989; GISSI, 1999). The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione trial was a randomised, open-label, secondary prevention trial with 11,324 people. They were assigned in a 2x2 factorial design to treatment with 850-882mg eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), 300mg

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vitamin E, both, or neither within three months of myocardial infarction (GISSI, 1999). After six months there was a small reduction of triglycerides in the group on fish oil (3.4%) and the group on fish oil and vitamin E (0.9%), compared with those not on fish oil, but no difference in other lipid parameters. Four way analysis of the primary endpoint of non-fatal myocardial infarction, CHD death and non-fatal stroke after follow up for 42 months showed reduction by 20% on fish oil (p<0.008), compared with 12% on vitamin E (p=NS). At the end of the study 28.5% of people on fish oil and 26.2% on vitamin E had permanently discontinued the medication. Of the total cohort 10,683 subjects (14.8%) were classified as having diabetes, but there has not been a separate analysis of this group. Evidence for benefit in diabetic subjects is therefore indirect and based on one secondary prevention study at this stage. Burr et al (1989) randomised 2,033 men who were recovering from a myocardial infarction to receive or not to receive advice on reducing fat in the diet, increasing fish intake and increasing the ratio of polyunsaturated fat to saturated fat in the diet. In the Diet and Reinfarction Trial (DART) those who were given the dietary advice to increase fish intake had a 29% (CI 0.54-0.92, p<0.05) reduction in 2 year all cause mortality compared to those who were not given the advice. There is no evidence that hormone replacement therapy reduces the risk of coronary heart disease in postmenopausal women with Type 2 diabetes Observational studies in postmenopausal women without diabetes show that use of hormone replacement therapy (HRT) is associated with a 50% reduction in the risk of coronary artery disease (Stampfer et al, 1991). Several mechanisms have been proposed for this potential cardioprotective effect of HRT including improved lipid profiles, improved vasodilatory properties, improved insulin sensitivity and effects on clotting factors (Sattar et al, 1996). However, clinical trial data do not support these observational data. The Heart and Estrogen/progestin Replacement Study (HERS) was a randomised, double blinded, placebo-controlled trial in which 2,763 women with coronary disease aged less than 80 years were treated with 0.625mg conjugated equine oestrogen plus 2.5mg medroxyprogesterone acetate or placebo for an average of 4.1 years. HRT was not associated with a reduction in primary CHD event (MI or CHD death), with a relative hazard (RH) of 0.99 (CI 0.80-1.22, p=0.91) despite a net 11% lower LDL cholesterol level (p<0.001) and a 10% higher HDL cholesterol level (p<0.001) compared with placebo. More women in the HRT group than in the placebo group experienced venous thromboembolic events (34 v 12, RH 2.89 [CI 1.50-5.58], p=0.002), and the RH remained elevated over a 4-year period in the HRT group (Hulley et al, 1998). In the HERS trial 19% of subjects had diabetes treated with oral medication or insulin, but there has not been a separate analysis of the diabetic group. The Women’s Health Initiative study (Manson et al, 2003) also found that combined hormone therapy did not have cardiac protective effect. Of 16,608 postmenopausal women aged 50-79years including 2.4% with previous CHD (number with diabetes not specified), 8,506 were randomly assigned to conjugated equine estrogen 0.625mg/day plus medroxyprogesterone acetate 2.5mg/day and 8,102 to placebo. The 2 groups were comparable at baseline except that more women in the placebo group had a history of coronary revascularisation (1.5 v 1.1%, p=0.04). At one year, women in the hormone group had lower levels of total and LDL cholesterol (-5.4%, -12.7%, respectively), and higher levels of HDL cholesterol (+7.3%) and triglycerides (+6.9%) than women in the placebo group (all p<0.05). However, after a mean follow-up of 5.2 years, combined hormone therapy was associated with increased risk for CHD (adjusted HR 1.24 [0.97-1.60]), nonfatal MI (adjusted HR 1.28 [0.97-1.70]), and death due to CHD (adjusted HR 1.10 [0.65-1.89]). The absolute rates of CHD were 39 cases per 10,000 person-year in the hormone group compared to 33

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cases per 10,000 person-year in the placebo group. Among women with diabetes, the risk of CHD was 45% higher in the hormone group (adjusted HR 1.45 [0.84-2.49]). The absolute rates of CHD were 124 and 112 cases per 10,000 person-year, respectively. The authors concluded that hormone therapy should not be prescribed for the prevention of cardiovascular disease. A similar lack of beneficial effects was reported in a case-control study of women with treated diabetes who had had a MI (n=212) compared with controls without prior MI (n=122). Relative to never users of oestrogen, the risk of MI was lower for current oestrogen users (RR 0.51 [CI 0.22-1.15]) and the risk of MI tended to decline with each additional year of use (RR 0.78 [CI 0.56-1.08]), but these differences were not significant (Kaplan et al, 1998). Lipid modifying therapy in Type 2 diabetes is considered to be cost effective Analyses of the long-term costs and benefits of treatment for lipid abnormalities in people with diabetes have generally assessed the role of statin therapy as most of the major cardiovascular outcome trials have used statins. Based on the results of the 4S trial, which was a secondary prevention study of simvastatin therapy, savings from reduced hospitalisation of the diabetic group offset 67 to 76% of the drug cost (Jonsson et al, 1999). Using 1995-1997 Swedish costs, each life-year gained was estimated to cost from 1,600 Euros (based on clinical history of diabetes) to 3,200 Euros (based on a fasting glucose ≥7.0 mmol/L). Cholesterol reduction in people with diabetes and pre-existing CHD remained highly cost-effective when analyses were based on drug and hospitalisation costs in 10 other European countries. Cost-effectiveness of secondary prevention therapy in people with diabetes has also been analysed based on US costs, using a model of risk from the Lipid Research Clinics Program Prevalence and Follow-up Cohort, validated by comparison with data from 4S (Grover et al, 2000). Costs per year of life saved were estimated in 1996 US dollars for men and women as 4,000 with pretreatment LDL cholesterol of 5.46mmol/L to 8,000 with pretreatment LDL cholesterol of 3.85mmol/L. Estimates of the cost-effectiveness of primary prevention therapy were also made based on the Lipid Research Clinics model (Grover et al, 2000). For men with pretreatment LDL cholesterol of 5.46mmol/L, costs in 1996 US dollars per year of life saved range from 4,000 for 60 year olds to 10,000 for 70 year olds; for women the range was about 9,000 to 15,000. At the lower LDL cholesterol level of 3.85mmol/L, the cost per year of life saved ranged from $7,000 to $15,000 for men and from $24,000 and $40,000 for women. The same group has extended their analysis to compare cost-effectiveness in Canada, France, Germany, Italy, Spain and the UK (Grover et al, 2001). Regardless of the health care costs in these countries, the cost-effectiveness of simvastatin in people with diabetes without CHD was similar to that in people with CHD, but without diabetes. The WOSCOPS trial was a primary prevention study of pravastatin treatment in men with mean total cholesterol 7.0mmol/L. An economic benefit analysis based on results of the WOSCOPS trial indicated that for the 40% of men at highest risk, which is likely to include all those with Type 2 diabetes, the cost per year of life gained was £5,601 based on 1996 costs. If the survival curves are discounted at 6% per year as recommended by the Treasury, the cost per year of life gained rises to £13,995 (Caro et al, 1997). Brandle et al (2003) performed an analysis to assess the cost and cost effectiveness of statin therapy for primary prevention of major coronary events in people with diabetes in the U.S, especially in the population with LDL cholesterol level of 2.6-3.3 mmol/L. Cost was estimated from a health system perspective and treatment effectiveness from the diabetic subgroup of the HPS and UKPDS. Based on data from the NHANES III, it is estimated that

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3.0 million people with diabetes and without CHD have an LDL cholesterol of 2.6-3.3 mmol/L and 5.9 million with an LDL cholesterol of >3.3 mmol/L. Treatment of LDL cholesterol of 2.6-3.3 mmol/L to achieve LDL cholesterol <2.6 mmol/L cost $US600 to $US1,000 per person per year depending on the statin prescribed, while the annual cost in people with LDL cholesterol >3.3 mmol/L ranges from $US700 to $US2,100. It was estimated that statin therapy could prevent approximately 71,000 major coronary events per year in people with diabetes and LDL cholesterol level ≥2.6 mmol/L. Annual incremental cost per person, defined as the cost of statin treatment plus the cost of major coronary events treated with statin minus the cost of major coronary events without statin treatment, ranged from $US480 to $US950 in the subgroup with LDL cholesterol between 2.6 and 3.3 mmol/L and from $US590 to $US1,920 in the subgroup with LDL cholesterol >3.3 mmol/L, respectively. Glasziou et al (2002) evaluated the cost-effectiveness of pravastatin in the LIPID trial in which people had a history of unstable angina or previous myocardial infarction and with an average cholesterol level were randomised to take pravastatin 40mg daily or matching placebo. During a mean follow-up of 6 years, the all-cause mortality was 11.0% in the pravastatin group compared with 14.1% in the placebo group, and this represented a relative reduction of 22% (p<0.001). Hospital admissions for coronary heart disease and coronary revascularisation were reduced by 20%. During this period, the cost of pravastatin was $A4,913 per person but reduced total hospitalisation costs by $A1,385 and costs of other long term medications by $A360 per person. The incremental cost of pravastatin treatment was $A3,246 per person. The cost per death prevented within the study period was $A107,730. Extrapolating long-term survival from the placebo group, the discounted cost per life year saved was $A19,938. These results are considered cost effective for accepted treatments in high income countries. Modelling has been used to assess the cost-effectiveness of pravastatin for reduction in serum cholesterol level in people with Type 2 diabetes and a high total cholesterol level of ≥5.2 mmol/L (The CDC Diabetes Cost-effectiveness Group, 2002). The risk reduction of 31% was achieved with pravastatin in people without a history of CHD and of 25% in people with CHD. While reduction in serum cholesterol level directly lowered the cumulative incidence of CHD complications, the increase in life expectancy led to an increase in diabetic complications cost, and this outweighed cost reductions from CHD. The incremental total cost was $US18,033. The cost-effectiveness ratio for reduction in serum cholesterol level was $US51,889 per QALY, and decreased gradually with age, with the lowest cost-effectiveness ratios for people aged 45-84 years as the risk of CHD increased. There is very little current information on the cost-effectiveness of lipid modifying therapy with fibrates in Type 2 diabetes, although data for secondary prevention with gemfibrozil could be derived from the results of the VAHIT study, which included a high proportion of men with diabetes. One analysis involving fibrate therapy developed a clinical outcomes model based on 6 statistically significant CVD risk factors from the Framingham study (Haffner & Ashraf 2000). Changes of these risk factors in response to treatment with 2 fibrates and 6 statins were used to predict the anticipated reduction of CHD in people with Type 2 diabetes. Cost comparison analysis found that fenofibrate was equivalent to simvastatin and atorvastatin in its potential to reduce the medical expenses of treating cardiovascular events and that these 3 agents were potentially more cost-effective than the other fibrate and statins that were evaluated. The primary target in people with Type 2 diabetes is an LDL cholesterol of 2.5mmol/L There is a lack of consensus to support the routine use of statins in all people with Type 2 diabetes for the primary prevention of a vascular event. As reviewed in the Background to this Section, the various international and national guidelines advocate different approaches to controlling blood lipids in people with diabetes. No guideline supports the routine use of

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lipid lowering agents in all people with diabetes but rather their use is based on above target lipid levels or if calculated risk of a future vascular event is increased above a certain threshold. A consideration in this regard is the issue of the co-occurrence and management of more than one cardiovascular risk factor when the benefits of simultaneous treatment of risk factors is uncertain. This is highlighted by 2 recent studies which have failed to show a clear benefit in people with diabetes being well treated with antihypertensive therapy when statins are added (ALLHAT-LLT, 2002b; Sever et al, 2003). Most of the beneficial effects of lipid modifying therapy are explained by the changes in lipid levels achieved during the study. Total and LDL cholesterol lowering have been the most studied lipid levels and most of the study findings, especially with statins, have equated outcomes and LDL cholesterol lowering. None of the many lipid modifying studies has specifically addressed the question of optimal goals for lipids. Most of the data which can be used to address this question come from studies using lipid lowering medication. Most lipid lowering therapy studies have used a fixed dose of a medication (mostly a statin) although a few have compared the effects of attaining different lipid targets. Setting a specific lipid target is supported by data which indicate that although statins are known to have effects on improving endothelial dysfunction, plaque stabilisation, inhibiting inflammatory processes, antithrombotic effects and reducing smooth muscle proliferation, most studies show that most of the effect of statins is due to their lipid lowering effects. For example, Simes et al (2002) showed that in the LIPID study 67% of the pravastatin effect in reducing fatal CHD and nonfatal myocardial and 96% of the effect in reducing the expanded endpoint of fatal CHD, nonfatal myocardial infarction, unstable angina and coronary revascularisation could be explained by on-study lipid levels. Recommendations on lipid targets are based on • establishing a relationship between a lipid parameter and improved outcomes • actual lipid levels achieved during the study • the characteristics of the relationship between the lipid parameter and improved outcomes There are 3 models which describe the relationship between lipid levels and cardiovascular outcomes: • linear model – in which there is progressive and continuing benefit with lower (or in the

case of HDL cholesterol higher) lipid levels • curvilinear model – in which there is a continuous but progressively smaller benefit at

lower (or in the case of HDL cholesterol higher) lipid levels • threshold model – in which the benefits cease when a particular lipid level is reached Unfortunately, the different lipid lowering intervention studies have reported different findings on the model which best explains their results. Baseline and lipid levels achieved in therapeutic randomised controlled trials of studies designed to evaluate clinical outcomes which involved more than 1,000 people which included or were exclusively performed in people with diabetes are summarised in Table 20. LDL Cholesterol The studies shown in Table 20 achieved a reduction in LDL cholesterol of 1mmol/L or more and the actual level achieved was influenced by the baseline level. The LDL cholesterol levels achieved in the secondary prevention statin studies ranged from 1.9 to 3.1 mmol/L.

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The recent meta-analysis by Law et al (2003) concluded that lipid lowering therapy reduced the risk of ischaemic heart disease (IHD) by lowering LDL cholesterol. In 58 randomised controlled trials of different methods of reducing LDL cholesterol including fibrates, statin, niacin, or resins, 52% of a total of 148,321 subjects (diabetes not specified) had known vascular disease at entry. The reduction in IHD events increased with the duration of treatment. With each 1.0mmol/L reduction in LDL cholesterol, the risk of IHD events was lowered by 11% in the first year, 24% in the second year, 33% in years three to five, and by 36% in the sixth and subsequent years (p<0.001 for trend). Overall, in 49 trials that lasted more than one year, the reduction in IHD events after treatment for two or more years was 51% with a reduction in mean LDL cholesterol of ≥1.5mmol/L, compared with a 30% with a reduction in mean LDL cholesterol of 1.0mmol/L, and 20% with a reduction in mean LDL cholesterol of 0.5mmol/L (p<0.001 for trend). This is consistent with a curvilinear relationship between increasing reduction in LDL cholesterol and improved outcomes. A recent retrospective analysis of 16,470 people (including 3,430 with diabetes) by Rubins et al (2003) confirmed a beneficial effect of lipid-lowering medications (mainly statins) on total mortality in people with established CHD in a usual clinical care setting. During an average 5.9 years follow-up, there were 4,821 recorded deaths (51%) in untreated people compared with 1,245 deaths (18%) in treated people. On average, the treated cohort survived 15 months (CI 449-493 days) longer than the untreated cohort (1,981±6 v 1,510±8 days, p<0.0001). After adjusting for age, previous use of lipid-modifying medication, other cardiovascular medications and pretreatment cholesterol level, there was a 24% reduction in total mortality with lipid-modifying treatment (HR 0.76, CI 0.69-0.84, p<0.0001). There was a significant trend towards greater benefit in those with highest baseline total cholesterol level (p<0.0001 for trend). The beneficial effect of treatment in reducing mortality was less in people with diabetes (8% reduction [HR 0.92, p>0.38] compared with people without diabetes (32% reduction [HR 0.68, CI 0.61-0.76, p<0.0001]. The relationship of LDL cholesterol and improved outcomes has been different in the different studies. The results of the secondary prevention 4S study are consistent with a curvilinear relationship between LDL cholesterol and major coronary events. Pedersen et al (1998) analysed the relationship between serum lipids and clinical outcomes. After 1 year of simvastatin treatment, each 1mmol/L reduction of total and LDL cholesterol was associated with a 22.5% and a 27.8% reduction (CI 11.9-31.9%, p=0.0001; CI 17.6-36.8%, p<0.0001, respectively) in major coronary events. Modelling LDL cholesterol showed the incremental benefit became progressively less as the LDL reduction increased. On the other hand the results of CARE and LIPID secondary studies favour the threshold model. In the CARE study CHD event rates decreased progressively as LDL cholesterol levels fell from 4.5 to 3.2mmol/L but from 3.2 to 1.8mmol/L, CHD events did not decline further. (Sacks et al, 1998) The LIPID study reported a 24% reduction in the primary end point of coronary death and nonfatal myocardial infarction. However in the pravastatin treated subjects with a baseline LDL cholesterol level <3.6mmol/L there was a non significant 16% reduction in events (CI -4, 32%) (LIPID Study Group, 1998). A pooled analysis of the CARE and LIPID data showed a reduction in coronary death and nonfatal infarction of 22% (CI 7-34%; p=0.005) in subjects with LDL cholesterol <3.6mmol/L at baseline. However further analyses showed no difference in event rates with LDLcholesterol <3.2mmol/L again suggesting that treating to a LDL cholesterol level of 3.2mmol/L may be sufficient and that further LDL-cholesterol lowering might not provide additional benefit. (Sacks et al, 2002). These data question the benefit of lipid lowering therapy when baseline LDL cholesterol levels range from 2.6 to 3.3mmol/L.

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However the situation may be different in people with diabetes. Sacks et al (2002) analysed the data from the CARE and LIPID trials and found that pravastatin significantly reduced the CHD event rate in people with diabetes compared with people without diabetes in whom LDL cholesterol was lower than 3.2mmol/L. Of 13,173 people with CHD (mean age 60 years), 2,607 had a baseline LDL cholesterol less than 3.2mmol/L (mean LDL cholesterol 2.9±0.3 mmol/L). Treatment with pravastatin lowered LDL cholesterol by 32% and triglycerides by 14%, and raised HDL cholesterol by 6% compared with placebo in people with low LDL cholesterol (all p<0.001). During a mean 5.5 years follow-up, pravastatin reduced the CHD events from 34% to 22% in people with diabetes and low LDL cholesterol (RR 0.56, CI 0.37-0.83, p=0.004). This risk reduction was significantly different from the effect in nondiabetic people with low LDL of <3.2mmol/L (RR 1.06, CI 0.89-1.27) (diabetes v nondiabetic, p=0.005). In the PROSPER study (Shepherd et al, 2002), 5,804 elderly people (aged 70-82 years, 623 with diabetes) with previous cardiovascular disease were randomised to pravastatin 40 mg/day or placebo for an average of 3.2 years. Pravastatin resulted in a 15% reduction in the incidence of the combined primary endpoint (HR 0.85, CI 0.74-0.97; p=0.014), 19% reduction in CHD death or nonfatal myocardial infarction (HR 0.81, CI 0.69-0.94, p=0.006) and 24% reduction in mortality from CHD (HR 0.76, CI 0.58-0.99, p=0.043). Fatal or nonfatal stroke was not affected (HR 1.03, CI 0.81-1.31, p=0.8). With regard to baseline LDL cholesterol levels, the incidence of the primary endpoint was significantly reduced in people with LDL cholesterol >4.1mmol/L (HR 0.77, CI 0.60-0.98) compared with people with LDL <3.4mmol/L (HR 0.88, CI 0.80-1.10) and LDL 3.4-4.1mmol/L (HR 0.88, CI 0.70-1.10). Among people with diabetes (n=623) the incidence of the primary endpoint was higher (HR 1.27, CI 0.90-1.80) compared with people without diabetes (HR 0.79, CI 0.59-0.91) (between groups p=0.015). The findings of the Heart Protection Study (2002a) strongly support the linear model in that there was no threshold effect evident and the benefit of lipid lowering therapy applied equally to people with a baseline LDL cholesterol above and below 3.5mmol/L. In the HPS the average difference in LDL cholesterol between the simvastatin and placebo group over 5 years was 1mmol/L. In people with an initial LDL cholesterol <3mmol/L the average LDL cholesterol difference was 0.9mmol/L (actual level 1.8mmol/L in the simvastatin group v 2.7mmol/L in the placebo group). In people with a baseline LDL cholesterol <3 mmol/L, there was a 4.8% reduction in first major vascular event with simvastatin treatment, which was similar to the 5.7% reduction in people with a baseline LDL cholesterol of 3-3.5mmol/L and a 5.2% reduction with baseline LDL cholesterol > 3.5mmol/L. The absolute event rate with simvastatin was 17.6%, 19.0% and 22.0% respectively for the 3 groups. In people with LDL cholesterol < 2.5mmol/L which was further reduced to 1.7mmol/L with simvastatin, the risk reduction was about as great as those with higher LDL cholesterol levels. In the HPS report on people with diabetes (HPS Collaborative Group, 2003), the above findings were also apparent. However, although the risk reductions were similar in the diabetic and non diabetic cohorts, it is interesting to note that the diabetic subgroup with a baseline LDL cholesterol <3.0mmol/L had a lower absolute event rate than in the non diabetic subgroup with an LDL cholesterol < 3.0mmol/L. The results of studies which have compared more and less aggressive lipid lowering have all shown better outcomes with lower lipid levels, a finding which is consistent with either the linear or curvilinear model.

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In a 24-month multicentre, randomised controlled trial, Cannon et al (2004) compared the effects of pravastatin 40mg/day with atorvastatin 80mg/day in 4,162 people (mean age 58 years, 17.6% with diabetes) who had experienced an acute myocardial infarction or unstable angina within the proceeding 10 days. At baseline, the lipid levels were comparable between the two groups. During the follow-up, the median LDL cholesterol level achieved was 2.46mmol/L (interquartile rage 2.04-2.92mmol/L) in the pravastatin group and 1.60mmol/L (interquartile range 1.29-2.04mmol/L) in the atorvastatin group (atorvastatin v pravastatin, p<0.001). The median HDL cholesterol level rose by 8.1% in the pravastatin group and 6.5% in the atorvastatin group (p<0.001). Overall, high-dose atorvastatin therapy resulted in a 16% reduction (CI 5-26) in the rate of combined primary endpoint compared with standard-dose pravastatin therapy (22.4 v 26.3%, p=0.005). The benefit appeared to be greater among people with a baseline LDL cholesterol of ≥3.24mmol/L, with a 34% reduction, compared with a 7% reduction in the event rate among those with a baseline LDL cholesterol of <3.24mmol/L (p<0.02). Among 734 people with diabetes, the 2-year event rates were reduced from 34.6% in the pravastatin group to 28.8% in the atorvastatin group (no p value reported but not significant from Figure 5) compared with a significant reduction from 24.6% with pravastatin to 21.0% with atorvastatin in the 3,428 people without diabetes. In the Post Coronary Artery Bypass Graft (Post-CABG) Trial (Knatterud et al, 2000) lipid lowering therapy was used to achieve an LDL cholesterol of <2.2mmol/L (aggressive therapy) or <3.6mmol/L (moderate therapy) from a baseline LDL cholesterol of between 3.4 and 4.5mmol/L. The achieved LDL-cholesterol levels were 2.4-2.5mmol/L with aggressive therapy and 3.4-3.5mmol/L with moderate therapy. There was significantly less progression of saphenous vein bypass graft narrowing, cardiovascular death or nonfatal infarction (15.1% v 20.3%; p=0.03), and composite endpoint of death, nonfatal infarction, stroke, or coronary

revascularisation (30.6% v 40.2%; p=0.001) in the aggressively treated subjects.

White et al (2001) compared the effect of aggressive lipid-lowering therapy on progression of atherosclerosis in the left main coronary artery (LMCA) in 402 people (7% with diabetes) randomly selected from the Post-CABG Trial. Lovastatin 40-80mg/day achieved an LDL of 1.6-2.2mmol/L in the aggressive lipid-lowering group (n=203), and 2.5-5mg/day lovastatin achieved an LDL of 3.4-3.6mmol/L in the moderate lipid-lowering group (n=199). People with aggressive treatment had less progression of luminal narrowing in the LMCA segment, less substantial lesion progression and fewer developed occlusion in the LMCA compared with the moderate treatment group. In the Post-CABG trial reported by Hoogwerf et al (1999) 116 people had Type 2 diabetes of whom 63 were randomly assigned to aggressive lipid lowering and 53 were assigned to moderate lipid lowering. LDL cholesterol was reduced from 3.9mmol/L at baseline to 2.5 mmol/L with aggressive therapy and to 3.5mmol/L with moderate therapy. Over the 4-year period, there was a general reduction in RR for clinical events associated with aggressive lipid lowering therapy, with a 47% reduction in combined endpoint (14.9 v 26.2%, RR 0.53 [CI 0.18-1.60]), a 33% reduction in death (6.5 v 9.6%, RR 0.67 [CI 0.12-3.75]) and a 60% reduction in MI (4.8 v 11.6%, RR 0.40 [CI 0.07-2.47]) but none of these was significant. Also fewer people treated with aggressive lipid lowering therapy had a PTCA during the study period (4.9 v 7.9%, RR 0.61 [CI 0.09-4.39]), but again this did not reach significance. In the GREACE study (Athyros et al, 2002b), 1,600 people (19.6% with diabetes) were randomly assigned to atorvastatin (10-80mg/day) treatment or to usual care. Treatment with atorvastatin lowered total cholesterol to 4.3mmol/L, LDL cholesterol to 2.6mmol/L and increased HDL cholesterol to 1.09mmol/L. In the usual care group the corresponding levels were 6.4mmol/L, 4.4mmol/L and 1.04mmol/L. After 3 years, 97% of people in the atorvastatin group compared with only 3% of people in the usual care group achieved the

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NCEP recommended LDL cholesterol target of <2.6mmol/L. Overall, atorvastatin significantly reduced risk of total mortality (RR 0.57, CI 0.39-0.78; p=0.0021), CHD mortality (RR 0.53, CI 0.29-0.74, p=0.0017), coronary morbidity (RR 0.46, CI 0.25-0.71; p<0.0001) and stroke (RR 0.53, CI 0.30-0.82; p=0.034). People with diabetes also benefited from atorvastatin therapy, with a 58% reduction in all cardiac events (p<0.0001). In the open-label, multicentre Atorvastatin Versus Revascularization Treatments (AVERT)

Trial, 341 people (54 with diabetes) with stable coronary artery disease who were referred for revascularisation were randomised to receive lipid-lowering therapy with atorvastatin 80mg/day (n=164) or to undergo PTCA followed by usual care (n=177) (Pitt et al, 1999). Atorvastatin treatment achieved an LDL cholesterol of 2.0mmol/L while in the angioplasty/usual care group LDL cholesterol was 3.1mmol/L. Over an 18-month period, people in the atorvastatin group had 36% (CI 5-67%) fewer ischaemic events (p=0.048). A number of studies in progress should provide more data on this issue. The Treating to New Targets (TNT) Study has randomised 10,000 people with coronary disease and LDL cholesterol levels between 3.4 and 6.5mmol/L to treatment with atorvastatin 10mg/day or 80 mg/day with the aim of achieving LDL cholesterol levels of 2.6 and 1.9mmol/L on the low

and high doses, respectively. The study will assess the effect on coronary death or nonfatal myocardial infarction over a 5 year period and is due for completion in 2004. The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial has enrolled 12,000 people with a myocardial infarction with LDL cholesterol levels >3.5

mmol/L. Participants have been randomized to 20mg/day or 80mg/day of simvastatin. This 5-year study is due to finish at the end of 2004. The Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) study has randomised 8,888 people with previous

myocardial infarction to simvastatin 20mg/day, increasing to 40mg/day if total cholesterol remains >4.9mmol/L, or to atorvastatin 80mg/day. The study will run for 5.5 years and will finish in early 2005. The above studies, with the exception of a subset of the HPS, were all conducted in people with established heart disease. There are insufficient data available on the relationship between lipid levels and outcomes in people without established vascular disease. Furthermore no studies have examined outcomes in relation to aggressive and less aggressive lipid lowering for the primary prevention of cardiovascular disease. Data from the analysis of the WOSCOPS primary prevention study (West of Scotland Coronary Prevention Study Group, 1998) show that the benefit of pravastatin was independent of baseline LDL cholesterol with maximal risk reduction occurring when LDL cholesterol concentrations fell by 24%, and greater lowering of LDL gave no additional reduction in risk. In WOSCOPS, the average LDL cholesterol level achieved on pravastatin therapy was relatively high at 3.8 mmol/L and this relationship may be different with lower levels. In the HPS report in people with diabetes (HPS Collaborative Group, 2003), there were 1,343 people without known occlusive arterial disease at randomisation whose pretreatment LDL cholesterol was 3.0 mmol/L. There was a marginally significant 30% (CI 1-50%) reduction in first major vascular events (p<0.05). Overall, these studies support either a linear or curvilinear model to explain the relationship between LDL cholesterol lowering and improved cardiovascular outcomes. The continued benefit with lower LDL cholesterol levels is not consistent with the threshold model, unless the threshold is well below 2 mmol/L.

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Table 20 Lipid Levels Achieved in the Studies with Lipid Modifying Medications LDL Cholesterol HDL Cholesterol Triglycerides Baseline After Baseline After Baseline After STATIN Studies Secondary Prevention ALLHAT-LLT 3.77 2.70 1.23 1.26 1.70 1.64 ASCOT 3.44 2.28 1.31 1.30 1.66 1.32 CARE 3.52 2.57 0.97 1.01 1.85 1.61 GREACE 4.66 2.57 1.01 1.09 2.08 1.45 HPS 3.2 2.3 1.06 1.07 2.3 2.0 LIPID 3.88 2.91 0.93 0.98 1.60 1.42

Post-CABG (diabetes cohort) 3.93

2.49 (aggressive) 3.49 (moderate)

0.93 - 2.09 -

PROSPER 3.8 2.5 1.30 1.37 1.5 1.3 TIMI Pravastatin

2.75 Atorvastatin 2.75

2.46 1.60

1.01 0.98

1.09 1.04

1.71 1.79

- -

4S 4.80 3.10 1.13 1.21 1.69 1.54 Primary Prevention AFCAPS/ TEXCAPS 3.89 2.96 0.98 1.05 1.78 1.61

WOSCOPS 4.97 3.68 1.14 1.20 1.83 1.61 CARDS 3.10 1.90 1.30 1.32 1.70 1.30 HPS No separate data reported FIBRATE Studies Secondary Prevention BIP 3.83 - 0.90 1.06 1.64 1.30 DAIS 3.38 3.14 1.01 1.09 2.59 1.84 VA-HIT 2.9 2.9 0.82 0.89 1.8 1.3 Primary Prevention HHS 5.18 4.44 1.18 1.26 2.42 1.79 SENDCAPS 3.66 3.31 1.02 1.04 2.24 1.44

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The currently available combined data from the various intervention studies and studies which have compared aggressive with less aggressive treatment support an LDL cholesterol target of 2.5mmol/L or less. This conclusion has also been reached by other guidelines discussed in the Background to this Section including NCEP (NCEP, 2001; NCEP, 2002) and American Diabetes Association (ADA, 2003). It should be noted that these data are derived from studies which have focussed on secondary prevention in people who have had a previous vascular event. Data on primary prevention are limited. It should also be noted that the majority of people treated with statins do not achieve LDL cholesterol levels of 2.5mmol/l. The lipid assessment project (L-TAP) showed that among 4,888 people treated with statins only 38% reached NCEP LDL cholesterol targets (Pearson et al, 2000). However the Atorvastatin Comparative Cholesterol Efficacy and Safety Study (ACCESS) demonstrated that it is possible to achieve NCEP targets in 80% or more of people with aggressive statin treatment (Andrews et al, 2001). Some programs have been shown to increase the achievement of lipid targets. In an Australian randomised controlled trial, Vale et al (2002) compared the coach model (n=121) with usual medical care (n=124) on the change of total cholesterol level over a 6-month period. The five-step coaching intervention, which assisted people with established CHD to achieve the target total cholesterol level of <4.5mmol/L was achieved by a dietitian who ascertained attitude and beliefs about achieving the target lipid level, explaining the rationale of recommended therapy, assertiveness training, goal setting and reassessment at the next coaching session. The number of people taking lipid-lowering medications was 67 in both groups. At 6 months, the mean total and LDL cholesterol levels were significantly lower in the coaching group than in the usual care group (5.0 v 5.5mmol/L, p=0.0001; 3.1 v 3.6mmol/L, p=0.0004, respectively). 31% of people in the coaching group compared with only 10% in the usual care group achieved the target total cholesterol of <4.5mmol/L (p<0.001). Multivariate analysis showed that coaching intervention and being prescribed statins were both highly significant predictors of the final total cholesterol level (p<0.0001 and p<0.0003, respectively).

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HDL Cholesterol and Triglycerides Although the role of LDL cholesterol as a risk factor for CVD is established, the statin studies show that lowering LDL cholesterol produces only a partial reduction in CVD of the order of 30% or so. Clearly other lipids and risk factors are important in determining CVD. This is emphasised by the results of intervention studies with fibrates which have little effect on LDL cholesterol but have a significant effect in reducing CVD. As reviewed in Section 1 a low HDL cholesterol and elevated triglycerides are frequently observed in people with Type 2 diabetes. Epidemiological studies have shown that a low HDL cholesterol predicts an increased risk of coronary artery disease for any LDL cholesterol level (Assmann et al, 1996) and the risk associated with a low HDL cholesterol is as high as for a high LDL cholesterol (Castelli et al, 1986). Hokanson and Austin (1996) performed a meta-analysis of prospective population based studies and showed that triglycerides were an independent risk factor for CVD. Among 57,277 subjects aged 15-81 years (diabetes not specified), a 1mmol/L increase in mean triglycerides level was significantly associated with increased risk of CVD in both men (n=46,413) (RR 1.32, CI 1.26-1.29) and in women (n=10,864) (RR 1.76, CI 1.50-2.07). After adjustment for HDL cholesterol and other risk factors, there was still a 14% increased CVD risk (RR 1.14, CI 1.05-1.28) in men and a 37% increased CVD risk (RR 1.37, CI 1.13-1.66) in women. The results of intervention studies emphasise that non-LDL cholesterol and possibly triglycerides are important in reducing CVD. The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) Rubins et al, 1999) studied 2,531 men (mean age 64.7 years) with established CHD, HDL cholesterol ≤1.0mmol/L and LDL cholesterol ≤3.6mmol/L. People randomised to treatment with gemfibrozil 600mg twice daily had a 31% reduction in triglycerides (1.3mmol/L v 1.9mmol/L, p<0.001), a 6% increase in HDL cholesterol (0.9mmol/L v 0.8mmol/L, p<0.001), but no change in LDL cholesterol at one year (2.9mmol/L for both groups) compared with placebo. Gemfibrozil reduced nonfatal myocardial infarction or CHD death by 22% (p<0.006). Although baseline triglycerides predicted coronary artery events in univariate analysis, this relationship became non significant in mutlivariate analysis which included HDL cholesterol. In the VA-HIT study, a separate analysis of the pre-specified group with diabetes (627 individuals or 25% of subjects) showed a 24% reduction of the endpoint nonfatal myocardial infarction, CHD death and confirmed stroke (p=0.05). The Bezafibrate Infarction Prevention (BIP) study randomised 3,090 people with established CHD, HDL cholesterol ≤1.17mmol/L, triglycerides ≤3.3mmol/L and LDL cholesterol ≤4.7 mmol/L to bezafibrate 400mg daily or placebo (BIP Study, 2000). On treatment, HDL cholesterol increased to 1.06mmol/L and triglycerides decreased to 1.3mmol/L from a baseline of 0.90mmol/L and 1.6mmol/L respectively. While the 7.3% reduction in the primary endpoint of nonfatal myocardial infarction or CHD death was not significant (p=0.26), the post hoc analysis of the subgroup with triglycerides ≥2.2mmol/L showed a 39% reduction in this endpoint (p<0.02). The Diabetes Atherosclerosis Intervention Study (DAIS) randomised 418 people with diabetes aged 40 to 65 years to treatment with fenofibrate 200mg daily or placebo for an average of 4 years (DAIS, 2001). At baseline mean LDL cholesterol was 3.4mmol/L, HDL cholesterol was 1.03mmol/L, triglycerides were 2.4mmol/L and 48% had prior clinical evidence of CHD. There was a significant 0.24mmol/L reduction in LDL cholesterol, a 0.07mmol/L increase in HDL cholesterol and 0.75mmol/L reduction in triglycerides in the

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fenofibrate treated group. Primarily an angiographic study, the DAIS results show that fenofibrate treatment was associated with 40% less progression in minimum lumen diameter (p=0.029), 42% less progression in percentage diameter stenosis (p=0.02) and a 23% non significant reduction in combined clinical endpoints. The Helsinki Heart Study (Frick et al, 1987), a primary prevention study, randomised 4,081 asymptomatic men to treatment with gemfibrozil 600mg twice daily or placebo and showed a 34% reduction (p<0.02) in nonfatal myocardial infarction and cardiac death. A post hoc analysis (Manninen et al, 1989) showed that the reduction of CHD with gemfibrozil was greatest in subjects with HDL cholesterol in the lower tertile (<1.08mmol/L) or triglycerides in the upper tertile (>2.08mmol/L). In the subgroup of 1,131 people with LDL cholesterol ≥4.5mmol/L and triglycerides >2.0mmol/L there was a 43% reduction in CHD events (p<0.02) with only a 7.5% reduction in LDL cholesterol level for gemfibrozil compared with placebo treatment. In the 4S study, apart from the significant influence of LDL cholesterol lowering in improving outcomes, each 0.1mmol/L increase of HDL cholesterol was associated with a 3.7% reduction (CI -0.3, 7.5%, p=0.07) in major coronary events. Reductions in triglycerides did not contribute to risk reduction but all 4S participants were recruited on the basis of having triglycerides ≤2.5mmol/L (Pedersen et al, 1998). In the Pravastatin Pooling Project (Sacks et al, 2000), in both the pravastatin and placebo treated groups there was a parallel inverse relationship between coronary events and HDL cholesterol, demonstrating that low levels of HDL cholesterol were an independent risk factor despite a decrease in LDL cholesterol produced by pravastatin and that statins did affect the HDL cholesterol associated risk. In summary there is strong epidemiological and clinical trial data which support a significant role for low HDL cholesterol as an independent risk factor for coronary artery disease. However there are few data to guide recommendations on initiation of treatment or therapeutic goals for HDL cholesterol and other lipid parameters in people with Type 2 diabetes. Implications for clinical practice The following is a summary of the current evidence used to make the clinical practice recommendations for interventions to improve lipid levels for the primary prevention of cardiovascular disease in people with Type 2 diabetes: • Most of the evidence on improved outcomes relates to lowering LDL cholesterol • Increasing HDL cholesterol also has a role in improving outcomes • Reducing triglycerides seem important only when levels are at least more than 2mmol/L • Although individual studies report variable results, the following average changes can be

achieved with interventions to improve lipids LDL Cholesterol HDL Cholesterol Triglycerides Lifestyle changes ↓10% ↑10% ↓15%

Improved diabetes control ↓5-10% ↑5% ↓10%

Statins ↓35% ↑5% ↓10%

Fibrates ↓5-10% ↑10% ↓35%

• Therapeutic interventions are available to substantially change LDL cholesterol (statins)

and triglcyerides (fibrates) • No therapeutic agent is available which can alter HDL cholesterol by a similar magnitude

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• Most statin intervention studies achieved a mean LDL cholesterol of the order of 2.5mmol/L

Taking the above into consideration and acknowledging that more data are required before the evidence base is complete, current data support the NCEP recommendations which set an LDL target of 2.5mmol/L for people with diabetes and which recommend interventions to reduce triglycerides as shown in the following flow chart.

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Lipid Control Treatment Algorithm for People with Type 2 Diabetes and no Known Vascular Disease (Adapted from NCEP Guidelines)

LDL Cholesterol <2.5 mmol/L

LDL Cholesterol 2.5 – 3.5 mmol/L

LDL Cholesterol >3.5 mmol/L

No statin therapy Lifestyle advice Improve diabetes control

Lifestyle advice Improve diabetes control Commence statin therapy

LDL cholesterol remains >2.5 mmol/L after 3 months Consider statin therapy

Triglycerides 2-4 mmol/L Triglycerides > 4 mmol/L

Lifestyle advice Improve diabetes control

Triglycerides remain 2-4 mmol/L after 3 months If taking a statin, intensify therapy Or consider treatment with a fibrate

Lifestyle advice Improve diabetes control

Triglycerides remain >4 mmol/L after 3 months Commence fibrate

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Summary - effects of lipid modifying agents or hormone replacement therapy on cardiovascular disease risk • In the diabetic subgroup of the 4S study treatment with simvastatin reduced major CHD

events by 42%, not significantly different from the 32% reduction in the cohort with normal glucose tolerance

• In the CARE study pravastatin resulted in a 13% reduction (p=NS) of myocardial infarction or CHD death in the group with diabetes and a 26% reduction (p=0.04) in the non-diabetic group, but a significant reduction in revascularisation procedures (32%, p=0.04) and total coronary events (25%, p=0.05) for those with diabetes

• In the LIPID study there was a 19% reduction of myocardial infarction or CHD death in the group with diabetes and a 25% reduction in the non-diabetic group (p=NS for diabetes compared with non-diabetes)

• Because the absolute risk of major CHD events (myocardial infarction or CHD death) is greater in people with diabetes, an equivalent reduction in relative risk with statin therapy means a greater number of cardiac events prevented in the diabetic group

• In the AFCAPS/TexCAPS study using lovastatin there was a 43% risk reduction in acute major coronary events in the diabetic group which was not different from the 36% reduction for the total cohort

• A post hoc analysis of the 4S in people with IFG showed a relative risk reduction for major coronary events of 38% with simvastatin, not significantly different to the 32% reduction in people with normal fasting glucose. A similar outcome was observed with IFG in the CARE study using pravastatin

• In VA-HIT treatment with gemfibrozil 600mg twice daily in the diabetic subgroup showed a 24% reduction of the endpoint nonfatal myocardial infarction, CHD death and confirmed stroke

• Although there are some data in people without diabetes, there is no evidence that ϖ-3 polyunsaturated fatty acids (fish oil) reduce the risk of recurrent cardiovascular disease in people with Type 2 diabetes

• There is no evidence that hormone replacement therapy reduces the risk of coronary disease in postmenopausal women with Type 2 diabetes

• Based on the results of the 4S trial, savings from reduced hospitalisation of the diabetic group offset 67 to 76% of the drug cost and each life-year gained was estimated to cost from 1,600 Euros (based on clinical history of diabetes) to 3,200 Euros (based on fasting glucose ≥7.0 mmol/L)

• Estimates of the cost-effectiveness of primary prevention therapy indicate that for men with pretreatment LDL cholesterol of 5.46mmol/L, costs per life year saved range from $US 4,000 for 60 year olds to $US10,000 for 70 year olds; for women the range is about $US9,000 to $US15,000

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Effects of lipid modifying agents or hormone replacement therapy on cardiovascular disease risk

Evidence

Level of Evidence Author


Magnitude Rating

Relevance Rating

Andrews TC (2001) (Adults – US) III-2 Cohort High High + Low

ALLHAT Collaborative Research Group (2002b) (Adults – US; Canada; Puerto Rico)

II RCT High Low Low

Assmann G (1996) (Adults – Germany) III-2 Cohort High High + Low

Athyros VG (2002b) (Adults – Greece) II RCT High High + High

BIP Study Group (2000) (Adults – Israel) II RCT Medium High + Low

Blauw GJ (1997) I Meta-analysis High High + Low

Brandle M (2003) (Adults – US) II RCT High High + High

Byington RP (2001) (Adults – US) III-2 Cohort High High + High

Burr ML (1989) (Adults-UK) II RCT High High + High

Cannon CP (2004) (Adults – US; Canada) II RCT High High + High

CARDS (2004) (Adults – multicountries) II RCT High High + High

Caro J (1997) (Men – Scotland) II RCT Medium High + Low

Castelli WP (1986) (Adults – US) III-2 Cohort High High + Low

DAIS (2001) (Adults – Canada, Finland, Sweden, France)

II RCT High High + High

Downs JR (1998) (Adults – US) II RCT High High + Low

Elkeles RS (1998) (Adults – UK: England) II RCT High High + High

Friedberg CE (1998) I Meta-analysis High High+ High

Frick MH (1987) (Adult men – Finland) II RCT Medium High + Low

GISSI (1999) (Adults – Italy) II RCT High High + Low

Glasziou PP (2002) (Adults – Australia; NZ) II RCT High High + Low

Goldberg RB (1998) (Adults – US, Canada) II RCT High High + High

Grover SA (2000) (Adults – Canada) III-2 Cohort Medium Medium+ High

Grover SA (2001) (Adults – Canada, UK & Europe) III-2 Cohort Medium High + High

Haffner SM (1999) (Adults – Scandinavia) II RCT High High + High

Haffner SM (2000) I Systematic review High High + High

Heart Protection Study (2002a) (Adults – UK) II RCT High High + High

Heart Protection Study (2002b) (Adults – UK) II RCT High High + High

Heart Protection Study (2003) (Adults – UK) II RCT High High + High

For magnitude rating: + lipid modifying agents reduce cardiovascular disease; High = clinically important & statistically significant; Medium = small clinical importance & statistically significant; Low = no statistically significant effect. Criteria for Quality and Relevance ratings are detailed in Appendix 9. E= estrogen therapy

165



Author


Magnitude Rating

Relevance Rating

Heart Protection Study (2004) (Adults – UK) II RCT High High + High

Hokanson JE (1996) I Meta-analysis High High + Low

Hoogwerf BJ (1999) (Adults – US) II RCT Medium Low High

Huang ES (2001) I Systematic review High High + High

Hulley S (1998) (Adult women – US) II RCT High Low Low

Inoue I (1994) (Adults – Japan) III-2 Cohort Medium High + Low

Jonsson B (1999) (Adults – Sweden) III-2 Cohort Medium High + High

Kaplan RC (1998) (Adults women – US) III-2 Case-control High High + High

Keech A (2001) (Adults-Australia, NZ) II RCT High High + Low

Keech A (2003) (Adults-Australia, NZ) II RCT High High + High

Knatterud GL (2000) (Adults – US) II RCT High High + Low

Koskinen P (1992) (Adult men – Finland) II RCT High Low High

Law MR (2003) I Meta-analysis High High+ Low LIPID Study Group (1998) (Adults – Australia, NZ) II RCT High High + Low

Manninen V (1989) (Adults – Scandinavia) II RCT High High + Low

Manson JE (2003) (Women – multicentres) II RCT High Low High

McIntosh A (2001) I Systematic review High High + High

Pearson TA (2000) (Adults – US) III-2 Cohort High High + Low

Pedersen TR (1998) (Adults - III-2 Cohort High High + Low

Pyorala K (1997) (Adults – Scandinavia) II RCT High High + High

Robins SJ (2001) (Adult men – US) II RCT High High + Low

Rubins HB (1999) (Adult men – US) II RCT High High + High

Rubins HB (2002) (Adult men – US) II RCT High High + High

Rubins HB (2003) (Adult – US) III Cohort Medium High + High

Sacks FM (1996) (Adults – US, Canada) II RCT High High + High

Sacks FM (1998) (Adults – US, Canada) III-2 Cohort High High + Low



4S Study (1994) (Adults – Scandinavia) II RCT High High + Low

Sever PS (2003) (Adults – multi countries) II RCT High High + High

Shepherd J (1995) (Adults – UK: Scotland) II RCT High High + Low

Shepherd J (2002) (Adults – UK; the Netherlands) II RCT High High + High


166



Author


Magnitude Rating

Relevance Rating

Simes RJ (2002) (Adults – Australia, NZ) III-2 Cohort High High + Low

Stampfer MJ (1991) (Adult women – US) III-2 Cohort High High E+ Low

Teo KK (2000) (Adults – Canada) II RCT High High + High

The CDD Diabetes Cost-Effectiveness Group (2002) II RCT High High + High

Vale MJ (2002) (Adults – Australia) II RCT High High + Low

Vasilios G (2002) (Adults – Greece) II RCT High High + Low

Waters D (1994) (Adults – Canada) II RCT High High + High

White HD (2000) (Adults – Australia, New Zealand)

II RCT High High + High

White CW (2001) (Adults – US) II RCT High High + Low

WOSCOPS Study Group (1998) (Adulsts – UK: Scotland)

III-2 Cohort High High+ Low


167

Lipid Disease: Evidence References Abraira C, Derler J. Large variations of sucrose in constant carbohydrate diets in Type II diabetes. Am J Med 1988;84:193-200. Abu-Lebdeh HS, Hodge DO, Nguyen TT. Predictors of macrovascular disease in patients with Type 2 diabetes mellitus. Mayo Clin Proc 2001;76:707-12. ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomised to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart attack Trial (ALLHAT). JAMA 2002a;288:2981-2997. ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolaemic, hypertensive patients randomised to pravastatin vs usual care. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAR-LLT). JAMA 2002b;288:2998-3007. Anderson JW, Allgood LD, Turner J, Oeltgen PR, Daggy BP. Effects of psyllium on glucose and serum lipid responses in men with Type 2 diabetes and hypercholesterolaemia. Am J Clin Nutr 1999;70:466-73. Andrews TC, Ballantyne CM, Hsia JA, Kramer JH. Achieving and maintaining National Cholesterol Education Program low-density lipoprotein cholesterol goals with five statins. Am J Med 2001;111:185-91. Assmann G, Cullen P, Schulte H. The Munster Heart Study (PROCAM). Results of follow-up at 8 years. European Heart Journal 1998;19:A2-11. Assmann G, Schulte H, von Eckardstein A, Huang Y. High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse choesterol transport. Atherosclerosis 1996;124 (Suppl):S11-20. Athyros VG, Papageorgiou AA, Athyrou VV, Demitriadis DS, Kontopoulos AG. Atorvastatin and micronised fenofibrate alone and in combination in Type 2 diabetes with combined hyperlipidaemia. Diabetes Care 2002a;25:1198-202. Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou VV, Symeouidis AN, Basayannis EO, Demitriadis DS, Kontopoulos AG. Treatment with atorvastatin to the National Cholesterol Educational Program Goal versus 'usual' care in secondary coronary heart disease prevention. Cur Med Res Opin 2002b;18:220-8. Avogaro A, Piliego T, Catapano A, Miola M, Tiengo A. The effect of gemfibrozil on lipid profile and glucose metabolism in hypertriglyceridaemic well-controlled non-insulin-dependent diabetic patients. Acta Diabetol 1999;36:27-33. Bantle JP, Swanson JE, Thomas W, Laine DC. Metabolic effects of dietary sucrose in type II diabetic subjects. Diabetes Care 1993;16:1301-5. Barnard RJ, Jung T, Inkeles SB. Diet and exercise in treatment of NIDDM - the need for early emphasis. Diabetes Care 1994;17:1469-72. Barrett-Connor E, Ensrud KE, Harper K, Mason TM, Sashegyi A, Krueger KA, Anderson PW. Post hoc analysis of data from the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial on the effects of three years of raloxifene treatment on glycaemic control and cardiovascular disease risk factors in women with and without Type 2 diabetes. Clin Ther 2003;25:919-30. Bell RA, Mayer-Davis EJ, Martin MA, D’Agostino Jr RB, Haffner SM. Association between alcohol consumption and insulin sensitivity and cardiovascular disease risk factors. The Insulin Resistance Atherosclerosis Study. Diabetes Care 2000;23:1630-6. Ben G, Gnudi L, Maran A, Gigante A, Duner E, Iori E, Tiengo A, Avogaro A. Effects of chronic alcohol intake on carbohydrate and lipid metabolism in subjects with Type II (non-insulin-dependent) diabetes. Am J Med 1991;90:70-6. Billingham MS, Milles JJ, Bailey CJ, Hall RA. Lipoprotein subfraction composition in non-insulin-dependent diabetes treated by diet, sulphonylurea, and insulin. Metabolism 1989;38:850-7.

168

BIP Group. Bezafibrate Infarction Prevention. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. The Benzafibrate Infarction Prevention (BIP) Study. Circulation 2000;102:21-7. Bishop N, Scorah CJ, Wales JK. The effect of vitamin C supplementation on diabetic hyperlipidaemia: a double blind crossover study. Diabetic Medicine 1985;2:121-4. Blauw GJ, Lagaay AM, Smelt AHM, Westendorp RGJ. Stroke, statins, and cholesterol. A meta-analysis of randomised, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors. Stroke 1997;28:946-50. Bonanome A, Visona A, Lusiani L, Beltramello G, Confortin L, S. B, Sorgato F, Costa F, Pagnan A. Carbohydrate and lipid metabolism in patients with non-insulin-dependent diabetes mellitus: effects of a low-fat, high-carbohydrate diet vs a diet high in monounsaturated fatty acids. Am J Clin Nutr 1991;54:586-90. Bos G, Dekker JM, Nijpels G, de Vegt F, Diamant M, Stehouwer CDA, Bouter LM, Heine RJ. A combination of high concentrations of serum triglyceride and non-high-density-lipoprotein-cholesterol is a risk factor for cardiovascular disease in subjects with abnormal glucose metabolism - The Hoorn Study. Diabetologia 2003;46:910-6. Brand JC, Colagiuri S, Crossman S, Allen A, Roberts DC, Truswell AS. Low-glycaemic index foods improve long-term glycemic control in NIDDM. Diabetes Care 1991;14:95-101. Brandle M, Davidson MB, Schriger DL, Lorber B, Herman WH. Cost effectiveness of statin therapy for the primary prevention of major coronary events in individuals with type 2 diabetes. Diabetes Care 2003;26:1796-801. Brown SA, Upchurch S, Anding R. Winter M, Ramirez G. Promoting weight loss in Type II diabetes. Diabetes Care 1996;19:613-24. Brussaard HE, Gevers Leuven JA, Kluft C, Krans HM, van Duyvenvoorde W, Buytenhek R, van der Laarse A, Princen HMG. Effect of 17 beta-estradiol on plasma lipids and LDL oxidation in postmenopausal women with Type II diabetes mellitus. Arterioscler Thromb Vasc Biol 1997;17:324-30. Burchfiel CM, Hamman RF, Marshall JA, Baxter J, Kahn LB, Amirani JJ. Cardiovascular risk factors and impaired glucose tolerance: the San Luis Valley Diabetes Study. Am J Epidemiol 1990;31:57-70. Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, Elwood PC, Deadman NM. Effects of changes in fat, fish, and fibre intakes on death and myocardial infarction: diet and reinfarction trial (DART). Lancet 1989;8666:757-61. Byington RP, Davis BR, Plehn JF, White HD, Baker J, Cobbe SM, Shepherd J. Reduction of stroke events with pravastatin: the Prospective Pravastatin Pooling (PPP) Project. Circulation 2001;103:387-92. Byrne CD, Wareham NJ, Brown DC, Clark PMS, Cox LJ, Day NE, Palmer CR, Wang TWM. Williams DR. Hales CN. Hypertriglyceridaemia in subjects with normal and abnormal glucose tolerance: relative contributions of insulin secretion, insulin resistance and suppression of plasma non-esterified fatty acids. Diabetelogia 1994;37:889-96. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM. Intensive versus moderate lipid owering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504. Caro J, KlittichW, McGuire A, Ford J, Norrie J, Pettitt D, McMurray J, Shepherd J. The West of Scotland coronary prevention study: economic benefit analysis of primary prevention with pravastatin. BMJ 1997;315:1577-82. Castelli WP. Epidemiology of triglycerides: A View from Framingham. Am J Cardiol 1992;70:H3-9. Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA 1986;256:2835-8.

169

Cathelineau G, de Champvallins M, Bouallouche A, Lesobre B. Management of newly diagnosed non-insulin-dependent diabetes mellitus in the primary care setting: effects of 2 years of gliclazide treatment - the Diadem Study. Metabolism 1997;46(Suppl 1):31-4. Ceriello A, Bortolotti N, Pirisi M, Crescentini A, Tonutti L, Motz E, Russo A, Giacomello R, Stel G, Taboga C. Total radical-trapping antioxidant parameter in NIDDM patients. Diabetes Care 1997b;20:194-7. Ceriello A, Bortolotti N, Pirisi M, Crescentini A, Tonutti L, Motz E, Russo A, Giacomello R, Stel G, Taboga C. Total plasma antioxidant capacity predicts thrombosis-prone status in NIDDM patients. Diabetes Care 1997a;20:1589-93. Chandalia M, Garg A, Lutjohann DVB, von Bergmann K, Grundy SM, Brinkley LJ. Beneficial Effects of High Dietary Fiber Intake in Patients with Type 2 Diabetes Mellitus. N Engl J Med 2000;342:1392-8. Chang CJ, Kao JT, Wu TJ, Lu FH, Tai TY. Serum lipids and lipoprotein (a) concentrations in Chinese NIDDM patients. Relation to metabolic control. Diabetes Care 1995;18:1191-4. Chen YD, Coulston AM, Zhou MY, Hollenbeck CB, Reaven GM. Why do low-fat high-carbohydrate diets accentuate postprandial lipemia in patients with NIDDM? Diabetes Care 1995;18:10-6. Chen YD, Swami S, Skowronski R, Coulston A, Reaven GM. Effect of variations in dietary fat and carbohydrates intake on postprandial lipemia in patients with noninsulin dependent diabetes mellitus. J Clin Endocrinol Metab 1993;76:347-51. Chew EY, Klein ML, Ferris FL 3rd, Remaley NA, Murphy RP, Chantry K, Hoogwerf BJ, Miller D. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Arch Ophthalmol 1996;114:1079-84. Christiansen C, Thomsen C, Rasmussen O, Hansen C, Hermansen K. The acute impact of ethanol on glucose, insulin, triacylglycerol, and free fatty acid responses and insulin sensitivity in type 2 diabetes. Br J Nutr 1996;76:669-75. Christiansen E, Schnider S, Palmvig B, Tauber-Lassen E, Pedersen O. Intake of a diet high in trans monounsaturated fatty acids or saturated fatty acids: effects on postprandial insulinemia and glycemia in obese patients with NIDDM. Diabetes Care 1997;20:881-7. Colagiuri S, Miller JJ, Edwards RA. Metabolic effects of adding sucrose and aspartame to the diet of subjects with noninsulin-dependent diabetes mellitus. Am J Clin Nutr 1989;50:474-8. Colhoun HM, Thomason MJ, Mackness MI, Maton SM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Fuller JH; Collaborative AtoRvastatin Diabetes Study (CARDS). Design of the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with Type 2 diabetes. Diabet Med 2002;19:201-11. Collaborative Atorvastatin Diabetes Study (CARDS) Group. www.cardstrial.org. Accessed June 23, 2004. Coniff RF, Shapiro JA, Robbins D, Kleinfield R, Seaton TB, Beisswenger P, McGill JB. Reduction of glycosylated hemoglobin and postprandial hyperglycemia by acarbose in patients with NIDDM. A placebo-controlled dose-comparison study. Diabetes Care 1995a;18:817-24. Coniff RF, Shapiro JA, Seaton TB, Bray GA. Multicenter, placebo-controlled trial comparing acarbose (BAY g 5421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus. Am J Med 1995b;98:443-51. Cooper PL, Wahlqvist ML, Simpson RW. Sucrose versus saccharin as an added sweetener in non-insulin-dependent diabetes: short-and medium-term metabolic effects. Diabet Med 1988;5:676-80. Coulston AM, Hollenbeck CB, Donner CC, Williams R, Chiou YA, Reaven GM. Metabolic effects of added dietary sucrose in individuals with non-insulin-dependent diabetes mellitus (NIDDM). Metabolism 1985;34:962-6. Coulston AM, Hollenbeck CB, Swislocki AL, Reaven GM. Persistence of hypertriglyceridemic effect of low-fat high-carbohydrate diets in NIDDM patients. Diabetes Care 1989;12:94-101.

170

Cowie CC, Howard BV, Harris MI. Serum lipoproteins in African Americans and Whites with non-insulin-dependent diabetes in the US population. Circulation 1994;90:1185-93. Csaszar A, Dieplinger H, Sandholzer C, Karadi I, Juhasz E, Drexel H, Halmos T, Romics L, Patsch JR, Utermann G. Plasma lipoprotein (a) concentration and phenotypes in diabetes mellitus. Diabetologia 1993;36:47-51. Dailey GE 3rd, Mohideen P, Fiedorek FT. Lipid effects of glyburide/metformin tablets in patients with Type 2 diabetes mellitus with poor glycaemic control and dyslipidaemia in an open-label extension study. Clin Ther 2002;24:1426-38. DAIS Investigators. Effects on fanofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 2001;357:905-10. Dean JD, Owens DR, Matthews SB. Apolipoprotein and lipid ratios in treated non-insulin dependent diabetics. Diabetes Res 1990;15:21-5. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med 1995;333:541-9. Derosa G, Mugellini A, Ciccarelli L, Crescenzi G, Fogari R. Comparison between repaglinide and glimepiride in patients with Type 2 diabetes mellitus: a one-year, randomised, double-blind assessment of metabolic parameters and cardiovascular risk factors. Clin Ther 2003;25:472-84. Devaraj S, Jialal I. Low-Density Lipoprotein Postsecretory Modicafiaction, monoctye Function, and Circulating Adhesion molecules in Type 2 Diabetic patients with and without Macrovascular complications: The Effect of alpha-Tocopherol Supplementation. Circulation 2000;102:191-6. Dimitriadis E, Griffin M, Owens D, Johnson A, Collins P, Tomkin GH. Oxidation of low-density lipoprotein in NIDDM: its relationship to fatty acid composition. Diabetologia 1995;38:1300-6. Dodson PM, Gibson JM. Long term follow-up of and underlying medical conditions in patients with diabetic exudative maculopathy. Eye 1991;5:699-703. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AMJr. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615-22. Dunstan DW, Mori TA, Puddey IB, Beilin LJ, Burke V, Morton AR, Stanton KG. The independant and combined effects of aerobic exercise and dietary fish intake on serum lipids and glycemic control in NIDDM. A randomized controlled study. Diabetes Care 1997;20:913-21. Elam MB, Hunninghake DB, Davis KB, Garg R, Johnson C, Egan D, Kostis JB, Sheps DS, Brinton EA. Effect of niacin on lipid and lipoprotein levels and glycaemic control in patients with diabetes and peripheral arterial disease. The ADMIT Study: A randomised trial. JAMA 2000;284:1263-70. Elkeles RS, Diamond JR, Poulter C, Dhanjil S, Nicolaides AN, Mahmood S, Richmond W, Mather H, Sharp P, Feher MD. Cardiovascular outcomes in Type 2 diabetes. A double-blind placebo-controlled study of bezafibrate: the St Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study. Diabetes Care 1998;21:641-8. Emanuele N, Azad N, Abraria C, Henderson W, Colwell J, Levin S, Nuttall F, Comstock J, Sawin C, Silbert C, Marcovina S, Lee HS, for the Veterans Affairs Cooperative Study in Diabetes Mellitus Group. Effect of intensive glycemic control on fibrinogen, lipids, and lipoproteins. Veterans Affairs Cooperative Study in Type II Diabetes Mellitus. Arch Intern Med 1998;158:2485-90. Eriksson J, Kohvakka A. Magnesium and Ascorbic Acid Supplementation in Diabetes Mellitus. Ann Nutr Metab 1995;39:217-23. Fanghanel G, Sanchez-Reyes L, Trujillo C, Sotres D, Espinosa-Campos J. Metformin's effects on glucose and lipid metabolism in patients with secondary failure to sulfonylureas. Diabetes Care 1996;19:1185-9.

171

Farrer M, Winocour PH, Evans K, Neil HA, Laker MF, Kesteven P, Alberti KG. Simvastatin in non-insulin-dependent diabetes mellitus: effect on serum lipids, lipoproteins and haemostatic measures. Diabetes Res Clin Pract 1994;23:111-9. Fasching P, Rohac M, Liener K, Schneider B, Nowotny P, Waldhausl W. Fish oil supplementation versus gemfibrozil treatment in hyperlipidemic NIDDM. Horm Metab Res 1996;28:230-6. Field Study Investigators. Personal communication. 2001. Fontbonne A, Eschwege E, Cambien F, Richard JL, Ducimetiere P, Thibult N, Warnet JM, Claude JR, Rosselin GE. Hypertriglyceridaemia as a risk factor of coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes. Results from the 11-year follow-up of the Paris Prospective Study. Diabetologia 1989;32:300-4. Franz MJ, Monk A, Barry B, McClain K, Weaver T, Cooper N, Upham P, Bergenstal R, Mazze R. Effectiveness of medical nutrition therapy provided by the dietitians in the management of non-insulin dependent diabetes mellitus: a randomised, controlled clinical trial. J Am Diet Assoc 1995;95:1009-17. Freed MI, Ratner R, Marcovina SM, Kreider MM, Biswas N, Cohen BR, Brunzell JD, Rosiglitazone Study 108 investigators. Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities in Type 2 diabetes mellitus. Am J Cardiol 2002;90:947-52. Freitas JP, Filipe PM, Rodrigo FG. Lipid peroxidation in type 2 normolipidemic diabetic patients. Diabetes Res Clin Pract 1997;36:71-5. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Maenpaa H, Malkonen M, Manttari M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjoblom T, Nikkila EA. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Saftey of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317:1237-45. Friedberg CE, Janssen MJ, Heine RJ, Grobbee DE. Fish oil and glycaemic control in diabetes. A meta-analysis. Diabetes Care 1998;21:494-500. Frost G, Wilding J, Beecham J. Dietary advice based on the glycaemic index improves dietary profile and metabolic control in Type 2 diabetic patients. Diabet Med 1994;11:397-401. Fuh MM, Lee MM, Jeng CY, Ma F, Chen YD, Reaven GM. Effect of low fat-high carbohydrate diets in hypertensive patients with non-insulin-dependent diabetes mellitus. Am J Hypertens 1990;3:527-32. Fuller JH, Stevens LK, Wang SL. Risk factors for cardiovascular mortality and morbidity: The WHO multinational study of vascular diseases in diabetes. Diabetologia 2001;44(Suppl 2):S54-64. Gardner SF, Marx MA, White LM, Granberry MC, Skelton DR, Fonseca VA. Combination of low-dose niacin and pravastatin improves the lipid profile in diabetic patients without compromising glycaemic control. Ann Pharmacother 1997;31:677-82. Garg A. High-monounsaturated-fat diets for patients with diabetes mellitus: a meta-analysis. Am J Clin Nutr 1998;67(Suppl 1):577-82. Garg A, Bantle JP, Henry RR, Coulston AM, Griver KA, Raatz SK, Brinkley L, Chen YD, Grundy SM, Huet BA, Reaven GM. Effects of varying carbohydrate content of diet in patients with non-insulin-dependent diabetes mellitus. JAMA 1994a;271:1421-8. Garg A, Grundy SM. Cholestyramine therapy for dyslipidaemia in non-insulin-dependent diabetes mellitus. Ann Intern Med 1994b;121:416-22. Garg A, Grundy SM, Koffler M. Effect of high carbohydrate intake on hyperglycemia, islet function, and plasma lipoproteins in NIDDM. Diabetes Care 1992a;15:1572-80. Garg A, Grundy SM, Unger RH. Comparison of effects of high and low carbohydrate diets on plasma lipoproteins and insulin sensitivity in patients with mild NIDDM. Diabetes 1992b;41:1278-85.

172

Gavish D, Leibovitz E, Shapira I, Rubinstein A. Bezafibrate and simvastatin combination therapy for diabetic dyslipidaemia: efficacy and safety. J Intern Med 2000;247:563-9. Gentile S, Turco S, Guarino G, Sasso CF, Amodio M, Magliano P, Salvatore T, Corigliano G, Agrusta M, De Simone G, Gaeta I, Oliviero B, Torella R. Comparative efficacy study of atorvastatin vs. simvastatin, pravastatin, lovastatin and placebo in Type 2 diabetic patients with hyercholesterolaemia. Diabetes Obes Metab 2000;2:355-62. Giansanti R, Rabini RA, Romagnoli F, Fumelli D, Sorichetti P, Boemi M, Fumelli P. Coronary heart disease, type 2 diabetes mellitus and cardiovascular disease risk factors: a study on a middle-aged and elderly population. Ach Gerontol Geriatr 1999;29:175-82. GISSI. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione Trial. Lancet 1999;354:447-55. Giugliano D, Quatraro A, Consoli G, Minei A, Ceriello A, De Rosa N, D'Onofrio F. Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. Eur J Clin Pharmacol 1993;44:107-12. Glasziou PP, Eckermann SD, Mulray SE, Simes RJ, Martin AJ, Kirby AC, Hall JP, Caleo S, White HD, Tonkin AM. Cholesterol-lowering therapy with pravastatin in patients with average cholesterol levels and established ischaemic heart disease: is it cost-effective? Med J Aust 2002;177:428-34. Goldberg R, La Belle P, Zupkis R, Ronca P. Comparison of the effects of lovastatin and gemfibrozil on lipids and glucose control in non-insulin-dependent diabetes mellitus. Am J Cardiol 1990;66:B16-21. Goldberg RB, Mellies MJ, Sacks FM, Moye LA, Howard BV, Howard WJ, Davis BR, Cole TG, Pfeffer MA, Braunwald E. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels. Subgroup analysis in the Cholesterol and Recurrent Events (CARE) Trial. Circulation 1998;98:2513-9. Grigoresco C, Rizkalla SW, Halfon P, Bornet F, Fontvieille AM, Bros M, Dauchy F, Tchobroutsky G, Slama G. Lack of detectable deleterious effects on metabolic control of daily fructose ingestion for 2 months in NIDDM patients. Diabetes Care 1988;11:546-50. Groop PH, Aro A, Stenman S, Groop L. Long-term effects of guar gum in subjects with non-insulin dependent diabetes mellitus. Am J Clin Nutr 1993;58:513-8. Grover SA, Coupal L, Zowall H, Alexander CM, Weiss TW, Gomes DR. How cost-effective is the treatment of dyslipidemia in patients with diabetes but without cardiovascular disease? Diabetes Care 2001;24:45-50. Grover SA, Coupal L, Zowall H, Dorais M. Cost-effectiveness of treating hyperlipidemia in the presence of diabetes: who should be treated? Circulation 2000;102:722-7. Grundy SM, Vega GL, McGovern ME, Tulloch BR, Kendall DM, Fitz-Patrick D, Ganda OP, Rosenson RS, Buse JB, Robertson DD, Sheehan JP; Diabetes Multicenter Research Group. Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidaemia associated with Type 2 diabetes. Results of the Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial. Arch Intern Med 2002;162:1568-76. Gumbiner B, Low CC, Reaven PD. Effects of a monounsaturated fatty acid-enriched hypocaloric diet on cardiovascular risk factors in obese patients with type 2 diabetes. Diabetes Care 1998;21:9-15. Gupta RR, Agrawal CG, Singh GP, Ghatak A. Lipid-lowering efficacy of psyllium hydrophilic mucilloid in non insulin dependent diabetes mellitus with hyperlipidaemia. Indian J Med Res 1994;100:237-41. Gylling H, Miettinen TA. Serum cholesterol and cholesterol and lipoprotein metabolism in hypercholesterolaemic NIDDM patients before and during sitostanol ester-margarine treatment. Diabetologia 1994;37:773-80. Gylling H, Miettinen TA. Effects of inhibiting cholesterol absorption and synthesis on cholesterol and lipoprotein metabolism in hypercholesterolaemic non-insulin-dependent diabetic men. J Lipid Res 1996;37:1776-85.

173

Gylling H, Miettinen TA. Cholesterol reduction by different plant stanol mixtures and with variable fat intake. Metabolism 1999;48:575-80. Haffner SM, Agil A, Mykkanen L, Stern MP, Jialal I. Plasma oxidisability in subjects with normal glucose tolerance, impaired glucose tolerance, and NIDDM. Diabetes Care 1995;18:646-53. Haffner SM, Alexander CM, Cook TJ, Boccuzzi SJ, Musliner TA, Pedersen TR, Kjekshus J, Pyorala K. Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels. Subgroup analyses in the Scandinavian Simvastatin Survival Study. Arch Intern Med 1999;159:2661-7. Haffner SM, Ashraf T. Predicting risk reduction of coronary disease in patients who are glucose intolerant: a comparison of treatment with fenofibrate and other lipid-modifying agents. Managed Care Interface 2000;13:52-8. Haffner SM, Morales PA, Stern MP, Gruber MK. Lp(a) concentrations in NIDDM. Diabetes 1992a;41:1267-72. Haffner SM, Moss SE, Klein BEK, Klein R. Lack of association between lipoprotein (a) concentrations and coronary heart disease mortality in diabetes: The Wisconsin Epidemiologic Study of Diabetic Retinopathy. Metabolism 1992b;41:194-7. Haffner SM, Mykkanen L, Stern MP, Paidi M, Howard BV. Greater effect of diabetes on LDL size in women than in men. Diabetes Care 1994;17:1164-71. Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck U, Schmechel H, Ziegelasch HJ, Lindner J, the DIS Group. Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up. Diabetologoia 1996;39:1577-83. Hanefeld M, Fischer S, Schulze J, Spengler M, Wargenau M, Schollberg K, Fucker K. Therapeutic potentials of acarbose as first-line drug in NIDDM insufficiently treated with diet alone. Diabetes Care 1991;14:732-7. Hanninen J, Takala J, Keinanen-Kiukaanniemi S. Albuminuria and other risk factors for mortality in patients with non-insulin-dependent diabetes mellitus aged under 65 years: a population-based prospective 5-year study. Diabetes Res Clin Prac 1999;43:121-6. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002a;360:7-22 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant supplementation in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002b;360:23-33 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005-16. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363:757-67. Heine RJ, Mulder C, Popp-Snijders C, van der Meer J, van der Veen EA. Linoleic-acid-enriched diet: long-term effects on serum lipoprotein and apolipoprotein concentrations and insulin sensitivity in noninsulin-dependent diabetic patients. Am J Clin Nutr 1989;49:448-56. Heilbronn LK, Noakes M, Clifton PM. Effect of energy restriction, weight loss, and diet composition on plasma lipids and glucose in patients with Type 2 diabetes. Diabetes Care 1999;22:889-95. Heilbronn LK, Noakes M, Clifton PM. The effect of high- and low-glycaemic index energy restricted diets on plasma lipid and glucose profiles in Type 2 diabetic subjects with varying glycaemic control. J Am Coll Nutr 2002;21:120-7. Hermann LS, Schersten B, Bitzen PO, Kjellstrom T, Lingarde F, Melander A. Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. A double-blind controlled study. Diabetes Care 1994;17:1100-9.

174

Hermansen K, Sondergaard M, Hoie L, Carstensen M, Brock B. Beneficial effects of a soy-based dietary supplement on lipid levels and cardiovascular risk markers in Type 2 diabetic subjects. Diabetes Care 2001;24:228-33. Herz M, Johns D, Reviriego J, Grossman LD, Godin C, Duran S, Hawkins F, Lochnan H, Escobar-Jimenez F, Hardin PA, Konkoy CS, Tan MH. A randomised, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycaemic control and dyslipidaemia in oral antihyperglycaemic medication-naïve patients with Type 2 diabetes mellitus. Clin Ther 2003;25:1074-95. Hiraga T, Kobayashi T, Okubo M, Nakanishi K, Sugimoto T, Ohashi Y, Murase T. Prospective study of lipoprotein (a) as a risk factor for atheroslcerotic cardiovascular disease in patients with diabetes. Diabetes Care 1995;18:241-4. Hoffmann J, Spengler M. Efficacy of 24-week monotherapy with acarbose, metformin, or placebo in dietary-treated NIDDM patients: the Essen-II Study. Am J Med 1997;103:483-90. Hokanson JE, Austin MA. Plasma triglycerides level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 1996;3:213-9. Hollander PA, Elbein SC, Hirsch IB, Kelley D, McGill J, Taylor T, Weiss SR, Crockett SE, Kaplan RA, Comstock J, Lucas CP, Lodewick PA, Canovatchel W, Chung J, Hauptman J. Role of orlistat in the treatment of obese patients with Type 2 diabetes. A 1-yr randomised double-blind study. Diabetes Care 1998;21:1288-94. Honkola A, Forsen T, Eriksson J. Resistance training improves the metabolic profile in individuals with type 2 diabetes. Acta Diabetol 1997;34:245-8. Hoogwerf BJ, Waness A, Cressman M, Canner J, Campeau L, Domanski M, Geller N, Herd A, Hickey A, Hunninghake DB, Knatterud GL, White C. Effects of aggressive cholesterol lowering and low-dose anticoagulation on clinical and angiographic outcomes in patients with diabetes. The Post Coronary Artery Bypass Graft Trial. Diabetes 1999;48:1289-94. Huang ES, Meigs JB, Singer DE. The effect of interventions to prevent cardiovascular disease in patients with Type 2 diabetes mellitus. Am J Med 2001;111:633-42. Hughes K, Choo M, Kuperan P, Ong CN, Aw TC. Cardiovascular risk factors in non-insulin-dependent diabetics compared to non-diabetic controls: a population-based survey among Asians in Singapore. Atherosclerosis 1998;136:25-31. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-13. James RW, Boemi M, Sirolla C, Amadio L, Fumelli P, Pometta D. Lipoprotein (a) and vascular disease in diabetic patients. Diabetologia 1995;38:711-4. Jonsson B, Cook JR, Pedersen TR. The cost-effectiveness of lipid lowering in patients with diabetes: results from the 4S trial. Diabetologia 1999;42:1293-301. Kanters SD, Algra A, de Bruint TW, Erkelens DW, Banga JD. Intensive lipid-lowering strategy in patients with diabetes mellitus. Diabet Med 1999;16:500-8. Kaplan RC, Heckbert SR, Weiss NS, Wahl PW, Smith NL, Newton KM, Psaty BM. Postmenopausal estrogens and risk of myocardial infarction in diabetic women. Diabetes Care 1998;21:1117-21. Keech A. Personal communication. 2001. Keech A, Colquhoun D, Best J, Kirby A, Simes RJ, Hunt D, Hague W, Beller E, Arulchelvam M, Baker J, Tonkin A; LIPID Study Group. Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial. Diabetes Care 2003;26:2713-21. Kelley DE, Wing R, Buonocore C, Sturis J, Polonsky K, Fitzsimmons M. Relative effects of calorie restriction and weight loss in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1993;77:1287-93.

175

Kirchgassler KU, Schmitz H, Bach G. Effectiveness and tolerability of 12-week treatment with micronised fenofibrate 200 mg in a drug-monitoring programme involving 9884 patients with dyslipidaemia. Clin Drug Invest 1998;15:197-204. Knatterud GL, Rosenberg Y, Campeau L, Geller NL, Hunninghake DB, Forman SA, Forrester JS, Gobel FL, Herd JA, Hickey A, Hoogwerf BJ, Terrin ML, White C. Long-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the post coronary artery bypass graft trial. Circulation 2000;102:157-65. Knopp RH, Frohlich J, Jokubaitis LA, Dawson K, Broyles FE, Gomez-Coronado D. Efficacy and safety of fluvastatin in patients with non-insulin-dependent diabetes mellitus and hyperlipidemia. Am J Med 1994b;96(Suppl 6A):S69-78. Koskinen P, Manttari M, Manninen V, Huttunen JK, Heinonen OP, Frick MH. Coronary heart disease incidence in NIDDM patients in the Helsinky Heart Study. Diabetes Care 1992;15:820-5. Kudlacek S, Schernthaner G. The effect of insulin treatment on HbA1c, body weight and lipids in Type 2 diabetic patients with secondary-failure to sulfonylureas. A five year follow-up study. Horm Metab Res 1992;24:478-83. Laakso M, Pyorala K. Adverse effects of obesity on lipid and lipoprotein levels in insulin-dependent and non-insulin-dependent diabetes. Metabolism 1990;39:117-22. Laakso M, Voutilainen E, Sarlund H, Aro A, Pyorala K, Penttila I. Serum lipids and lipoproteins in middle-aged non-insulin-dependent diabetics. Atherosclerosis 1985;56:271-81. Lahdenpera S, Tilly-Kiesi M, Vuorinen-Markkola H, Kuusi T, Taskinen MR. Effects of gemfibrozil on low-density liporotein particle size, density distribution, and composition in patients with Type 2 diabetes. Diabetes Care 1993;16:584-92. Lam KSL, Tui SC, Tsang MW, Ip TP, Tam SCF. Acarbose in NIDDM patients with poor control on conventional oral agents. A 24-week placebo-controlled study. Diabetes Care 1998;21:1154-8. Landstedt-Hallin L, Adamson U, Arner P, Bolinder J, Lins PE. Comparison of bedtime NPH or preprandial regular insulin combined with glibenclamide in secondary sulfonylurea failure. Diabetes Care 1995;18:1183-6. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423-7. Lee YM, Haastert B, Scherbaum W, Hauner H. A phytosterol-enriched spread improves the lipid profile of subjects with Type 2 diabetes mellitus. A randomised controlled trial under free-living conditions. Eur J Nutr 2003;42:111-7. Lehmann R, Vokac A, Niedermann K, Agosti K, Spinas GA. Loss of abdominal fat and improvement of the cardiovascular risk profile by regular moderate exercise training in patients with NIDDM. Diabetelogia 1995;38:1313-9. Lehmann R, Engler H, Honegger R, Riesen W, Spinas GA. Alterations of lipolytic enzymes and high-density lipoprotein subfractions induced by physical activity in Type 2 diabetes mellitus. Eur J Clin Invest 2001;31:37-44. Lehto S, Ronnemaa T, Haffner SM, Pyorala K, Kallio V, Laakso M. Dyslipidemia and hyperglycemia predict coronary heart disease events in middle-aged patients with NIDDM. Diabetes 1997;46:1354-9. Leinonen J, Rantalaiho V, Lehtimaki T, Koivula T, Wirta O, Pasternack A, Alho H. The association between the total antioxidant potential of plasma and the presence of coronary heart disease and renal dysfunction in patients with NIDDM. Free Rad Res 1998b;29:273-81. Leinonen JS, Rantalaiho V, Solakivi T, Koivula T, Wirta O, Pasternack A, Alho H, Lehtimaki T. Susceptibility of LDL to oxidation is not associated with the presence of coronary heart disease or renal dysfunction in NIDDM patients. Clin Chim Acta 1998a;275:163-74.

176

Leonhardt W, Hanefeld M, Muller G, Hora C, Meissner D, Lattke P, Paetzold A, Jaross W, Schroeder HE. Impact of concentrations of glycated hemoglobin, alpha-tocopherol, copper, and manganese on oxidation of low-density lipoproteins in patients with type I diabetes, type II diabetes and control subjects. Clin Chim Acta 1996;254:173-86. Ligtenberg PC, Hoekstra JB, Bol E, Zonderland ML, Erkelens DW. Effects of physical training on metabolic control in elderly type 2 diabetes mellitus patients. Clin Sci 1997;93:127-35. LIPID Study Group. Long-Term Intervention with Pravastatin in Ischaemic Disease. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-57. Low CC, Grossman EB, Gumbiner B. Potentiation of effects of weight loss by monounsaturated fatty acids in obese NIDDM patients. Diabetes 1996;45:569-75. Luscombe ND, Noakes M, Clifton PM. Diets high and low in glycemic index versus high monounsaturated fat diets: effects on glucose and lipid metabolism in NIDDM. Eur J Clin Nutr 1999;53:473-8. MacRury SM, Gordon D, Wilson R, Bradley H, Gemmell CG, Paterson JR, Rumley AG, MacCuish AC. A comparison of different methods of assessing free radical activity in Type 2 diabetes and peripheral vascular disease. Diabet Med 1993;10:331-5. Malerbi DA, Paiva ES, Duarte AL, Wajchenberg BL. Metabolic effect of dietary sucrose and fructose in type II diabetic subjects. Diabetes Care 1996;19:1249-56. Manley SE, Stratton IM, Cull CA, Frighi V, Eeley EA, Matthews DR, Holman RR, Turner RC, Neil HA, UKPDS Group. Effects of three months' diet after diagnosis of Type 2 diabetes on plasma lipids and lipoprotein (UKPDS 45). Diabet Med 2000;17:518-23. Manninen V, Huttunen JK, Heinonen OP, Tenkanen L, Frick MH. Relation between baseline lipid and lipoprotein values and the incidence of coronary heart disease in the Helsinki Heart Study. Am J Cardiol 1989;63:H42-7. Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Manttari M, Heinonen OP, Frick MH. Joint effects of serum triglycerides and LDL cholesterol and HDL cholesterol concentration on coronary heart disease risk in the Helsinki Heart Study. Circulation 1992;85:37-45. Manning PJ, Allum A, Jones S, Sutherland WH, Williams SM. The effect of hormone replacement therapy on cardiovascular risk factors in Type 2 diabetes. A randomised controlled trial. Arch Intern Med 2001;161:1772-6. Manson JE, Colditz GA, Stampfer MJ, Willett WC, Krolewski AS, Rosner B, Arky RA, Speizer FE, Hennekens CH. A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women. Arch Intern Med 1991;151:1141-7. Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, Trevisan M, Black HR, Heckbert SR, Detrano R, Strickland OL, Wong ND, Crouse JR, Stein E, Cushman M; Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523-34. Manzato E, Zambon A, Lapolla A, Zambon S, Braghetto L, Crepaldi G, Fedele D. Lipoprotein abnormalities in well-treated Type II diabetic patients. Diabetes Care 1993;16:469-75. Markovic TP, Campbell LV, Balasubramanian S, Jenkins AB, Fleury AC, Simons LA, Chisholm DJ. Beneficial effect on average lipid levels from energy restriction and fat loss in obese individuals with or without type 2 diabetes. Diabetes Care 1998;21:695-700. Mattock MB, Keen H, Viberti GC, El-Gohari MR, Murrells TJ, Scott GS, Wing JR, Jackson PG. Coronary heart disease and urinary albumin excretion rate in Type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1988;31:82-7. Mayer-Davis EJ, Levin S, Marshall JA. Heterogeneity in associations between macronutrient intake and lipoprotein profile in individuals with Type 2 diabetes. Diabetes Care 1999;22:1632-9.

177

McIntosh A, Hutchinson A, Feder G, Durrington P, Elkeles R, Hitman GA, Robson J, Home P, Peters J, Pandor A, Kaltenthaler E (2002). Clinical guidelines and evidence review for Type 2 diabetes: Lipids management. Sheffield: ScHARR, University of Sheffield. Meigs JB, Singer DE, Sullivan LM, Dukes KA, D'Agostino RB, Nathan DM, Wagner EH, Kaplan SH, Greenfield S. Metabolic control and prevalent cardiovacular disease in non-insulin-dependent diabetes mellitus (NIDDM): the NIDDM Patient Outcomes Research Team. Am J Med 1997;102:38-47. Milan Study on Atherosclerosis and Diabetes (MiSAD) Group. Prevalence of unrecognized silent myocardial ischemia and its association with atherosclerotic risk factors in noninsulin-dependent diabetes mellitus. Am J Cardiol 1997;79:134-9. Milne RM, Mann JI, Chisholm AW, Williams SM. Long-term comparison of three dietary prescriptions in the treatment of NIDDM. Diabetes Care 1994;17:74-80. Montori VM, Farmer A, Wollan PC, Dinneen SF. Fish oil supplementation in type 2 diabetes. Diabetes Care 2000;23:1407-15. Nacitarhan S, Ozben T, Tuncer N. Serum and urine malondialdehyde levels in NIDDM patients with and without hyperlipdemia. Free Radic Biol Med 1995;19:893-6. Nielsen FS, Voldsgaard AI, Gall MA, Rossing P, Hommel E, Andersen P, Dyerberg J, Parving HH. Apolipoprotein (a) and cardiovascular disease in Type 2 (non-insulin-dependent) diabetic patients with and without diabetic nephropathy. Diabetologia 1993;36:438-44. Niemeijer-Kanters SD, Dallinga-Thie GM, de Ruijter-Heijstek FC, Algra A, Erkelens DW, Banga JD, Jansen H. Effect of intensive lipid-lowering strategy on low-density lipoprotein particle size in patients with Type 2 diabetes mellitus. Atherosclerosis 2001;156:209-16. Niemi MK, Keinanen-Kiukaanniemi SM, Salmela PI. Long-term effects of guar gum and microcrystalline cellulose on glycaemic control and serum lipids in Type 2 diabetes. Eur J Clin Pharmacol 1988;34:427-9. Niskanen L, Turpeinen A, Penttila I, Uusitupa MI. Hyperglycemia and compositional lipoprotein abnormalities as predictors of cardiovascular mortality in type 2 diabetes. Diabetes Care 1998;21:1861-9. Niskanen L, Uusitupa M, Sarlund H, Siitonen O, Voutilainen E, Penttila I, Pyorala K. Microalbuminuria predicts the development of serum lipoprotein abnormalities favouring atherogenesis in newly diagnosed Type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1990;33:237-43. O'Brien T, Nguyen TT, Harrison JM, Bailey KR, Dyck PJ, Kottke BA. Lipids and Lp (a) lipoprotein levels and coronary artery disease in subjects with non-insulin-dependent diabetes mellitus. Mayo Clin Proc 1994;69:430-5. O'Dea K, Traiandes K, Irealnd P, Niall M, Sadler J, Hopper J, DeLuise M. The effects of diet differing in fat, carbohydrate and fibre on carbohydrate and lipid metabolism in Type II diabetes. Journal of the American Dietetic Association 1989;89:1076-86. Ogawa S, Takeuchi K, Sugimura K, Fukuda M, Lee R, Ito S, Sato T. Bezafibrate reduces blood glucose in Type 2 diabetes mellitus. Metabolism 2000;49:331-4 O'Neal DN, O'Brien RC, Timmins KL, Grieve GD, Lau KP, Nicholson GC, Kotowicz MA, Best JD. Gemfibrozil treatment increases low-density lipoprotein particle size in type 2 diabetes mellitus but does not alter in vitro oxidisability. Diabet Med 1998;15:870-7. Osei K, Bossetti B. Dietary fructose as a natural sweetener in poorly controlled Type 2 diabetes: a 12-month crossover study of effects on glucose, lipoprotein and apolipoprotein metabolism. Diabet Med 1989;6:506-11. Osei K, Falko J, Bossetti BM, Holland GC. Metabolic effects of fructose as a natural sweetener in the physiologic meals of ambulatory obese patients with Type II diabetes. Am J Med 1987;83:249-55. Paolisso G, Balb iV, Volpe C, Varricchio G, Gambardella A, Saccomanno F, Ammendola S, Varricchio M, D'Onofrio F. Metabolic benefits deriving from chronic vitamin C supplementation in aged non-insulin dependent diabetics. J Am Coll Nutr 1995;14:387-92.

178

Parfitt VJ, Desomeaux K, Bolton CH, Hartog M. Effects of high monounsaturated and polyunsaturated fat diets on plasma lipoproteins and lipid peroxidation in Type 2 diabetes mellitus. Diabet Med 1994;11:85-91. Parillo M, Giacco R, Ciardullo AV, Rivellese AA, Riccardi G. Does a high carbohydrate diet have different effects in NIDDM patients treated with diet alone or hypoglycemic drugs? Diabetes Care 1996;19:498-500. Parker B, Noakes M, Luscombe N, Clifton, P. Effect of a high-protein, high-monounsaturated fat weight loss diet on glycaemic control and lipid levels in Type 2 diabetes. Diabetes Care 2002;25:425-30. Pearson TA, Laurora I, Chu H, Kafonek S. The lipid treatment assessment project (L-TAP). A multicentre survey to evaluate the percentages of dyslipidaemic patients receiving lipid-lowering therapy and achieving low-density cholesterol goals. Arch Int Med 2000;160:459-67. Pedersen TR, Olsson AG, Faergeman O, Kjekshus J, Wedel H, Berg K, Wilhelmsen L, Haghfelt T, Thorgeirsson G, Pyorala K, Miettinen T, Christophersen B, Tobert JA, Musliner TA, Cook TJ, for the Scandinavian Simvastatin Survival Study Group. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 1998;97:1453-60. Perera M, Sattar N, Petrie JR, Hillier C, Small M, Connell JM, Lowe GD, Lumsden MA. The effects of transdermal estradiol in combination with oral morethisterone on lipoproteins, coagulation, and endothelial markers in postmenopausal women with Type 2 diabetes: A randomised, placebo-controlled study. J Clin Endocrinol Metab 2001;86:1140-3. Petersen M, Pedersen H, Major-Pedersen A, Jensen T, Marckmann P. Effect of fish oil versus corn oil supplementation on LDL and HDL subclasses in Type 2 diabetic patients. Diabetes Care 2002;25:1704-8. Pick ME, Hawrysh ZJ, Gee MI, Toth E, Garg ML, Hardin RT. Oat bran concentrate bread products improve long-term control of diabetes: a pilot study. J Am Diet Assoc 1996;96:1254-61. Poirier P, Catellier C, Tremblay A, Nadeau A. Role of body fat loss in the exercise-induced improvement of the plasma lipid profile in non-insulin-dependent diabetes mellitus. Metabolism 1996;45:1383-7. Pownall HJ, Ballantyne CM, Kimball KT, Simpson SL, Yeshurun D, Gotto AM Jr. Effect of moderate alcohol consumption on hypertriglyceridemia. Arch Intern Med 1999;159:981- 87. Pyorala K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997;20:614-20. Rains SG, Wilson GA, Richmond W, Elkeles RS. The effect of glibenclamide and metformin on serum lipoproteins in Type 2 diabetes. Diabet Med 1988;5:653-8. Ravid M, Brosh D, Ravid-Safran D, Levy Z, Rachmani R. Main risk factors for nephropathy in Type 2 diabetes mellitus are plasma cholesterol levels, mean blood pressure, and hyperglycemia. Arch Intern Med 1998;158:998-1004. Raz I, Hauser E, Bursztyn M. Moderate exercise improves glucose metabolism in uncontrolled elderly patients with non-insulin-dependent diabetes mellitus. Isr J Med Sci 1994;30:766-70. Reaven PD, Herold DA, Barnett J, Edelman S. Effects of vitamin E on susceptibility of low-density lipoprotein and low density lipoprotein subfractions to oxidation and on protein glycation in NIDDM. Diabetes Care 1995;18:807-16. Rigla M, Sanchez-Quesada JL, Ordonez-Llanos J, Prat T, Caixas A, Jorba O, Serra JR, de Leiva A, Perez A. Effect of physical exercise on lipoprotein(a) and low-density lipoprotein modification in Type 1 and Type 2 diabetic patients. Metabolism 2000;49:640-7. Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ. Moderate alcohol intake and lower risk of coronary heart disease: metanalysis of effects on lipids and haemostatic factors. BMJ 1999;319:1523-8.

179

Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ, McNamara JR, Kashyap ML, Hershman JM, Wexler LF, Rubins HB; VA-HIT Study Group. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA 2001;285:1585-91. Rodier M, Colette C, Gouzes C, Michel F, Crastes de Paulet A, Monnier L. Effects of insulin therapy upon plasma lipid fatty acids and platelet aggregation in NIDDM with secondary failure to oral antidiabetic agents. Diabetes Res Clin Pract 1995;28:19-28. Rodriguez-Moran M, Guerrero-Romero F, Lazcano-Burciaga G. Lipid- and glucose-lowering efficacy of plantago psyllium in Type II diabetes. J Diabetes Complications 1998;12:273-8. Ronnemaa T, Laakso M, Kallio V, Pyorala K, Marniemi J, Puukka P. Serum lipids, lipoproteins, and apolipoproteins and the excessive occurrence of coronary heart disease in non-insulin-dependent diabetic patients. Am J Epidemiol 1989;130:632-45. Ronnemaa T, Marniemi J, Puukka P, Kuusi T. Effects of long-term physical exercise on serum lipids, lipoproteins and lipid metabolizing enzymes in Type 2 (non-insulin-dependent) diabetic patients. Diabetes Res 1988;7:79-84. Rosenblatt S, Miskin B, Glazer NB, Prince MJ, Robertson KE; Pioglitazone 026 Study Group. The impact of pioglitazone on glycaemic control and atherogenic dyslipidaemia in patients with Type 2 diabetes mellitus. Coron Artery Dis 2001;12:413-23. Rovellini A, Sommariva D, Branchi A, Maraffi F, Montalto C, Gandini R, Fasoli A. Effects of slow release bezafibrate on the lipid pattern and on blood glucose of Type 2 diabetic patients with hyperlipidaemia. Pharmacol Res 1992;25:237-45. Rubins HB, Nelson DB, Noorbaloochi S, Nugent S. Effectiveness of lipid-lowering medications in outpatients with coronary heart disease in the Department of Veterans Affairs System. Am J Cardiol 2003;92:1177-82. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410-8. Rubins HB, Robins SJ, Collins D, Nelson DB, Elam MB, Schaefer EJ, Faas FH, Anderson JW. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Arch Int Med 2002;162:2597-604. Ruiz J, Thillet J, Huby T, James RW, Erlich D, Flandre P, Froguel P, Chapman J, Passa P. Association of elevated lipoprotein (a) levels and coronary heart disease in NIDDM patients. Relationship with apolipoprotein (a) phenotypes. Diabetologia 1994;37:585-91. Rustemeijer C, Schouten JA, Voerman HJ, Hensgens HE, Donker AJ, Heine RJ. Pravastatin compared to bezafibrate in the treatment of dyslipidaemia in insulin-treated patients with Type 2 diabetes mellitus. Diabetes Metab Res Rev 2000;16:82-7. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-9. Sacks FM, Moye LA, Davis BR, Cole TG, Rouleau JL, Nash DT, Pfeffer MA, Braunwald E. Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the Cholesterol and Recurrent Events trial. Circulation 1998;97:1446-52. Sacks FM, Tonkin AM, Shepherd J, Braunwald E, Cobbe S, Hawkins CM, Keech A, Packard C, Simes J, Byington R, Furberg CD, for the Prospective Pravastatin Pooling Project Investigators Group. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors. The Prospective Pravastatin Pooling Project. Circulation 2000;102:1893-900. Sacks FM, Tonkin AM, Craven T, Pfeffer MA, Shepherd J, Keech A, Furberg CD, Braunwald E. Coronary heart disease in patients with low LDL-cholesterol. Benefit of pravastatin in diabetics and enhanced role for HDL-cholesterol and triglycerides as risk factors. Circulation 2002;105:1424-8.

180

Saito I, Folsom AR, Brancati FL, Duncan BB, Chambless LE, McGovern PG. Nontraditional risk factors for coronary heart disease incidence among persons with diabetes: The Atherosclerosis Risk in Communities (ARIC) Study. Ann Intern Med 2000;133:81-91. Salomaa VV, Tuomilehto J, Jauhiainen M, Korhonen HJ, Stengard J, Uusitupa M, Pitkanen M, Penttila I. Hypertriglyceridemia in different degrees of glucose intolerance in a Finnish population-based study. Diabetes Care 1992;15:657-65. Scandinavian Simvistatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-9. Scheffer PG, Bos G, Volwater HG, Deker JM, Heine RJ, Teerlink T. Association of LDL size with in vitro oxidisability and plasma levels of in vivo oxidised LDL in Type 2 diabetic patients. Diabet Med 2003;20:563-7. Schneider J, Erren T, Zofel P, Kaffarnik H. Metformin-induced changes in serum lipids, lipoproteins, and apoproteins in non-insulin-dependent diabetes mellitus. Atherosclerosis 1990;82:97-103. Schneider SH, Khachadurian AK, Amorosa LF, Clemow L, Ruderman NB. Ten-year experience with an exercise-based outpatient life-style modification program in the treatment of diabetes mellitus. Diabetes Care 1992;15:1800-10. Schweitzer M, Tessier D, Vlahos WD, Leiter L, Collet JP, McQueen MJ, Harvey L, Alaupovic P. A comparison of pravastatin and gemfibrozil in the treatment of dyslipoproteinaemia in patients with non-insulin-dependent diabetes mellitus. Atherosclerosis 2002;162:201-10. Seghieri G, Alviggi L, Caselli P, De Giorgio LA, Breschi C, Gironi A, Niccolai M, Bartolomei GC. Serum lipids and lipoproteins in Type 2 diabetic patients with persistent microalbuminuria. Diabet Med 1990;7:810-4. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149-58. Seviour PW, Teal TK, Richmond W, Elkeles RS. Serum lipids, lipoproteins and macrovascular disease in non-insulin-dependent diabetics: a possible new approach to prevention. Diabet Med 1988;5:166-71. Sharrett AR, Ballantyne CM, Coady SA, Heiss G, Sorlie PD, Catellier D, Patsch W; Atherosclerosis Risk in Communities Study Group. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions. The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001;104:1108-13. Sheehan JP, Wei IW, Ulchaker M, Tserng KY. Effect of high fiber intake in fish oil-treated patients with non-insulin-dependent diabetes mellitus. Am J Clin Nutr 1997;66:1183-7. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG; PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-30. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolaemia. N Engl J Med 1995;333:1301-7. Siegel RD, Cupples A, Schaefer EJ, Wilson PW. Lipoproteins, apolipoproteins, and low-density lipoprotein size among diabetics in the Framingham Offspring Study. Metabolism 1996;45:1267-72. Simes RJ, Marschner IC, Hunt D, Colquhoun D, Sullivan D, Stewart RA, Hague W, Keech A, Thompson P, White H, Shaw J, Tonkin A; LIPID Study Investigators. Relationship between lipid levels and clinical outcomes in the LongpTerm Intervention with Pravastatin in Ischemic Disease (LIPIDS) trial: to what extent is the reduction in coronary events with Pravastatin explained by on-study lipid levels? Circulation 2002;105:1162-9.

181

Skarfors ET, Wegener TA, Lithell H, Selinus I. Physical training as treatment for Type 2 (non-insulin-dependent) diabetes in elderly men. A feasibility study over 2 years. Diabetologia 1987;30:930-3. Smith SJ, Cooper GR, Myers GL, Sampson EJ. Biological variability in concentrations of serum lipids: sources of variation among results from published studies and composite predicted values. Clin Chem 1993;39:1012-22. Soedamah-Muthu SS, Colhoun HM, Thomason MJ, Betteridge DJ, Durrington PN, Hitman GA, Fuller JH, Julier K, Mackness MI, Neil HA; CARDS Investigators. The effect of atorvastatin on serum lipids, lipoproteins and NMR spectroscopy defined lipoprotein subclasses in Type 2 diabetic patients with ischaemic heart disease. Atherosclerosis 2003;167:243-55. Solfrizzi V, Panza F, Colacicco AM, Capurso C, D'Introno A, Torres F, Baldassarre G, Capurso A. Relation of lipoprotein(a) as coronary risk factor to Type 2 diabetes mellitus and low-density lipoprotein cholesterol in patients ≥65 years of age (The Italian Longitudinal Study on Aging). Am J Cardiol 2002;89:825-9. Sprecher DL, Pearch GL, Park EM, Pashkow F, Hoogwerf BJ. Preoperative triglycerides predict post-coronary artery bypass graft survival in diabetic patients. Diabetes Care 2000;23:1648-53. Stamler J, Vaccaro O, Neaton JD, Wentworth D, for the Multiple Risk Factor Intervention Trial Research Group. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434-44. Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the Nurses' Health Study. N Engl J Med 1991;325:756-62. Suraniti S, Bled F, Girault A, Fressinaud P, Marre M. Serum lipids and urinary albumin excretion in non insulin-dependent diabetics. Mol Cell Biochem 1992;109:197-200. Syvanne M, Hilden H, Taskinen MR. Abnormal metabolism of postprandial lipoproteins in patients with non-insulin-dependent diabetes mellitus is not related to coronary artery disease. J Lipid Res 1994;35:15-26. Teo KK, Burton JR, Buller CE, Plante S, Catellier D, Tymchak W, Dzavik V, Taylor D, Yokoyama S, Montague TJ, for the SCAT Investigators. Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis. The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Circulation 2000;102;1748-54. The CDC Diabetes Cost-effectiveness Group. Cost-effectiveness of intensive glycaemic control, intensified hypertension control, and serum cholesterol level reduction for Type 2 diabetes. JAMA 2002;287:2542-51. The Diabetes Atorvastatain Lipid Intervention (DALI) Study Group. The effect of aggressive versus standard lipid lowering by atorvastatin on diabetic dyslipidemia: the DALI study: a double-blind, randomized, placebo-controlled trial in patients with type 2 diabetes and diabetic dyslipidemia. Diabetes Care 2001;24:1335-41. Thomsen C, Rasmussen OW, Hansen KW, Vesterlund M, Hermansen K. Comparison of the effects on the diurnal blood pressure, glucose, and lipid levels of a diet rich in monounsaturated fatty acids with a diet rich in polyunsaturated fatty acids in Type 2 diabetic subjects. Diabet Med 1995;12:600-6. Tikkanen MJ, Laakso M, Ilmonen M, Helve E, Kaarsalo E, Kilkki E, Saltevo J. Treatment of hypercholesterolemia and combined hyperlipidemia with simvastatin and gemfibrozil in patients with NIDDM. A multicenter comparison study. Diabetes Care 1998;21:477-81. Tkac I, Kimball BP, Lewis G, Uffelman K, Steiner G. The severity of coronary atherosclerosis in Type 2 diabetes mellitus is related to the number of circulating triglycerides-rich lipoprotein particles. Arterioscler Thromb Vasc Biol 1997;17:3633-8. Tsalamandris C, Panagiotopoulos S, Sinha A, Cooper ME, Jerums G. Complementary effects of pravastatin and nicotinic acid in the treatment of combined hyperlipidaemia in diabetic and non-diabetic patients. J Cardiovasc Risk 1994;1:231-9. Tsalamandris C, Panagiotopoulos S, Allen TJ, Waldrip L, Van Gaal B, Goodall I, Jerums G. Long-term intraindividual variability of serum lipids in patients with type 1 and type II diabetes. J Diab Complications 1998;12:208-14.

182

Tsihlias EB, Gibbs AL, McBurney MI, Wolever TM. Comparison of high- and low-glycaemic-index breakfast cereals with monounsaturated fat in the long-term dietary management of Type 2 diabetes. Am J Clin Nutr 2000;72:439-49. Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR, Holman RR, for the United Kingdom Prospective Diabetes Study Group. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS:23). BMJ 1998;316:823-8. UKPDS 11. UK Prospective Diabetes Study (UKPDS) XI: Biochemical risk factors in Type 2 diabetic patients at diagnosis compared with age-matched normal subjects. Diabet Med 1994;11:534-4. Upritchard JE, Sutherland WH, Mann JI. Effect of supplementation with tomato juice, vitamin E, and vitamin C on LDL oxidation and products of inflammatory activity in Type 2 diabetes. Diabetes Care 2000;23:733-8. Uusitupa M, Siitonen O, Voutilainen E, Aro A, Hersio K, Pyorala K, Penttila I, Ehnholm C. Serum lipids and lipoproteins in newly diagnosed non-insulin-dependent (Type II) diabetic patients, with special reference to factors influencing HDL-cholesterol and triglycerides levels. Diabetes Care 1986;9:17-22. Vakkilainen J, Steiner G, Ansquer JC, Aubin F, Rattier S, Foucher C, Hamsten A, Taskinen MR; DAIS Group. Relationships between low-density lipoprotein particle size, plasma lipoproteins, and progression of coronary artery disease. The Diabetes Atherosclerosis Intervention Study (DAIS). Circulation 2003;107:1733-7. Vale MJ, Jelinek MV, Best JD, Santamaria JD. Coaching patients with coronary heart disease to achieve the target cholesterol: a method to bridge the gap between evidence-based medicine and the "real world" - randomized controlled trial. J Clin Epidemiol 2002;55:245-52. Vanninen E, Uusitupa M, Siitonen O, Laitinen J, Lansimies E. Habitual physical activity, aerobic capacity and metabolic control in patients with newly-diagnosed Type 2 (non-insulin-dependent) diabetes mellitus: effect of 1-year diet and exercise intervention. Diabetologia 1992;35:340-6. Velho G, Erlich D, Turpin E, Neel D, Cohen D, Froguel P, Passa P. Lipoprotein (a) in diabetic patients and normoglycaemic relatives in familial NIDDM. Diabetes Care 1993;16:742-7. Vessby B, Karlstrom B, Boberg M, Lithell H, Berne C. Polyunsaturated fatty acids may impair blood glucose control in Type 2 diabetic patients. Diabet Med 1992;9:126-33. Vinik AI, Colwell JA. Effects of gemfibrozil on triglycerides levels in patients with NIDDM. Diabetes Care 1993;16:37-44. Vuorinen-Markkola H, Yki-Jarvinen H, Taskinen MR. Lowering of triglycerides by gemfibrozil affects neither the glucoregulatory nor antilipolytic effect of insulin in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993;36:161-9. Wagner AM, Jorba O, Bonet R, Ordonez-Llanos J, Perez A. Efficacy of atorvastatin and gemfibrozil, alone and in low does combination, in the treatment of diabetic dyslipidaemia. J Clin Endocrinol Metab 2003;88:3212-7. Walker KZ, Piers LS, Putt RS, Jones JA, O'Dea K. Effects of regular walking on cardiovascular risk factors and body composition in normoglycaemic women and women with Type 2 diabetes. Diabetes Care 1999;22:555-61. Wasenius A, Stugaard M, Otterstad JE, Froyshov D. Diurnal and monthly intra-individual variability of the concentration of lipids, lipoproteins and apoproteins. Scand J Clin Lab Invest 1990;50:635-42. Waters D, Higginson L, Gladstone P, Kimball B, Le May M, Boccuzzi SJ, Lesperance J, the CCAIT Study Group. Effects of monotherapy with an HMG-CoA reductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography. The Canadian Coronary Atherosclerosis Intervention Trial. Circulation 1994;89:959-68. Wei M, Gibbons LW, Mitchell TL, Kampert JB, Blair SN. Alcohol intake and incidence of Type 2 diabetes in men. Diabetes Care 2000;23:18-22. West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 1998;97:1440-5.

183

White HD, Simes RJ, Anderson NE, Hankey GJ, Watson JD, Hunt D, Colquhoun DM, Glasziou P, MacMahon S, Kirby AC, West MJ, Tonkin AM. Pravastatin therapy and the risk of stroke. N Engl J Med 2000;343:317-26. White CW, Gobel FL, Campeau L, Knatterud GL, Forman SA, Forrester JS, Geller NL, Herd JA, Hickey A, Hoogwerf BJ, Hunninghake DB, Rosenberg Y, Terrin ML; Post Coronary Artery Bypass Graft Trial Investigators. Effect of an aggressive lipid-lowering strategy on progression of atherosclerosis in the left main coronary artery from patients in the Post Coronary Artery Bypass Graft Trial. Circulation 2001;104:2660-5. Wing RR, Blair E, Marcus M, Epstein LH, Harvey J. Year-long weight loss treatment for obese patients with type II diabetes: does including an intermittent very-low-calorie diet improve outcome? Am J Med 1994;97:354-62. Wolever TM. Tsihlias EB. McBurney MI. Le NA. Long-term effect of reduced carbohydrate or increased fiber intake on LDL particle size and HDL composition in subjects with type 2 diabetes. Nutr Res 2003;23:15-26. Wolffenbuttel BH, Sels JP, Rondas-Colbers GJ, Menheere PP, Nieuwenhuijzen Kruseman AC. Comparison of different insulin regimens in elderly patients with NIDDM. Diabetes Care 1996;19:1326-32.

184

Lipid Disease: General References American Diabetes Association. Dyslipidaemia management in adults with diabetes. Diabetes Care 2003;26(Suppl 1):S83-6. Anderson KM, Odell PM, Wilson PW, Kannel WB. Cardiovascular disease risk profiles. Am Heart J 1991;121:293-8 Assmann G. Cullen P. Schulte H. The Munster Heart Study (PROCAM). Results of follow-up at 8 years. Eur Heart J 1998;19(Suppl A):A2-11. Assmann G, Funke H. HDL metabolism and atherosclerosis. J Cardiovasc Pharmacol 1990;16 (Suppl 9):S15-20. Barakat HA, Carpenter JW, McLendon VD, Khazanie P, Leggett N, Heath J, Marks R. Influence of obesity, impaired glucose tolerance, and NIDDM on LDL structure and composition. Possible link between hyperinsulinemia and atherosclerosis. Diabetes 1990;39:1527-33. Barter PJ, O'Brien RC. Achievement of target plasma cholesterol levels in hypercholesterolaemic patients being treated in general practice. Atherosclerosis 2000;149:199-205. Branchi A, Rovellini A, Torri A, Sommariva D. Accuracy of calculated serum low-density lipoprotein cholesterol for the assessment of coronary heart disease risk in NIDDM patients. Diabetes Care 1998;21:1397-402. British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, British Diabetic Association. Joint British recommendations on prevention of coronary heart disease in clinical practice: summary. BMJ 2000; 320:705-8. Brunzell JD, Hokanson JE. Dyslipidemia of central obesity and insulin resistance. Diabetes Care 1999;22(Suppl 3):C10-3. Carey DG, Jenkins AB, Campbell LV, Freund J, Chisholm DJ. Abdominal fat and insulin resistance in normal and overweight women: Direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM. Diabetes 1996;45:633-8. Castelli WP. Epidemiology of triglycerides: A View from Framingham. Am J Cardiol 1992;70:H3-9. Colagiuri S, Best J. Lipid-lowering therapy in people with Type 2 diabetes. Curr Opin Lipidol 2002;13:617-23. De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, Ebrahim S, Faergeman O, Graham I, Mancia G, Manger Cats V, Orth-Gomer K, Perk J, Pyorala K, Rodicio JL, Sans S, Sansoy V, Sechtem U, Silber S, Thomsen T, Wood D. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J 2003;24:1601-10. Expert Committee on the diagnosis and classification of diabetes mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20:1183-97. Expert Panel on Detection, Evaluation, and Treatment in High Blood Cholesteral in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486-97. Flegal KM. Blood lipid levels in Type 2 diabetes. What are the effects of diet? Diabetes Care 1999;22:1605-6. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502. Garg A. Insulin resistance in the pathogenesis of dyslipidemia. Diabetes Care 1996;19:387-9. Garg A, Grundy M. Diabetic dyslipidemia and its therapy. Diabetes Rev 1997;5:425-33.

185

Goldberg RB. The benefits of lowering cholesterol in subjects with mild hyperglycaemia. Arch Intern Med 1999;159:2627-8. Gomez-Perez FJ, Aguilar-Salinas CA, Lopez-Alvarenga JC, Perez- Jauregui J, Guillen-Pineda LE, Rull JA. Lack of agreement between the World Health Organization category of impaired glucose tolerance and the American Diabetes Association category of impaired fasting glucose. Diabetes Care 1998;21:1886-8. Grundy SM, Balady GJ, Criqui MH, Fletcher G, Greenland P, Hiratzka LF, Houston-Miller N, Kris-Etherton P, Krumholz HM, LaRosa J, Ockene IS, Pearson TA, Reed J, Washington R, Smith SC Jr. Primary prevention of coronary heart disease: Guidance from Framingham: A statement for healthcare professionals from the AHA task force on risk reduction. Circulation 1998;97:1876-87. Haffner SM. The insulin resistance syndrome revisited. Diabetes Care 1996;19:275-7. Haffner SM. Management of dyslipidemia in adults with diabetes. Diabetes Care 1998;21:160-78. Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA 1990;263:2893-8. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002a;360:7-22 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005-16. Himsworth HP. Diabetes mellitus. It's differentiation into insulin-sensitive and insulin-insensitive types. Lancet 1936;1:127-30. Jackson R. Guidelines on preventing cardiovascular disease in clinical practice. BMJ 2000a;320:659-61. Jackson R. Updated New Zealand cardiovascular disease risk-benefit prediction guide. BMJ 2000b;320:709-10. Kannel WB. Cholesterol and risk of coronary heart disease and mortality in men. Clin Chem 1988;34 (Suppl B):53-9. Karter AJ, Mayer-Davis EJ, Selby JV, D'Agostino RB Jr, Haffner SM, Sholinsky P, Bergman R, Saad MF, Hamman RF. Insulin sensitivity and abdominal obesity in African-American, Hispanic, and non-Hispanic white men and women. The Insulin Resistance and Atherosclerosis Study. Diabetes 1996;45:1547-55. Laakso M. Lipids and lipoproteins as risk factors for coronary heart disease in non-insulin-dependent diabetes mellitus. Ann Med 1996;28:341-5. Laakso M. Dyslipidemia, morbidity, and mortality in non-insulin-dependent diabetes mellitus. Lipoproteins and coronary heart disease in non-insulin-dependent diabetes mellitus. J Diabetes Complications 1997;11:137-41. Laakso M, Lehto S, Penttila I, Pyorala K. Lipids and lipoproteins predicting coronary heart disease mortality and morbidity in patients with non-insulin-dependent diabetes. Circulation 1993;88:1421-30. LIPID Study Group. Long-Term Intervention with Pravastatin in Ischaemic Disease. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-57. Manninen V, Koskinen P, Manttari M, Huttunen JK, Canter D, Frick HM. Predictive value for coronary heart disease of baseline high-density and low-density lipoprotein cholesterol among Fredrickson type IIa subjects in the Helsinki Heart Study. Am J Cardiol 1990;66:A24-7. Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Manttari M, Heinonen OP, Frick MH. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment. Circulation 1992;85:37-45. McGarry JD. What if Minkowski had been ageusic? An alternative angle on diabetes. Science 1992;258:766-70.

186

McIntosh A, Hutchinson A, Feder G, Durrington P, Elkeles R, Hitman GA, Robson J, Home P, Peters J, Pandor A, Kaltenthaler E (2002). Clinical guidelines and evidence review for Type 2 diabetes: Lipids Management. Sheffield: ScHARR, University of Sheffield. McPhillips JB, Barrett-Connor E, Wingard DL. Cardiovascular disease risk factors prior to the diagnosis of impaired glucose tolerance and non-insulin-dependent diabetes mellitus in a community of older adults. Am J Epidemiol 1990;131:443-53. MRC/BHF Heart Protection Study. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: Early safety and efficacy experience. Eur Heart J 1999;20:725-41. MRFIT Research Group. Relationship between baseline risk factors and coronary heart disease and total mortality in the multiple risk factor intervention trial. Prev Med 1986;15:254-73. National Heart Foundation of Australia & The Cardiac Society of Australia and New Zealand. Lipid Management Guidelines - 2001. MJA 2001;175(Suppl):S57-88. Neaton JD, Wentworth D. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research Group. Arch Intern Med 1992;152:56-64. Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Lancet 1995;346:1647-53. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988;37:1595-607. Reaven GM, Chen YD, Jeppesen J, Maheux P, Krauss RM. Insulin resistance and hyperinsulinemia in individuals with small, dense low density lipoprotein particles. J Clin Invest 1993;92:141-6. Rivellese AA. Monounsaturated and marine omega-3 fatty acids in NIDDM patients. Metabolic effects of high-MUFA diets in comparison with high-CHO diets. Ann NY Acad Sci 1997;827:302-9. Ruderman NB, Schneider SH. Diabetes, Exercise and Atheroscierosis. Diabetes Care 1992;15:1787-93. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-9. Sattar N, Jaap AJ, MacCuish AC. Hormone replacement therapy and cardiovascular risk in post-menopausal women with NIDDM. Diabet Med 1996;13:782-8. Shaw JTE, Purdie DM, Neil HAW, Levy JC, Turner RC. The relative risks of hyperglycaemia, obesity and dyslipidaemia in the relatives of patients with Type II diabetes mellitus. Diabetologia 1999;42:24-7. Simopoulos AP. Omega-6/omega-3 fatty acid ratio and trans fatty acids in non-insulin-dependent diabetes mellitus. Ann NY Acad Sci 1997;827:327-38. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the multiple risk factor intervention trial. Diabetes Care 1993;16:434-44. Steiner G. Lipid intervention trials in diabetes. Diabetes Care 2000;23(Suppl 2):B49-53. Stern MP, Mitchell BD, Haffner SM, Hazuda HP. Does glycemic control of type II diabetes suffice to control diabetic dyslipidemia? A community perspective. Diabetes Care 1992;15:638-44. Stevens RJ, Kothari V, Adler AI, Stratton IM, United Kingdom Prospective Diabetes Study (UKPDS) Group. The UKPDS risk engine: a model for the risk of coronary heart disease in Type II diabetes (UKPDS 56). Clin Sci 2001;101:671-9. Stewart MW, Humphriss DB, Berrish TS, Barriocanal LA, Trajano LR, Alberti KG, Walker M. Features of syndrome X in first-degree relatives of NIDDM patients. Diabetes Care 1995;18:1020-2.

187

The National Cholesterol Education Program Expert Panel. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. National Institute of Health. 2002 UK Department of Health. National Services Framework for Coronary Disease. Modern Standards and Service Models. London, Department of Health, 2000. UKPDS. The UK Prospective Diabetes Study 33: Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998;352:837-53. Utermann G. The mysteries of lipoprotein(a). Science 1989;246:904-10. Vague J. The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr 1956;4:20-34. Wadden TA. Treatment of obesity by moderate and severe caloric restriction. Results of clinical research trials. Ann Intern Med 1993;119:688-93. White HD, Simes RJ, Anderson NE, Hankey GJ, Watson JD, Hunt D, Colquhoun DM, Glasziou P, MacMahon S, Kirby AC, West MJ, Tonkin AM. Pravastatin therapy and the risk of stroke. N Engl J Med 2000;343:317-26. Wilson PW, Abbott RD, Castelli WP. High density lipoprotein cholesterol and mortality. The Framingham heart study. Arteriosclerosis 1988;8:737-41. Wilson PW. High-density lipoprotein, low-density lipoprotein and coronary artery disease. Am J Cardiol 1990;66:A7-10. Women's Health Initiative Study Group. Design of the Women's Health Initative clinical trial and observational study. Control Clin Trials 1998;19:61-109. Yeo WW, Yeo KR. Predicting CHD in patients with diabetes mellitus. Diabet Med 2001:18:341-4.

188

Lipid Disease: Others References Abate N, Vega GL, Garg A, Grundy SM. Abnormal cholesterol distribution among lipoprotein fractions in normolipidemic patients with mild NIDDM. Atherosclerosis 1995;118:111-22. Abbate SL, Brunzell JD. Pathophysiology of hyperlipidemia in diabetes mellitus. J Cardiovasc Pharmacol 1990;16(Suppl 9):1-7. Abbott WG, Boyce VL, Grundy SM, Howard BV. Effects of replacing saturated fat with complex carbohydrate in diets of subjects with NIDDM. Diabetes Care 1989;12:102-7. Abraira C, Colwell J, Nuttall F, Sawin CT, Henderson W, Comstock JP, Emanuele NV, Levin SR, Pacold I, Lee HS. Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes. Arch Int Med 1997;157:181-8. Adkins JC, Faulds D. Micronised fenofibrate. A review of its pharmacodynamic properties and clinical efficacy in the management of dyslipidaemia. Drugs 1997;54:615-33. Agardh CD, Nilsson-Ehle P, Schersten B. Improvement of the plasma lipoprotein pattern after institution of insulin treatment in diabetes mellitus. Diabetes Care 1982;5:322-5. Aguilar-Salinas CA, Gomez-Perez FJ, Posadas-Romero C, Vazquez-Chavez C, Meaney E, Gulias-Herrero A, Guillen LE, Alvarado Vega A, Mendoza Perez E, Eduardo Romero-Nava L, Angelica Gomez-Diaz R, Salinas-Orozco S, Moguel R, Novoa G. Efficacy and safety of atorvastatin in hyperlipidaemic, Type 2 diabetic patients. A 34-week, multicentre, open-label study. Atherosclerosis 2000;152:489-96. Ajani UA, Gaziano JM, Lotufo PA, Liu S, Hennekens CH, Buring JE, Manson JE. Alcohol consumption and risk of coronary heart disease by diabetes status. Circulation 2000;102:500-5. Alberti KG, Jones IR, Laker MF, Swai AB, Taylor R. Effect of bezafibrate on metabolic profiles in non-insulin-dependent diabetes mellitus. J Cardiovasc Pharmacol 1990;16(Suppl 9):S21-4. Alcolado JC, Pacy PJ, Beevers M, Dodson PM. Risk factors for peripheral vascular disease in hypertensive subjects with Type 2 diabetes mellitus. Diabet Med 1992;9:904-7. Allen JK, Hensley WJ, Nicholls AV, Whitfield JB. An enzymatic and centrifugal method for estimating high-density lipoprotein cholesterol. Clin Chem 1979;25:325-7. Altomare E, Vendemiale G, Chicco D, Procacci V, Cirelli F. Increased lipid peroxidation in Type 2 poorly controlled diabetic patients. Diabete Metab 1992;18:264-71. American Diabetes Association. Consensus Statement. Detection and management of lipid disorders in diabetes. Diabetes Care 1993;16(Suppl 2):106-12. American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 1998;21:179-82. American Diabetes Association. Nutrition recommendations and principles for people wirh diabetes mellitus. Diabetes Care 1998;(Suppl 1):32-5. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care 1998;21(Suppl 1):523-31. American Diabetes Association. Role of fat replacers in diabetes medical nutrition therapy. Diabetes Care 1999;22(Suppl 1):90-1. American Diabetes Association. Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care 2003;26(Suppl 1):S51-61. American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 2004;27(Suppl 1):S68-71.

189

American Diabetes Association. Physical activity/exercise and diabetes. Diabetes Care 2004;27(Suppl 1):S58-62. American Diabetes Association. Hypertension management in adults with diabetes. Diabetes Care 2004;27(Suppl 1):S65-7. Andersen E, Hellstrom P, Kindstedt K, Hellstrom K. Effects of a high-protein and low-fat diet vs a low-protein and high-fat diet on blood glucose, serum lipoproteins, and cholesterol metabolism in noninsulin-dependent diabetics. Am J Clin Nutr 1987;45:406-13. Anderson JW. Physiological and metabolic effects of dietary fiber. Fed Proc 1985;44:2902-6. Andersson B, Mattsson LA, Hahn L, Marin P, Lapidus L, Holm G, Bengtsson BA, Bjorntorp P. Estrogen replacement therapy decreases hyperandrogenicity and improves glucose homeostasis and plasma lipids in postmenopausal women with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997;82:638-43. Annuzzi G, Rivellese A, Capaldo B, Di Marino L, Iovine C, Marotta G, Riccardi G. A controlled study on the effects of n-3 fatty acids on lipid and glucose metabolism in non-insulin-dependent diabetic patients. Atherosclerosis 1991;87:65-73. Ansell BJ, Waters DD; National Cholesterol Education Program Adult Treatment Panel-III Guidelines. Reassessment of National Cholesterol Education Pprograme Adults Treatment Panel-III Guidelines: one year later. Am J Cardiol 2002;90:524-5. Appel LJ, Stason WB. Ambulatory blood pressure monitoring and blood pressure self-measurement in the diagnosis and management of hypertension. Ann Intern Med 1993;118:867-82. Armstrong D, Abdella N, Salman A, Miller N, Rahman EA, Bojancyzk M. Relationship of lipid peroxides to diabetic complications. Comparison with conventional laboratory tests. J Diabetes Comp 1992;6:116-22. Armstrong AM, Chestnutt JE, Gormley MJ, Young IS. The effect of dietary treatment on lipid peroxidation and antioxidant status in newly diagnosed noninsulin dependent diabetes. Free Radic Biol Med 1996;21:719-26. Aronoff S, Rosenblatt S, Braithwaite S, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes. A 6-month randomized placebo-controlled dose-response study. Diabetes Care 2000;23:1605-11. Attia N, Durlach V, Paul JL, Soni T, Betoulle D, Girard-Globa A. Modulation of low density lipoprotein subclasses by alimentary lipemia in control and normotriglyceridemic non-insulin-dependent diabetic subjects. Atherosclerosis 1995;113:197-209. Austin MA, Edwards KL. Small, dense low density lipoproteins, the insulin resistance syndrome and noninsulin-dependent diabetes. Curr Opin Lipidol 1996;7:167-71. Austin MA, Mykkanen L, Kuusisto J, Edwards KL, Nelson C, Haffner SM, Pyorala K, Laakso M. Prospective study of small LDLs as a risk factor for non-insulin dependent diabetes mellitus in elderly men and women. Circulation 1995;92:1770-8. Axelrod L. Perspectives in diabetes. Omega-3 fatty acids in diabetes mellitus. Gift from the sea? Diabetes 1989;38:539-43. Axelrod L, Camuso J, Williams E, Kleinman K, Briones E, Schoenfeld D. Effects of a small quantity of w-3 fatty acids on cardiovascular risk factors in NIDDM. A randomized, prospective, double-blind, controlled study. Diabetes Care 1994;17:37-44. Axelsen M, Smith U, Eriksson JW, Taskinen MR, Jansson PA. Postprandial hypertriglyceridemia and insulin resistance in normoglycemic first-degree relatives of patients with Type 2 diabetes. Ann Intern Med 1999;131:27-31. Babiy AV, Gebicki JM, Sullivan DR, Willey K. Increased oxidizability of plasma lipoproteins in diabetic patients can be decreased by probucol therapy and is not due to glycation. Biochem Pharmacol 1992;43:995-1000.

190

Bagdade JD, Kelley DE, Henry RR, Eckel RH, Ritter MC. Effects of multiple daily insulin injections and intraperitoneal insulin therapy on cholesteryl ester transfer and lipoprotein lipase activities in NIDDM. Diabetes 1997;46:414-20. Bak JF, Gerdes LU, Sorensen NS, Pedersen O. Effects of perindopril on insulin sensitivity and plasma lipid profile in hypertensive non-insulin-dependent diabetic patients. Am J Med 1992;92(Suppl 4B):S69-72. Bakker-Arkema RG, Davidson MH, Goldstein RJ, Davignon J, Isaacsohn JL, Weiss SR, Keilson LM, Brown WV, Miller VT, Shurzinske LJ, Black DM. Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. JAMA 1996;275:128-33. Bakogianni MC, Kalofoutis CA, Skenderi KI, Kalofoutis AT. Clinical evaluation of plasma high-density lipoprotein subfractions (HDL2, HDL3) in non-insulin-dependent diabetics with coronary artery disease. J Diabetes Complications 2001;15:265-9. Bantle JP, Swanson JE, Thomas W, Laine DC. Metabolic effects of dietary fructose in diabetic subjects. Diabetes Care 1992;15:1468-76. Barnard RJ, Ugianskis EJ, Martin DA, Inkeles SB. Role of diet and exercise in the management of hyperinsulinemia and associated atherosclerotic risk factors. Am J Cardiol 1992;69:440-4. Barrett-Connor E. Postmenopausal estrogen and prevention bias. Ann Intern Med 1991a;115:455-6. Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. JAMA 1991b;265:1861-7. Barrett-Connor E, Grundy SM, Holdbrook MJ. Plasma lipids and diabetes mellitus in an adult community. Am J Epidemiol 1982;115:657-63. Barrett-Connor E, Philippi T, Khaw KT. Lipoproteins as predictors of ischemic heart disease in non-insulin-dependent diabetic men. Am J Prev Med 1987;3:206-10. Bassett DR Jr, Ainsworth BE, Leggett SR, Mathien CA, Main JA, Hunter DC, Duncan GE. Accuracy of five electronic pedometers for measuring distance walked. Med Sci Sports Exerc 1996;28:1071-7. Baynes C, Elkeles RS, Henderson AD, Richmond W, Johnston DG. The effects of glibenclamide on glucose homeostasis and lipoprotein metabolism in poorly controlled Type 2 diabetes. Horm Metab Res 1993;25:96-101. Baynes C, Feher MD, Elkeles RS. The effect of treatment of non-insulin-dependent diabetes mellitus (NIDDM) on serum lipids and lipoproteins. Q J Med 1989;72:579-87. Baynes C, Henderson AD, Hughes CL, Richmond W, Johnston DG, Elkeles RS. Determinants of mild fasting hypertriglyceridaemia in non-insulin-dependent diabetes. J Intern Med 1991;229:267-73. Beckman JA, Creager MA, Libby P. Diabetes and atherossclerosis: Epidemiology, pathophysiology, and management. JAMA 2002;287:2570-81. Bell DS. A comparison of lovastatin, an HMG-CoA reductase inhibitor, with gemfibrozil, a fibrinic acid derivative, in the treatment of patients with diabetic dyslipidemia. Clin Ther 1995;17:901-10. Bell DS, Wagenknecht LE. Effect of gemfibrozil on intermediate-density lipoproteins in NIDDM patients. A retrospective study. Diabetes Care 1992;15:146-7. Berglund L. Diet and drug therapy for lipoprotein (a). Curr Opin Lipidol 1995;6:48-56. Bermudez OI, Velez-Carrasco W, Schaefer EJ, Tucker KL. Dietary and plasma lipid, lipoprotein, and apolipoprotein profiles among elderly Hispanics and non-Hispanics and their association with diabetes. Am J Clin Nutr 2002;76:1214-21. Best JD, Jerums G, Newnham HH, O'Brien RC. Diabetic dyslipidaemia. Australian Diabetes Society position statement. Med J Aust 1995;162:91-3.

191

Best JD, Nicholson GC, O'Neal DN, Kotowicz MA, Tebbutt NC, Chan KW, Sanders KM. Atorvastatin and simvastatin reduce elevated cholesterol in non-insulin dependent diabetes. Diab Nutr Metab 1996;9:74-80. Bestehorn HP, Rensing UF, Roskamm H, Betz P, Benesch L, Schemeitat K, Blumchen G, Claus J, Mathes P, Kappenberger L, Wieland H, Neiss A. The effect of simvastatin on progression of coronary artery disease. The Multicenter coronary Intervention Study (CIS). Eur Heart J 1997;18:226-34. Betteridge D. Cholesterol is the major atherogenic lipid in NIDDM. Diabetes Metab Rev 1997;13:99-104. Betteridge DJ. Diabetic dyslipidemia. Am J Med 1994;96(Suppl 6A):S25-31. Betteridge DJ. LDL heterogeneity: implications for atherogenicity in insulin resistance and NIDDM. Diabetologia 1997;40(Suppl 1):S149-51. Betteridge DJ. Diabetic dyslipidaemia. Eur J Clin Invest 1999;29(Suppl 2):12-6. Bhatnagar D, Durrington PN, Kumar S, Mackness MI, Dean J, Boulton AJ. Effect of treatment with a hydroxymethylglutaryl coenzyme A reductase inhibitor on fasting and postprandial plasma lipoproteins and cholesteryl ester transfer activity in patients with NIDDM. Diabetes 1995;44:460-5. Bierman EL. Atherogenesis in diabetes. Arterioscler Thromb 1992;12:647-56. Biesbroeck RC, Albers JJ, Wahl PW, Weinberg CR, Bassett ML, Bierman EL. Abnormal composition of high density lipoproteins in non-insulin-dependent diabetics. Diabetes 1982;31:126-31. Billingham MS, Milles JJ, Green A, Bailey CJ, Hall RA. Apolipoprotein assays: methodological considerations and studies in non-insulin-dependent diabetes treated by diet glibenclamide and insulin. Scand J Clin Invest 1989;49:239-47. Blaak EE, van Aggel-Leijssen DP, Wagenmakers AJ, Saris WH, van Baak MA. Impaired oxidation of plasma-derived fatty acids in Type 2 diabetic subjects during moderate-intensity exercise. Diabetes 2000;49:2102-7. Blair SN, Capuzzi DM, Gottlieb SO, Nguyen T, Morgan JM, Cater NB. Incremental reduction of serum total cholesterol and low-density lipoprotein cholesterol with the addition of plant stanol ester-containing spread to statin thearpy. Am J Cardiol 2000;86:46-52. Blanchard P, Anton B, Larousse C, Auget D, Mainard F, Charbonnel B, Krempf M. Plasma vitamin E, non-high-density lipoprotein cholesterol, and apolipoprotein B in diabetic patients. Clin Chem 1992;38:2339-40. Blonk MC, Jacobs MA, Friedberg CE, Nauta JJ, Teerlink T, Popp-Snijders C, Heine RJ. Determinants of insulin sensitivity and consequences for lipoproteins and blood pressure in subjects with non-insulin-dependent diabetes mellitus. Metabolism 1994;43:501-8. Bloomgarden ZT. American Diabetes Association Annual Meeting, 1999. Dyslipidemia, endothelial dysfunction, and glycosylation. Diabetes Care 2000;23:690-8. Bloomgarden ZT. American Diabetes Association Annual Meeting, 1999. More on cardiovascular disease. Diabetes Care 2000;23:845-52. Bo S, Gentile L, Cavallo-Perin P, Vineis P, Ghia V. Sex- and BMI-related differences in risk factors for coronary artery disease in patients with Type 2 diabetes mellitus. Acta Diabetol 1999;36:147-53. Boberg M, Pollare T, Siegbahn A, Vessby B. Supplementation with n-3 fatty acids reduces triglycerides but increases PAI-1 in non-insulin-dependent diabetes mellitus. Eur J Clin Invest 1992;22:645-50. Boemi M, Sirolla C, Amadio L, Fumelli P, Pometta D, James RW. Apoliprotein E polymorphism as a risk factor for vascular disease in diabetic patients. Diabetes Care 1995;18:504-8. Bonora E, Tessari R, Micciolo R, Zenere M, Targher G, Padovani R, Falezza G, Muggeo M. Intimal-medial thickness of the carotid artery in non-diabetic and NIDDM patients. Diabetes Care 1997;20:627-31.

192

Bonora E, Formentini G, Calcaterra F, Lombardi S, Marini F, Zenari L, Saggiani F, Poli M, Perbellini S, Raffaelli A, Cacciatori V, Santi L, Targher G, Bonadonna R, Muggeo M. HOMA-Estimated insulin resistance is an independent predictor of cardiovascular disease in Type 2 diabetic subjects. Diabetes Care 2002;25:1135-41. Boogaerts JR, Malone-McNeal M, Archambault-Schexnayder J, Davis RA. Dietary carbohydrate induces lipogenesis and very-low-density lipoprotein synthesis. Am J Physiol 1984;246:E77-84. Borkman M, Chisholm DJ, Furler SM, Storlien LH, Kraegen EW, Simons LA, Chesterman CN. Effects of fish oil supplementation on glucose and lipid metabolism in NIDDM. Diabetes 1989;38:1314-9. Bowie A, Owens D, Collins P, Johnson A, Tomkin GH. Glycosylated low density lipoprotein is more sensitive to oxidation: implications for the diabetic patient? Atherosclerosis 1993;102:63-7. Boyne MS, Saudek CD. Effect of insulin therapy on macrovascular risk factors in Type 2 diabetes. Diabetes Care 1999;22(Suppl 3):C45-53. Brown WV. Lipoprotein disorders in diabetes mellitus. Med Clin North Am 1994;78:143-61. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ. Simvastatin and niacin, antioxidant vitamins, or the combination for the preventionof coronary disease: the HDL Atherosclerosis Treatment Study (HATS). N Engl J Med 2001;345:1583-92. Bruno G, Cavallo-Perin P, Bargero G, Borra M, D'Errico N, Pagano G. Glycaemic control and cardiovascular risk factors in Type 2 diabetes: a population-based study. Diabet Med 1998;15:304-7. Bruno G, Cavallo-Perin P, Bargero G, Borra M, D'Errico N, Macchia G, Pagano G. Hyperfibrinogenemia and metabolic symdrome in Type 2 diabetes: a population-based study. Diabetes Metab Res Rev 2001;17:124-30. Brussaard HE, Gevers Leuven JA, Frolich M, Kluft C, Krans HM. Short-term oestrogen replacement therapy improves insulin resistance, lipids and fibrinolysis in postmenopausal women with NIDDM. Diabetologia 1997;40:843-9. Buemann B, Tremblay A. Effects of exercise training on abdominal obesity and related metabolic complications. Sports Med 1996;21:191-212. Byington RP, Jukema JW, Salonen JT, Pitt B, Bruschke AV, Hoen H, Furberg CD, Mancini GB. Reduction in cardiovascular events during pravastatin therapy. Pooled analysis of clinical events of the pravastatin atherosclerosis intervention program. Circulation 1995;92:2419-25. Caixas A, Ordonez-Llanos J, de Leiva A, Payes A, Homs R, Perez A. Optimisation of glycaemic control by insulin therapy decreases the proportion of small dense LDL particles in diabetic patients. Diabetes 1997;46:1207-13. Caixas A, Perez A, Qrdonez-Llanos J, Bonet R, Rigla M, Castellvi A, Bayen L, de Leiva A. Lack of change of lipoprotein (a) levels by the optimization of glycemic control with insulin therapy in NIDDM patients. Diabetes Care 1997;20:1459-61. Calvert GD, Blight L, Franklin J, Oliver J, Wise P, Gallus AS. The effects of clofibrate on plasma glucose, lipoproteins, fibrinogen, and other biochemical and haematological variables in patients with mature onset diabetes mellitus. Eur J Clin Pharmacol 1980;17:355-62. Camelon KM, Hadell K, Jamsen PT, Ketonen KJ, Kohtamaki HM, Makimatilla S, Tormala ML, Valve RH. The Plate Model: a visual method of teaching meal planning. DAIS Project Group. Diabetes Atherosclerosis Intervention Study. J Am Diet Assoc 1998;98:1155-8. Campbell LV, Marmot PE, Dyer JA, Borkman M, Storlien LH. The high mono-unsaturated fat diet as a practical alternative for NIDDM. Diabetes Care 1994;17:177-82. Caplan GA, Colagiuri R, Lord SR, Ward JA. Execrise in older people with Type II diabetes maintains bone density despite weight loss. Aust J Ageing 1995;14:71-5.

193

Capstick F, Brooks BA, Burns CM, Zilkens RR, Steinbeck KS, Yue DK. Very low calorie diet (VLCD): a useful alternative in the treatment of the obese NIDDM patient. Diabetes Res Clin Pract 1997;36:105-11. Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand 1988;223:405-18. Cavallero E, Dachet C, Neufcour D, Wirquin E, Mathe D, Jacotot B. Postprandial amplification of lipoprotein abnormalities in controlled Type II diabetic subjects: relationship to postprandial lipemia and C-peptide/glucagon levels. Metabolism 1994;43:270-8. Ceriello A, Bortolotti N, Crescentini A, Motz E, Lizzio S, Russo A, Ezsol Z, Tonutti L, Taboga C. Antioxidant defences are reduced during the oral glucose tolerance test in normal and non-insulin-dependent diabetic subjects. Eur J Clin Invest 1998;28:329-33. Ceriello A, Bortolotti N, Motz E, Crescentini A, Lizzio S, Russo A, Tonutti L, Taboga C. Meal-generated oxidative stress in Type 2 diabetic patients. Diabetes Care 1998;21:1529-33. Chaiyakunapruk N, Boudreau D, Ramsey SD. Pharmaco-economic impact of HMG-CoA reductase inhibitors in Type 2 diabetes. J Cardiovasc Risk 2001;8:127-32. Chan JC, Tomlinson B, Nicholls MG, Swaminathan R, Cheung CK, Woo J, Cockram CS. Albuminuria, insulin resistance and dyslipidaemia in Chinese patients with non-insulin-dependent diabetes (NIDDM). Diabet Med 1996;13:150-5. Chen YD, Swami S, Skowronski R, Coulston A, Reaven GM. Differences in postprandial lipemia between patients with normal glucose tolerance and noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1993;76:172-7. Chen Z, Peto R, Collins R, MacMahon S, Lu J, Li W. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentration. BMJ 1991;303:276-82. Chlup R, Vaverkova H, Bartek J. Complementary insulin therapy improves blood glucose and serum lipid parameters in type 2 (non-insulin-dependent) diabetic patients. I. Effects on blood glucose control. Exp Clin Endocrinol Diabetes 1997;105(Suppl 2):70-3. Christiansen C, Thomsen C, Rasmussen O, Balle M, Hauerslev C, Hansen C, Hermansen K. Wine for Type 2 diabetic patients? Diabet Med 1993;10:958-61. Cohen MV, Byrne MJ, Levine B, Gutowski T, Adelson R. Low rate of treatment of hypercholesterolemia by cardiologists in patients with suspected and proven coronary artery disease. Circulation 1991;83:1294-304. Cole TG. Glycerol blanking in triglycerides assays: is it necessary? Clin Chem 1990;36:1267-8. Cominacini L, Garbin U, Fratta Pasini A, Campagnola M, Davoli A, Foot E, Sighieri G, Sironi AM, Lo Cascio V, Ferrannini E. Troglitazone reduces LDL oxidation and lowers plasma E-selectin concentration in NIDDM patients. Diabetes 1998;47:130-3. Coniff RF, Shapiro JA, Seaton TB, Hoogwerf BJ, Hunt JA. A double-blind placebo-controlled trial evaluating the safety and efficacy of acarbose for the treatment of patients with insulin-requiring Type 2 diabetes. Diabetes Care 1995;18:928-32. Connor WE, Prince MJ, Ullmann D, Riddle M, Hatcher L, Smith FE, Wilson D. The hypotriglyceridemic effect of fish oil in adult-onset diabetes without adverse glucose control. Ann NY Acad Sci 1993;683:337-40. Coppack SW. Postprandial lipoproteins in non-insulin-dependent diabetes mellitus. Diabet Med 1997;14(Suppl 1):S67-74. Cowie CC, Harris MI. Physical and metabolic characteristics of persons with diabetes. In: Harris MI, Cowie CC, Stern MP, Boyko EJ, Reiber GE, Bennett PH. Diabetes in America. 2nd ed. Washington DC: US Government Printing Office; 1995. p 117-64. Crepaldi G, Manzato E. Atherogenic factors in diabetes: the role of lipoprotein metabolism. Postgrad Med J 1988;64(Suppl 3):10-2.

194

Crespin SR. What does the future hold for diabetic dyslipidaemia? Acta Diabetol 2001;38(Suppl 1):S21-6. Crespo N, Alvarez R, Mas R, Illnait J, Fernandez L, Fernandez JC. Effects of polycosanol on patients with non-insulin-dependent diabetes mellitus and hypercholesterolemia: a pilot study. Curr Ther Res 1997;58:44-51. Cullen P. Evidence that triglycerides are an independent coronary heart disease risk factor. Am J Cardiol 2000;86:943-9. Cullen P, Schulte H, Assmann G. Smoking, lipoproteins and coronary heart disease risk. Data from the Munster Heart Study (PROCAM). Eur Heart J 1998;19:1632-41. Curtin A, Deegan P, Owens D, Collins P, Johnson A, Tomkin GH. Intestinally derived lipoprotein particles in non-insulin-dependent diabetic patients with and without hypertriglyceridaemia. Acta Diabetol 1995;32:244-50. Curtin A, Deegan P, Owens D, Collins P, Johnson A, Tomkin GH. Alterations in apolipoprotein B-48 in the postprandial state in NIDDM. Diabetologia 1994;37:1259-64. Curtin A, Deegan P, Owens D, Collins P, Johnson A, Tomkin GH. Elevated triglycerides-rich lipoproteins in diabetes. A study of apolipoprotein B-48. Acta Diabetol 1996;33:205-10. Cusi K, Cunningham GR, Comstock JP. Safety and efficacy of normalizing fasting glucose with bedtime NPH insulin alone in NIDDM. Diabetes Care 1995;18:843-51. Dall'Aglio E, Strata A, Reaven G. Abnormal lipid metabolism in treated hypertensive patients with non-insulin-dependent diabetes mellitus. Am J Med 1988;84:899-903. Darko DA, Dornhorst A, Kennedy G, Mandeno RC, Seed M. Glycaemic control and plasma lipoproteins in menopausal women with Type 2 diabetes treated with oral and transdermal combined hormone replacement therapy. Diabetes Res Clin Pract 2001;54:157-64. Davidson MB, Peters AL. An overview of metformin in the treatment of Type 2 diabetes mellitus. Am J Med 1997;102:99-110. Davis TM, Cull CA, Holman RR; UK Prospective Diabetes Study (UKPDS) Group. Relationship between ethnicity and glycaemic control, lipid profiles, and blood pressure during the first 9 years of Type 2 diabetes. (UKPDS 55). Diabetes Care 2001;24:1167-74. Davoren PM, Kelly W, Gries FA, Hubinger A, Whately-Smith C, Alberti KG. Long-term effects of a sustained-release preparation of acipimox on dyslipidemia and glucose metabolism in non-insulin-dependent diabetes mellitus. Metabolism 1998;47:250-6. de Man FH, Cabezas MC, Van Barlingen HH, Erkelens DW, de Bruin TW. Triglyceride-rich lipoproteins in non-insulin-dependent diabetes mellitus: post-prandial metabolism and relation to premature atherosclerosis. Eur J Clin Invest 1996;26:89-108. Dean JD, Matthews SB, Dolben J, Carolan G, Luzio S, Owens DR. Cholesterol rich apo B containing lipoproteins and smoking are independently associated with macrovascular disease in normotensive NIDDM patients. Diabet Med 1994;11:740-7. Dean JD, McCarthy S, Betteridge DJ, Whately-Smith C, Powell J, Owens DR. The effect of acipimox in patients with Type 2 diabetes and persistent hyperlipidaemia. Diabet Med 1992;9:611-5. Deegan P, Owens D, Collins P, Johnson A, Tomkin GH. Association between low-density lipoprotein composition and its metabolism in non-insulin-dependent diabetes mellitus. Metabolism 1999;48:118-24. DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:173-94. Delisle HF, Rivard M, Ekoe JM. Prevalence estimates of diabetes and of other cardiovascular risk factors in the two largest Algonquin communities of Quebec. Diabetes Care 1995;18:1255-9.

195

Despres JP. Increasing high-density lipoprotein cholesterol: an update on fenofibrate. Am J Cardiol 2001;88(Suppl 12A):30N-6N. Diabetes and Dyslipidaemia Working Party (1998). Position Statement on diabetic dyslipidaemia. Diabetes Drafting Group. Prevalence of small vessel and large vessel disease in diabetic patients from 14 centres. The World Health Organization Multinational Study of Vascular Disease in Diabetics. Diabetologia 1985;28(Suppl 1):615-40. Dimitriadis E, Griffin M, Collins P, Johnson A, Owens D, Tomkin GH. Lipoprotein composition in NIDDM: Effects of dietary oleic acid on the composition, oxidisability and function of low and high density lipoproteins. Diabetologia 1996;39:667-76. Donahue RP, Orchard TJ. Diabetes mellitus and macrovascular complications. An epidemiological perspective. Diabetes Care 1992;15:1141-55. Donnelly JP, McGrath LT, Brennan GM. Lipid peroxidation, LDL glycosylation and dietary fish oil supplementation in type II diabetes mellitus. Biochem Soc Trans 1993;22(Suppl 1):34S. Dunn FL, Raskin P, Bilheimer DW, Grundy SM. The effect of diabetic control on very low-density lipoprotein-triglycerides metabolism in patients with type II diabetes mellitus and marked hypertriglyceridemia. Metabolism 1984;33:117-23. Durrington PN, Winocour PH, Bhatnagar D. Bezafibrate retard in patients with insulin-dependent diabetes: effect on serum lipoproteins, fibrinogen, and glycemic control. J Cardiovasc Pharmacol 1990;16(Suppl 9):S30-4. Dyer RG, Stewart MW, Mitcheson J, George K, Alberti MM, Laker MF. 7-ketocholesterol, a specific indicator of lipoprotein oxidation, and malondialdehyde in non-insulin dependent diabetes and peripheral vascular disease. Clin Chim Acta 1997;260:1-13. Eaton CB, Monroe A, McQuade W, Eimer MJ. Cholesterol testing and management: a national comparison of family physicians, general internists, and cardiologists. J Am Board Fam Pract 1998;11:180-6. Einhorn D, Rendell M, Rosenzweig J, Egan JW, Mathisen AL, Schneider RL. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. The Pioglitazone 027 Study Group. Clin Ther 2000;22:1395-409. Elkeles RS. The effects of oral hypoglycaemic drugs on serum lipids and lipoproteins in non-insulin-dependent diabetes (NIDDM). Diabete Metab 1991;17:197-200. Eriksson J, Franssila-Kallunki A, Ekstrand A, Saloranta C, Widen E, Schalin C, Groop L. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med 1989;321:337-43. Erkelens DW. Diabetic dyslipidaemia. Eur Heart J 1998;19(Suppl H):H27-30. Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. Summary of the Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 1993;269:3015-23. Fagan TC, Sowers J. Type 2 diabetes mellitus. Greater cardiovascular risks and greater benefits of therapy. Arch Intern Med 1999;159:1033-4. Fagot-Campagna A, Nelson RG, Knowler WC, Pettitt DJ, Robbins DC, Go O, Welty TK, Lee ET, Howard BV. Plasma lipoproteins and the incidence of abnormal excretion of albumin in diabetic American Indians: the Strong Heart Study. Diabetologia 1998;41:1002-9. Falholt K, Jensen I, Lindkaer Jensen S, Mortensen H, Volund A, Heding LG, Noerskov Petersen P, Falholt W. Carbohydrate and lipid metabolism of skeletal muscle in Type 2 diabetic patients. Diabet Med 1988;5:27-31. Falko JM, Parr JH, Simpson RN, Wynn V. Lipoprotein analyses in varying degrees of glucose tolerance. Comparison between non-insulin-dependent diabetic, impaired glucose tolerant, and control populations. Am J Med 1987;83:641-7.

196

Farmer A, Dineen S. The effectiveness of diet supplementation with omega-3 fatty acids to improve glycaemic control and reduce total serum lipids in non-insulin dependent diabetes mellitus. In: The Cochrane Library 1999; Issue 2:Oxford, Update Software. Fasching P, Ratheiser K, Schneeweiss B, Rohac M, Nowotny P, Waldhausl W. No effect of short term dietary supplementation of saturated and poly- and monounsaturated fatty acids on insulin secretion and sensitivity in healthy men. Ann Nutr Metab 1996;40:116-22. Feher MD, Caslake M, Foxton J, Cox A, Packard CJ. Atherogenic lipoprotein phenotype in Type 2 diabetes: reversal with micronised fenofibrate. Diabetes Metab Res Rev 1999;15:395-9. Feher MD, Stevens J, Lant AF, Mayne PD. Importance of routine measurement of HDL with total cholesterol in diabetic patients. J Roy Society Med 1992;85:8-11. Feingold KR, Grunfeld C, Pang M, Doerrler W, Krauss RM. LDL subclass phenotypes and triglycerides metabolism in non-insulin-dependent diabetes. Arterioscler Thromb 1992;12:1496-502. Fenkci S, Fenkci V, Yilmazer M, Serteser M, Koken T. Effects of short-term transdermal hormone replacement therapy on glycaemic control, lipid metabolism, C-reactive protein and proteinuria in postmenopausal women with Type 2 diabetes or hypertension. Hum Reprod 2003;18:866-70. Feskens EJ, Virtanen SM, Rasanen L, Tuomilehto J, Stengard J, Pekkanen J, Nissinen A, Kromhout D. Dietary factors determining diabetes and impaired glucose tolerance. A 20-year follow-up of the Finnish and Dutch cohorts of the Seven Countries Study. Diabetes Care 1995;18:1104-12. Finney CP. Measurement issues in cholesterol screening: an overview for nurses. J Cardiovasc Nurs 1991;5:10-22. Fitzgerald AP, Jarrett RJ. Are conventional risk factors for mortality relevant in type 2 diabetes? Diabet Med 1991;8:475-80. Florkowski CM, Scott RS, Moir CL, Graham PJ. Lipid but not glycaemic parameters predict total mortality from Type 2 diabetes mellitus in Canterbury, New Zealand. Diabet Med 1998;15:386-92. Fontbonne A. Relationship between diabetic dyslipoproteinaemia and coronary heart disease risk in subjects with non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 1991;7:179-89. Fontbonne A, Charles MA, Juhan-Vague I, Bard JM, Andre P, Isnard F, Cohen JM, Grandmottet P, Vague P, Safar ME, Eschwege E. The effect of metformin on the metabolic abnormalities associated with upper-body fat distribution. BIGPRO Study Group. Diabetes Care 1996;19:920-6. Fontvieille AM, Rizkalla SW, Penfornis A, Acosta M, Bornet FR, Slama G. The use of low glycaemic index foods improves metabolic control for diabetic patients over five weeks. Diabet Med 1992;9:444-50. Forcheron F, Cachefo A, Thevenon S, Pinteur C, Beylot M. Mechanisms of the triglycerides- and cholesterol-lowering effect of fenofibrate in hyperlipidaemic Type 2 diabetic patients. Diabetes 2002;51:3486-91. Franceschini G. Epidemiologic evidence for high-density lipoprotein cholesterol as a risk factor for coronary artery disease. Am J Cardiol 2001;88(Suppl 12A):9N-13N. Frick MH, Syvanne M, Nieminen MS, Kauma H, Majahalme S, Virtanen V, Kesaniemi YA, Pasternack A, Taskinen MR. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Lopid Coronary Angiography Trial (LOCAT) Study Group. Circulation 1997;96:2137-43. Friday KE, Childs MT, Tsunehara CH, Fujimoto WY, Bierman EL, Ensinck JW. Elevated plasma glucose and lowered triglycerides levels from omega-3 fatty acid supplementation in Type II diabetes. Diabetes Care 1989;12:276-81. Friday KE, Dong C, Fontenot RU. Conjugated equine estrogen improves glycaemic control and blood lipoproteins in postmenopausal women with Type 2 diabetes. J Clin Endocrinol Metab 2001;86:48-52.

197

Frost RJ, Otto C, Geiss HC, Schwandt P, Parhofer KG. Effects of atorvastatin versus fenofibrate on lipoprotein profiles, low-density lipoprotein subfraction distribution, and hemorheologic parameters in type 2 diabetes mellitus with mixed hyperlipoproteinaemia. Am J Cardiol 2001;87:44-8. Fu CC, Chang CJ, Tseng CH, Chen MS, Kao CS, Wu TJ, Wu HP, Chuang LM, Chen CJ, Tai TY. Development of macrovascular diseases in NIDDM patients in Northern Taiwan. A 4-yr follow-up study. Diabetes Care 1993;16:137-43. Fuh MM, Shieh SM. Association of low plasma high density lipoprotein (HDL)-cholesterol concentration with documented coronary artery disease in males with non-insulin dependent diabetes mellitus. Horm Metab Res 1987;19:267-70. Fujimoto WY, Bergstrom RW, Leonetti DL, Newell-Morris LL, Shuman WP, Wahl PW. Metabolic and adipose risk factors for NIDDM and coronary disease in third-generation Japanese-American men and women with impaired glucose tolerance. Diabetologia 1994;37:524-32. Fulcher GR, Catalano C, Walker M, Farrer M, Thow J, Whately-Smith CR, Alberti KG. A double blind study of the effect of acipimox on serum lipids, blood glucose control and insulin action in non-obese patients with Type 2 diabetes mellitus. Diabet Med 1992a;9:908-14. Fulcher GR, Walker M, Catalano C, Agius L, Alberti KG. Metabolic effects of suppression of nonesterified fatty acid levels with acipimox in obese NIDDM subjects. Diabetes 1992b;41:1400-8. Fuller CJ, Chandalia M, Garg A, Grundy SM, Jialal I. RRR-alpha tocopheryl acetate supplementation at pharmacologic doses decreases low-density-lipoprotein oxidative susceptibility but not protein glycation in patients with diabetes mellitus. Am J Clin Nutr 1996;63:753-9. Fuller JH, McCartney P, Jarrett RJ, Keen H, Rose G, Shipley MJ, Hamilton PJ. Hyperglycaemia and coronary heart disease: the Whitehall Study. J Chronic Dis 1979;32:721-8. Furberg CD, Pitt B, Byington RP, Park JS, McGovern ME. Reduction in coronary events during treatment with pravastatin. PLAC I and PLAC II Investigators. Pravastatin Limitation of Atherosclerosis in the Coronary Arteries. Am J Cardiol 1995;76:60C-3C. Furuseth K, Berg K, Hanssen KF, Rutle O, Bruusgaard D, Vaaler S. Serum lipoprotein (a) and cardiovascular disease in non-insulin-dependent diabetes mellitus. Scand J Prim Health Care 1998;16:40-3. Gadsby R. Managing dyslipidaemia in Type 2 diabetes in primary care. Prac Diab Int 2000;17:S1-8. Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial intervention in people with type 2 diabetes mellitus and microalbuminuria: The Steno Type 2 Randomised Study. Lancet 1999;353:617-22. Gall MA, Rossing P, Skott P, Hommel E, Mathiesen ER, Gerdes LU, Lauritzen M, Volund A, Faergeman O, Beck-Nielsen H, Parving HH. Placebo-controlled comparison of captopril, metoprolol, and hydrochlorothiazide therapy in non-insulin-dependent diabetic patients with primary hypertension. Am J Hypertens 1992;5:257-65. Gallagher A, Henderson W, Abraira C. Dietary patterns and metabolic control in diabetic diets: a prospective study of 51 outpatient men on unmeasured and exchange diets. J Am Coll Nutr 1987;6:525-32. Gallou G, Ruelland A, Legras B, Maugendre D, Allanic H, Cloarec L. Plasma malondialdehyde in type 1 and type 2 diabetic patients. Clin Chim Acta 1993;214:227-34. Garber AJ. Diabetes and heart disease: a new strategy for managing lipid disorders. Geriatrics 1993;48:34-6, 9-41. Garber AJ. Vascular disease and lipids in diabetes. Med Clin North Am 1998;82:931-48. Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type 2 diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med 1997;102:491-7. Garg A. High-monounsaturated fat diet for diabetic patients. Is it time to change the current dietary recommendations? Diabetes Care 1994;17:242-6.

198

Garg A, Bonanome A, Grundy SM, Zhang Z-J, Unger RH. Comparison of a high-carbohydrate diet with a high-monounsaturated-fat diet in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 1988;319:829-34. Garg A, Grundy SM. Lovastatin for lowering cholesterol levels in non-insulin-dependent diabetes mellitus. N Engl J Med 1988;318:81-6. Garg A, Grundy SM. Gemfibrozil alone and in combination with lovastatin for treatment of hypertriglyceridemia in NIDDM. Diabetes 1989;38:364-72. Garg A, Grundy SM. Nicotinic acid as therapy for dyslipidaemia in non-insulin dependent diabetes mellitus. JAMA 1990;264:723-6. Garg A, Grundy SM. Management of dyslipidemia in NIDDM. Diabetes Care 1990;13:153-69. Garg A, Grundy SM. Treatment of dyslipidemia in patients with NIDDM. Diabetes Rev 1995;3:433-45. Garg A. Treatment of diabetic dyslipidaemia. Am J Cardiol 1998b;81(4A):47-51. Gaziano JM, Buring JE, Breslow JL, Goldhaber SZ, Rosner B, VanDenburgh M, Willett W, Hennekens CH. Moderate alcohol intake, increased levels of high density lipoprotein and its subfractions, and decreased risk of myocardial infarction. N Engl J Med 1993;329:1829-34. Geltner C, Lechleitner M, Foger B, Ritsch A, Drexel H. Patsch JR. Insulin improves fasting and postprandial lipaemia in Type 2 diabetes. Eur J Intern Med 2002;13:25-63. Gerstein HC. Cardiovascular and metabolic benefits of ACE inhibition. Moving beyond blood pressure reduction. Diabetes Care 2000;23:882-3. Gervaise N, Garigue MA, Lasfargues G, Lecomte P. Triglycerides, apo C3 and Lp B:C3 and cardiovascular risk in Type II diabetes. Diabetologia 2000;43:703-8. Ghazzi MN, Perez JE, Antonucci TK, Driscoll JH, Huang SM, Faja BW, Whitcomb RW. Cardiac and glycemic benefits of troglitazone treatment in NIDDM. Diabetes 1997;46:433-9. Ginsberg HN. Lipoprotein physiology in nondiabetic and diabetic states. Relationship to atherogenesis. Diabetes Care 1991;14:839-55. Godsland IF, Crook D, Simpson R, Proudler T, Felton C, Lees B, Anyaoku V, Devenport M, Wynn V. The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism. N Engl J Med 1990;323:1375-81. Goh YK, Jumpsen JA, Ryan EA, Clandinin MT. Effect of n-3 fatty acid on plasma lipids, cholesterol and lipoprotein fatty acid content in NIDDM patients. Diabetologia. 1997;40:45-52. Goldberg RB. Lipid disorders in diabetes. Endocrinologist 1997;7:436-42. Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes 1992;16:397-415. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. Am J Med 1977;62:707-14. Gotto AMJr. Triglycerides as a risk factor for coronary artery disease. Am J Cardiol 1998;82:Q22-5. Gould AL, Rossouw JE, Santanello NC, Heyse JE, Furberg CD. Cholesterol reduction yields clinical benefits: a new look at old data. Circulation 1995;91:2274-82. Grant PJ. The effects of metformin on cardiovascular risk factors. Diabetes Metab Rev 1995;11(Suppl 1):43-50. Grant PJ. The effects of high-and medium-dose metformin therapy on cardiovascular risk factors in patients with Type II diabetes. Diabetes Care 1996;19:64-6. Gray DS. The clinical uses of dietary fibre. American Family Physician 1995;2:419-25.

199

Greenfield M, Kolterman O, Olefsky J, Reaven GM. Mechanism of hypertriglyceridaemia in diabetic patients with fasting hyperglycaemia. Diabetologia 1980;18:441-6. Grundy SM. Dietary therapy in diabetes mellitus. Is there a single best diet? Diabetes Care 1991;14:796-801. Guillausseau P-J, Peynet J, Chanson P, Legrand A, Altman J-J, Poupon J, N'Guyen M, Rousselet F, Lubetzki J. Lipoprotein (a) in diabetic patients with and without chronic renal failure. Diabetes Care 1992;15:976-9. Gylling H, Miettinen TA. Cholesterol absorption, synthesis, and LDL metabolism in NIDDM. Diabetes Care 1997;20:90-5. Gylling H, Miettinen TA. Treatment of lipid disorders in non-insulin-dependent diabetes mellitus. Curr Opin Lipidol 1997;8:342-7. Hadden DR, Montgomery DAD, Skelly RJ, Trimble ER, Weaver JA, Wilson EA, Buchanan KD. Maturity onset diabetes mellitus: response to intensive dietary management. BMJ 1975;iii:276-78. Haffner SM. Compositional changes in lipoproteins of subjects with non-insulin-dependent diabetes mellitus. J Lab Clin Med 1991;118:109-10. Haffner SM. Lipoprotein (a) and diabetes. Diabetes Care 1993;16:835-40. Haffner SM. The prediabetic problem: development of non-insulin-dependent diabetes mellitus and related abnormalities. J Diabetes Complications 1997;11:69-76. Haffner SM. Diabetes, hyperlipidemia, and coronary artery disease. Am J Cardiol 1999b;83:F17-21. Haffner SM. Lipoprotein disorders associated with Type 2 diabetes mellitus and insulin resistance. Am J Cardiol 2002;90(Suppl):55i-61i. Haffner SM, Miettinen H. Insulin resistance implications for type II diabetes mellitus and coronary heart disease. Am J Med 1997;103:152-62. Haffner SM, Morales PA, Gruber MK, Hazuda HP, Stern MP. Cardiovascular risk factors in non-insulin-dependent diabetic subjects with microalbuminuria. Arterioscler Thrombo 1993;13:205-10. Haffner SM, Tuttle KR, Rainwater DL. Lack of change of lipoprotein (a) concentration with improved glycemic control in subjects with Type II diabetes. Metabolism 1992;41:116-20. Hancu N, Netea MG, Iancu S. Serum lipoprotein (a) is increased in hypertensive NIDDM patients. Diabetes Care 1995;18:879-80. Hanefeld M, Fischer S, Schmechel H, Rothe G, Schulze J, Dude H, Schwanebeck U, Julius U. Diabetes Intervention Study: multi-intervention trial in newly diagnosed NIDDM. Diabetes Care 1991;14:308-17. Hanefeld M, Schmechel H, Schwanebeck U, Lindner J, the DIS Group. Predictors of coronary heart disease and death in NIDDM: the Diabetes Intervention Study experience. Diabetologia 1997;40(Suppl. 1):123-4. Hanefeld M, Temelkova-Kurkschiev T. The postprandial state and the risk of atherosclerosis. Diabet Med 1997;14:6-11. Hanefeld M, Temelkova-Kurktschiev T, Kohler C. Effect of oral antidiabetics and insulin on lipids and coronary heart disease in non-insulin-dependent diabetes mellitus. Ann NY Acad Sci 1997;827:246-68. Hanefeld M, Weck M. Very low calorie diet therapy in obese non-insulin dependent diabetes patients. Int J Obes 1989;13(Suppl 2):33-7. Harano Y, Kageyama A, Nakao Y, Hara Y, Suzuki M, Sato A, Ikebuchi M, Shinozaki K, Tsushima M. Quantitative and qualitative derangement of apolipoprotein B-containing lipoproteins as a risk factor for diabetic macroangiopathy in nonobese NIDDM subjects. Diabetes 1996;45(Suppl 3):31-4.

200

Hasslacher C, Bostedt-Kiesel A, Kempe HP, Wahl P. Effect of metabolic factors and blood pressure on kidney function in proteinuric Type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993;36:1051-6. Hatton DC, Haynes RB, Oparil S, Kris-Etherton P, Pi-Sunyer FX, Resnick LM, Stern JS, Clark S, McMahon M, Morris C, Metz J, Ward A, Holcomb S, McCarron DA. Improved quality of life in patients with generalized cardiovascular metabolic disease on a prepared diet. Am J Clin Nutr 1996;64:935-43. Heesen BJ, Wolffenbuttel BHR, Leurs PB, Sels JPJE, Menheere PPCA, Jackle-Beckers SEC, Nieuwenhuijzen Kruseman AC. Lipoprotein (a) levels in relation to diabetic complications in patients with non-insulin-dependent diabetes. Eur J Clin Invest 1993;23:580-4. Hegele RA, Harris SB, Zinman B, Hanley AJG, Connelly PW. Increased plasma apolipoprotein b-containing lipoproteins associated with increased urinary albumin within the microalbuminuria range in Type 2 diabetes. Clin Biochem 1999;32:143-8. Heller FR, Jamart J, Honore P, Derue G, Novik V, Galanti L, Parfonry A, Hondekijn J-C, Buysschaert M. Serum lipoprotein (a) in patients with diabetes mellitus. Diabetes Care 1993;16:819-23. Hendra TJ, Britton ME, Roper DR, Wagaine-Twabwe D, Jeremy JY, Dandona P, Haines AP, Yudkin JS. Effects of fish oil supplements in NIDDM subjects. Controlled Study. Diabetes Care 1990;13:821-9. Henry RR, Scheaffer L, Olefsky JM. Glycemic effects of intensive caloric restriction and isocaloric refeeding in noninsulin- dependent diabetes mellitus. J Clin Endocrinol Metab 1985;61:917-25. Henry RR, Wiest-Kent TA, Scheaffer L, Kolterman OG, Olefsky JM. Metabolic consequences of very-low-calorie diet therapy in obese non-insulin-dependent diabetic and nondiabetic subjects. Diabetes 1986;35:155-64. Herd JA. The Lipoprotein and Coronary Atherosclerosis Study (LCAS): lipid and metabolic factors related to Atheroma and clinical events. Am J Med 1998;104(6A):42S-9S. Herd JA, Ballantyne CM, Farmer JA, Ferguson JJ, Jones PH, West S, Gould KL, Gotto Jr AM, for the LCAS Investigators. Effects of luvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [[LCAS]). Am J Cardiol 1997;80:278-86. Hermann LS, Karlsson J-E, Sjostrand A. Prospective comparative study in NIDDM patients of metformin and glibenclamide with special reference to lipid profiles. Eur J Clin Pharmacol 1991;41:263-5. Hirano T. Lipoprotein abnormalities in diabetic nephropathy. Kidney Int 1999;56(Suppl 7):22-4. Hirano T, Naito H, Kurokawa M, Ebara T, Nagano S, Adachi M, Yoshino G. High prevalence of small LDL particles in non-insulin-dependent diabetic patients with nephropathy. Atherosclerosis 1996;123:57-72. Hirano T, Oi K, Sakai S, Kashiwazaki K, Adachi M, Yoshino G. High prevalence of small dense LDL in diabetic nephropathy is not directly associated with kidney damage: a possible role of postprandial lipemia. Atherosclerosis 1998;141:77-85. Hirata-Dulas CAI, Rith-Najarian SJ, McIntyre MC, Ross C, Dahl DC, Keane WF, Kasiske BL. Risk factors for nephropathy and cardiovascular disease in diabetic Northern Minnesota American Indians. Clin Nephrol 1996;46:92-8. Hodge AM, Dowse GK, Zimmet PZ. Microalbuminuria, cardiovascular risk factors, and insulin resistance in two populations with a high risk of Type 2 diabetes mellitus. Diabet Med 1996;13:441-9. Hollenbeck CB, Chen YD, Greenfield MS, Lardinois CK, Reaven GM. Reduced plasma high density lipoprotein-cholesterol concentrations need not increase when hyperglycemia is controlled with insulin in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1986;62:605-8. Hollenbeck CB, Coulston AM. Effects of dietary carbohydrate and fat intake on glucose and lipoprotein metabolism in individuals with diabetes mellitus. Diabetes Care 1991;14:774-85. Hollenbeck CB, Coulston AM, Reaven GM. To what extent does increased dietary fibre improve glucose and lipid metabolism in patients with noninsulin-dependent diabetes mellitus (NIDDM)? Am J Clin Nutr 1986;43:16-24.

201

Hollenbeck CB, Coulston AM, Reaven GM. Effects of sucrose on carbohydrate and lipid metabolism in NIDDM patients. Diabetes Care 1989;12(Suppl 1):62-6. Hollenbeck CB, Johnston P, Varasteh BB, Chen YD, Reaven GM. Effects of metformin on glucose, insulin and lipid metabolism in patients with mild hypertriglyceridaemia and non-insulin dependent diabetes by glucose tolerance test criteria. Diabete et Metabolisme 1991;17:483-9. Holmes J, Hadden DR, Atkinson AB, Kennedy AL, Wilson EA. Assessment of diet adherence in relation to long-term follow up of non-insulin-dependent diabetics. Pract Diabetes 1987;4:276-8. Horita K, Eto M, Makino I. Apolipoprotein E2, renal failure and lipid abnormalities in non-insulin-dependent diabetes mellitus. Atherosclerosis 1994;107:203-11. Hostetter AL. Screening for dyslipidemia. Practice parameter. Am J Clin Pathol 1995;103:380-5. Howard BV. Lipoprotein metabolism in diabetes mellitus. J Lipid Res 1987;28:613-28. Howard BV. Diabetes and plasma lipoproteins in Native Americans. Studies of the Pima Indians. Diabetes Care 1993;16(Suppl 1):284-91. Howard BV, Howard WJ. Dyslipidemia in non-insulin-dependent diabetes mellitus. Endocr Rev 1994;15:263-74. Howard BV, Knowler WC, Vasquez B, Kennedy AL, Pettitt DJ, Bennett PH. Plasma and lipoprotein cholesterol and triglycerides in the Pima Indian population. Comparison of diabetics and nondiabetics. Arteriosclerosis 1984;4:462-71. Howard BV, Savage PJ, Nagulesparan M, Bennion LJ, Davis M, Bennett PH. Changes in plasma lipoproteins accompanying diet therapy in obese diabetics. Atherosclerosis 1979;33:445-56. Howard BV, Xiaoren P, Harper I, Foley JE, Cheung MC, Taskinen M-R. Effect of sulfonylurea therapy on plasma lipids and high density lipoprotein composition in non-insulin-dependent diabetes mellitus. Am J Med 1985;79(Suppl 3B):78-85. Howard BV, Robbins DC, Sievers ML, Lee ET, Rhoades D, Devereux RB, Cowan LD, Gray RS, Welty TK, Go OT, Howard WJ. LDL Cholesterol as a strong predictor of coronary heart disease in diabetic individuals with insulin resistance and low LDL. Arterioscler Thromb Vasc Biol 2000;20:830-5. Hwu CM, Kwok CF, Chen HS, Shih KC, Lee SH, Hsiao LC, Lin SH, Ho LT. Lack of effect of simvastatin on insulin sensitivity in Type 2 diabetic patients with hypercholesterolaemia: results from double-blind, randomized, placebo-controlled crossover study. Diabet Med 1999;16:749-54. Hypertension in Diabetes Study Group. Hypertension in Diabetes Study (HDS): I. Prevalence of hypertension in newly presenting type 2 diabetic patients and the association with the risk factors for cardiovascular and diabetic complications. J Hypertens 1993;11:309-17. Ikeda T, Ohtani I, Fujiyama K, Hoshino T, Tanaka Y, Tekeuchi T, Mashiba H. Apolipoprotein levels in non-insulin-dependent diabetes mellitus with clinical macroangiopathy. Diabete Metabolisme 1991;17:373-8. Imperatore G, Rivellese A, Galasso R, Celentano E, Iovine C, Ferrara A, Riccardi G, Vaccaro O. Lipoprotein (a) concentrations in non-insulin-dependent diabetes mellitus and borderline hyperglycemia: a population-based study. Metabolism 1995;44:1293-7. Inoue Y, Kaku K, Okubo M, Hatao K, Hatao M, Kaneko T, Matsumura S, Ando S, Fujii S. A multi-centre study of the efficacy and safety of pravastatin in hypercholesterolaemic patients with non-insulin-dependent diabetes mellitus. Curr Med Res Opin 1994;13:187-94. Inoue I, Takahashi K, Katayama S, Akabane S, Negishi K, Suzuki M, Ishii J, Kawazu S. Improvement of glucose tolerance by benzafibrate in non-obese patients with hyperlipidemia and impaired glucose tolerance. Diabetes Res Clin Pract 1994;25:199-205.

202

Isomaa B, Henricsson M, Almgren P, Tuomi T, Taskinen MR, Groop L. The metabolic syndrome influences the risk of chronic complications in patients with Type II diabetes. Diabetologia 2001;44:1148-54. Israelson B. Role of alcohol, glucose intolerance and obesity in hypertriglyceridemia. Atherosclerosis 1986;62:123-7. Iwamoto Y, Kosaka K, Kuzuya T, Akanuma Y, Shigeta Y, Kaneko T. Effect of combination therapy of troglitazone and sulphonylureas in patients with Type 2 diabetes who were poorly controlled by sulphonylurea therapy alone. Diabet Med 1996a;13:365-70. Iwamoto Y, Kosaka K, Kuzuya T, Akanuma Y, Shigeta Y, Kaneko T. Effects of troglitazone. A new hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy. Diabetes Care 1996b;19:151-6. Jain SK, McVie R, Jaramillo JJ, Palmer M, Smith T, Meachum ZD, Little RL. The effect of modest vitamin E supplementation on lipid peroxidation products and other cardiovascular risk factors in diabetic patients. Lipids 1996;31:87-90. James RW, Pometta D. The distribution profiles of very low density and low density lipoproteins in poorly-controlled male, Type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1991;34:246-52. Janus ED. Apoliproptein (a) and atherogenesis. Pathology 1993;25:291-3. Jarvi AE, Karlstrom BE, Granfeldt YE, Bjorck IE, Asp NG, Vessby BO. Improved glycemic control and lipid profile and normalized fibrinolytic activity on a low-glycemic index diet in Type 2 diabetic patients. Diabetes Care 1999;22:10-8. Jeck T, Riesen WF, Keller U. Comparison of bezafibrate and simvastatin in the treatment of dyslipidaemia in patients with NIDDM. Diabet Med 1997;14:564-70. Jenkins AB, Chisholm DJ. Glucoregulation during exercise in NIDDM. Diabetes Care 1991;14:350. Jenkins DJ, Wolever TM, Taylor RH, Barker H, Fielden H, Baldwin JM, Bowling AC, Newman HC, Jenkins AL, Goff DV. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr 1981;34:362-6. Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. Triglycerides concentration and ischemic heart disease. An eight-year follow-up in the Copenhagen Male Study. Circulation 1998;97:1029-36. Jeppesen J, Zhou MY, Chen YD, Reaven GM. Effect of metformin on postprandial lipemia in patients with fairly to poorly controlled NIDDM. Diabetes Care 1994a;17:1093-9. Jeppesen J, Zhou MY, Chen YD, Reaven GM. Effect of glipizide treatment on postprandial lipaemia in patients with NIDDM. Diabetologia 1994b;37:781-7. Jialal I. A practical approach to the laboratory diagnosis of dyslipidemia. Am J Clin Pathol 1996;106:128-38. Jiao S, Kameda K, Matsuzawa Y, Kubo M, Nonaka K, Tarui S. Influence of endogenous hyperinsulinism on high density lipoprotein2 level in Type 2 (non-insulin-dependent) diabetes mellitus and impaired glucose tolerance. Atherosclerosis 1986;60:279-86. Johnson BF, LaBelle P, Wilson J, Allan J, Zupkis RV, Ronca PD. Effects of lovastatin in diabetic patients treated with chlorpropamide. Clin Pharmacol Ther 1990;48:467-72. Johnson JL, Wolf SL, Kubadi UM. Efficacy of insulin and sulfonylurea combination therapy in type II diabetes. Arch Intern Med 1996;156:259-64. Jokubaitis LA, Knopp RH, Frohlich J. Efficacy and safety of fluvastatin in hyperlipidaemic patients with non-insulin-dependent diabetes mellitus. J Intern Med 1994;236(Suppl 736):103-7. Jones PJ, Ntanios FY, Raeini-Sarjaz M, Vanstone CA. Cholesterol-lowering efficacy of sitostanol-containing phytosterol mixture with a prudent diet in hyperlipidemic men. Am J Clin Nutr 1999;69:1144-50.

203

Josse RG. Acarbose for the treatment of Type II diabetes: the results of a Canadian multi-centre trial. Diabetes Res Clin Pract 1995;28(Suppl 1):S167-72. Joven J, Vilella E. Serum levels of lipoprotein (a) in patients with well-controlled non-insulin-dependent diabetes mellitus. JAMA 1991;265:1113-4. Kado S, Murakami T, Aoki A, Nagase T, Katsura Y, Noritake M, Matsuoka T, Nagata N. Effect of acarbose on postprandial lipid metabolism in type 2 diabetes mellitus. Diabetes Res Clin Pract 1998;41:49-55. Kahri J, Vuorinen-Markkola H, Tilly-Kiesi M, Lahdenpera S, Taskinen MR. Effect of gemfibrozil on high density lipoprotein subspecies in non-insulin dependent diabetes mellitus. Relations to lipolytic enzymes and to the cholesteryl ester transfer protein activity. Athersclerosis 1993;102:79-89. Kalix B, Meynet MC, Garin MC, James RW. The apolipoprotein epsilon2 allele and the severity of coronary artery disease in Type 2 diabetic patients. Diabet Med 2001;18:445-50. Kannel WB. Lipids, diabetes and coronary heart disease: insights from the Framingham Study. Am Heart J 1985;110:1100-6. Kannel WB. Framingham study insights into hypertensive risk of cardiovascular disease. Hypertens Res 1995;18:181-96. Karlander SG, Gutniak MK, Efendic S. Effects of combination therapy with glyburide and insulin on serum lipid levels in NIDDM patients with secondary sulfonlyurea failure. Diabetes Care 1991;14:963-7. Kasama T, Yoshino G, Iwatani I, Iwai M, Hatanaka H, Kazumi T, Oimomi M, Baba S. Increased cholesterol concentration in intermediate density lipoprotein fraction of normolipidemic non-insulin-dependent diabetics. Atherosclerosis 1987;63:263-6. Kasim SE, Stern B, Khilnani S, McLin P, Baciorowski S, Jen C. Effects of omega-3 fish oils on lipid metabolism, glycemic control, and blood pressure in Type II diabetic patients. J Clin Endocrinol Metab 1988;67:1-5. Kaukua J, Turpeinen A, Uusitupa M, Niskanen L. Clustering of cardiovascular risk factors in Type 2 diabetes mellitus: prognostic significance and tracking. Diabetes Obes Metab 2001;3:17-23. Kaysen GA, de Sain-van der Velden MG. New insights into lipid metabolism in the nephrotic syndrome. Kidney Int Suppl 1999;71:S18-21. Kazumi T, Yoshino G, Ishida Y, Iwatani I, Morita S, Tateiwa M, Kasuga M, the Hyogo Pravastatin Study Group. Long-term efficacy and tolerability of pravastatin in hypercholesterolemia in patients with non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract 1995b;27:61-8. Kazumi T, Yoshino G, Ohki A, Matsuba K, Ino T, Amano M, Kasuga M, the Hyogo Simvastatin Study Group. Long-term effects of simvastatin in hypercholesterolemic patients with NIDDM and additional atherosclerotic risk factors. Horm Metab Res 1995a;27:239-43. Keilani T, Schlueter WA, Levin ML, Batlle DC. Improvement of lipid abnormalities associated with proteinuria using fosinopril, an angiotensin-converting enzyme inhibitor. Ann Intern Med 1993;118:246-54. Kennedy L, Walshe K, Hadden DR, Weaver JA, Buchanan KD. The effect of intensive dietary therapy on serum high density lipoprotein cholesterol in patients with Type 2 (non-insulin-dependent) diabetes mellitus: a prospective study. Diabetologia 1982;23:24-7. Kesavulu MM, Rao BK, Giri R, Vijaya J, Subramanyam G, Apparao C. Lipid peroxidation and antioxidant enzyme status in Type 2 diabetes with coronary heart disease. Diabetes Res Clin Prac 2001;53:33-9. Kikuchi T, Onuma T, Shimura M, Tsutsui M, Boku A, Matsui J, Takebe K. Different change in lipoprotein (a) levels from lipid levels of other lipoproteins with improved glycemic control in patients with NIDDM. Diabetes Care 1994;17:1059-61. Kimura H, Suzuki Y, Gejyo F, Karasawa R, Miyazaki R, Suzuki S, Arakawa M. Apolipoprotein E4 reduces risk of diabetic nephropathy in patients with NIDDM. Am J Kidney Dis 1998;31:666-73.

204

King AB. A comparison in a clinical setting of the efficacy and side effects of three thiazolidinediones. Diabetes Care 2000;23:557. Kirkman MS, Weinberger M, Landsman PB, Samsa GP, Shortliffe EA, Simel DL, Feussner JR. A telephone-delivered intervention for patients with NIDDM. Effect on coronary risk factors. Diabetes Care 1994;17:840-6. Kissebah AH. Low density lipoprotein metabolism in non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 1987;3:619-51. Kitabchi AE, Sora AG, Radparvar A, Lawson-Grant V. Combined therapy of insulin and tolazamide decreases insulin requirement and serum triglycerides in obese patients with noninsulin-dependent diabetes mellitus. Am J Med Sci 1987;294:10-4. Klaya F, Durlach V, Bertin E, Monier F, Monboisse J-C, Gillery P. Evaluation of serum glycated lipoprotein (a) levels in noninsulin-dependent diabetic patients. Clin Biochem 1997;30:227-30. Klein R, Klein EK, Wang Q, Jensen SC. Treatment and control of hypercholesterolemia and hypertension in persons with and without diabetes. Am J Prev Med 1995;11:329-35. Klotzsch SG, McNamara JR. Triglycerides measurements: a review of methods and interferences. Clin Chem 1990;36:1605-13. Knopp RH, Frolich JJ. Efficacy and safety of fluvastatin in patients with non-insulin-dependent diabetes mellitus and hyperlipidemia: preliminary report. Am J Cardiol 1994a;73:D39-41. Ko GTC, Mak TWL, Yeung VTF, Chan DCF, Lam CWK, Tsang LWW, Chow C-C, Cockram CS. Short-term efficacy and tolerability of combination therapy with lovastatin and acipimox in Chinese patients with type 2 diabetes mellitus and mixed dyslipidemia. J Clin Pharmacol 1998;38:912-7. Ko GTC, Yeung VFY, Tsang LWW, Chow C-C, Cockram CS. Comparison of the effects of gemfibrozil (600 mg twice daily and 900 mg once daily) on lipid and glucose levels in Chinese patients with non-insulin diabetes mellitus. Curr Ther Res 1995;56:1033-40. Kobayashi M, Shigeta Y, Hirata Y, Omori Y, Sakamoto N, Nambu S, Baba S. Improvement of glucose tolerance in NIDDM by clofibrate. Randomized double-blind study. Diabetes Care 1988;11:495-9. Koch M, Gradaus F, Schoebel F-C, Leschke M, Grabensee B. Relevance of conventional cardiovascular risk factors for the prediction of coronary artery disease in diabetic patients on renal replacement therapy. Nephrol Dial Transplant 1997;12:1187-91. Koch M, Thomas B, Tschope W, Ritz E. Survival and predictors of death in dialysed diabetic patients. Diabetologia 1993;36:1113-7. Koev D, Zlateva S, Susic M, Babic D, Profozic V, Skrabalo Z, Langrova H, Cvrkalova A, Rajecova E, Klimes I, Sebokova E, Hanzen E, Lacko A, Kreze A, Rybka J, Gus M, Kalits I, Karadi I, Romics L, Leoski JJr, Orlandini L. Improvement of lipoprotein lipid composition in Type II diabetic patients with concomitant hyperlipoproteinemia by acipimox treatment. Diabetes Care 1993;16:1285-90. Konttinen A, Kuisma I, Ralli R, Pohjola S, Ojala K. The effect of gemfibrozil on serum lipids in diabetic patients. Ann Clin Res 1979;11:240-5. Kostner GM, Karadi I. Lipoprotein alterations in diabetes mellitus. Diabetologia 1988;31:717-22. Kramer-Guth A, Quaschning T, Greiber S, Wanner C. Potential role of lipids in the progression of diabetic nephropathy. Clin Nephrol 1996;46:262-5. Kramer-Guth A, Quaschning T, Pavenstadt H, Galle J, Nauck M, Baumstark MW, Schollmeyer P, Marz W, Wanner C. Uptake and metabolism of lipoproteins from patients with diabetes mellitus type II by glomerular epithelial cells. Nephrol Dial Transplant 1997;12:1336-43. Kreisberg RA. Diabetic dyslipidemia. Am J Cardiol 1998;82:U67-73.

205

Kremph M, Berthezene F, Wemeau JL, Moinade S, Desriac I, Amelineau E, Passa P. Efficacy of low-dose pravastatin in patients with mild hyperlipidemia associated with Type 2 diabetes mellitus. Diabetes Metab 1997;23:131-6. Krook A, Holm I, Pettersson S, Wallberg-Henriksson, H. Reduction of risk factors following lifestyle modification programme in subjects with Type 2 (non-insulin dependent) diabetes mellitus. Clin Physiol & Func Im 2003;23:21-30. Kumar S, Prange A, Schulze J, Lettis S, Barnett AH. Troglitazone, an insulin action enhancer, improves glycaemic control and insulin sensitivity in elderly Type 2 diabetic patients. Diabet Med 1998;15:772-9. Kuusi T, Yki-Jarvinen H, Kauppinen-Makelin R, Jauhiainen M, Ehnholm C, Kauppila M, Seppala P, Viikari J, Kujansuu E, Rajala S, Lahti J, Niskanen L, Marjanen T, Salo S, Ryysy L, Tulokas T, Taskinen M-R. Effect of insulin treatment on serum lipoprotein (a) in non-insulin-dependent diabetes. Eur J Clin Invest 1995;25:194-200. Kuusisto J, Mykkanen L, Pyorala K, Laakso M. NIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes 1994;43:960-7. Kuusisto J, Lempiainen P, Mykkanen L, Laakso M. Insulin resistance syndrome predicts coronary heart disease events in elderly Type 2 diabetic men. Diabetes Care 2001;24:1629-33. Laakso M. Epidemiology of diabetic dyslipidemia. Diabetes Rev 1995;3:408-22. Laakso M, Pyorala K, Voutilainen E, Marniemi J. Plasma insulin and serum lipids and lipoproteins in middle-aged non-insulin-dependent and non-diabetic patients. Am J Epidemiol 1987;125:611-21. Lahdenpera S, Syvanne M, Kahri J, Taskinen MR. Regulation of low-density lipoprotein particle size distribution in NIDDM and coronary disease: importance of serum triglycerides. Diabetologia 1996;39:453-61. Laitinen JH, Ahola IE, Sarkkinen ES, Winberg RL, Harmaakorpi-Iivonen PA, Uusitupa MI. Impact of intensified dietary therapy on energy and nutrient intakes and fatty acid composition of serum lipids in patients with recently diagnosed non-insulin-dependent diabetes mellitus. J Am Diet Assoc 1993;93:276-83. Lakatos J, Molnar M, Toth K. Efficacy and tolerance of 400 mg bezafibrate in diabetic and hyperlipidaemic patients. Acta Physiologica Hungarica 1996;84:433-5. Lalor BC, Bhatnagar D, Winocour PH, Ishola M, Arrol S, Brading M, Durrington PN. Placebo-controlled trial of the effects of guar gum and metformin on fasting blood glucose and serum lipids in obese, Type 2 diabetic patients. Diabet Med 1990;7:242-5. Lam KSL, Cheng IKP, Janus ED, Pang RWC. Cholesterol-lowering therapy may retard the progression of diabetic nephropathy. Diabetologia 1995;38:604-9. Lam KSL, Pang RWC, Wat MS, Lauder IJ, Janus ED. Apolipoprotein (a) levels and phenotypes in NIDDM patients with microalbuminuria and albuminuria. Nephrol Dial Transplant 1996;11:2229-36. Lam TH, Liu LJ, Janust ED, Lam SL, Hedley AJ, for the Hong Kong Cardiovascular Risk Factor Prevalence Study Steering Committee. Fibrinogen, other cardiovascular risk factors and diabetes mellitus in Hong Kong: a community with high prevalence of Type 2 diabetes mellitus and impaired glucose tolerance. Diabet Med 2000;17:798-806. Lampman RM, Schteingart DE. Effects of exercise training on glucose control, lipid metabolism, and insulin sensitivity in hypertriglyceridemia and non-insulin dependent diabetes mellitus. Med Sci Sports Ex 1991;23:703-12. Lane JT, Subbaiah PV, Otto ME, Bagdade JD. Lipoprotein composition and HDL particle size distribution in women with non-insulin-dependent diabetes mellitus and the effects of probucal treatment. J Lab Clin Med 1991;118:120-8. Latinen J, Uusitupa M, Ahola I, Siitonen O. Metabolic and dietary determinants of serum lipids in obese patients with recently diagnosed non-insulin-dependent diabetes. Ann Med 1994;26:119-24.

206

Lavezzari M, Milanesi G, Oggioni E, Pamparana F. Results of a phase IV study carried out with acipimox in Type II diabetic patients with concomitant hyperlipoproteinaemia. J Int Med Res 1989;17:373-80. Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? BMJ 1994;308:367-72. Lawrence JR, Campbell GR, Barrington H, Malcolm EA, Brennan G, Wiles DH, Paterson JR. Clinical and biochemical determinants of plasma lipid peroxide levels in type 2 diabetes. Ann Clin Biochem 1998;35:387-92. Laws A, Marcus EB, Grove JS, Curb JD. Lipids and lipoproteins as risk factors for coronary heart disease in men with abnormal glucose tolerance: the Honolulu Heart Program. J Int Med 1993;234:471-8. Leatherdale B. HRT in diabetes: Time for action. Pract Diabetes Int 1998;15:70. Lebovitz HE. Effects of oral antihyperglycemic agents in modifying macrovascular risk factors in Type 2 diabetes. Diabetes Care 1999;22(Suppl 3):C41-4. Ledesma RL, Munari ACF, Dominguez BCH, Montalvo SC, Luna MHH, Juarez C, Lira SM. Monounsaturated fatty acids (avocado) rich diet for mild hypercholesterolemia. Arch Med Res 1996;27:519-23. Lee NA, Reasner CA. Beneficial effect of chromium supplementation on serum triglycerides levels in NIDDM. Diabetes Care 1994;17:1449-52. Lees AM, Mok HYI, Lees RS, McCluskey MA, Grundy SM. Plant sterols as cholesterol-lowering agents: clinical trials in patients with hypercholesterolemia and studies of sterol balance. Atherosclerosis 1977;28:325-38. Lehto S, Ronnemaa T, Pyorala K, Laakso M. Predictors of stroke in middle-aged patients with non-insulin-dependent diabetes. Stroke 1996;27:63-8. Leonhardt W, Hanefeld M, Fischer S, Schulze J. Efficacy of alpha-glucosidase inhibitors on lipids in NIDDM subjects with moderate hyperlipidaemia. Eur J Clin Invest 1994;24(Suppl 3):45-9. Lerman-Garber I, Ichazo-Cerro S, Zamora-Gonzalez J, Cardoso-Saldana G, Posadas-Romero C. Effect of a high-monounsaturated fat diet enriched with avocado in NIDDM patients. Diabetes Care 1994;17:311-5. Lewis GF. Diabetic dyslipidemia: a case for aggressive intervention in the absence of clinical trial and cost effectiveness data. Can J Cardiol 1995;11(Suppl C):24-9. Lewis GF, O'Meara NM, Soltys PA, Blackman JD, Iverius PH, Pugh WL, Getz GS, Polonsky KS. Fasting hypertriglyceridemia in noninsulin-dependent diabetes mellitus is an important predictor of postprandial lipid and lipoprotein abnormalities. J Clin Endocrinol Metab 1991;72:934-45. Lewis GF, Steiner G. Hypertriglyceridemia and its metabolic consequences as a risk factor for atherosclerotic cardiovascular disease in non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 1996;12:37-56. Lilley SH, Spivey JM, Vadlamudi S, Otvos J, Cummings DM, Barakat H. Lipid and lipoprotein responses to oral combined hormone replacement therapy in normolipemic obese women with controlled Type 2 diabetes mellitus. J Clin Pharmacol 1998;38:1107-5. Lindstrom T, Arnqvist HJ, Olsson AG. Effect of different insulin regimens on plasma lipoprotein and apolipoprotein concentrations in patients with non-insulin-dependent diabetes mellitus. Atherosclerosis 1990;81:137-44. Lindstrom T, Olsson AG, Von Schenck H, Wallentin L, Arnqvist HJ. Insulin treatment improves microalbuminuria and other cardiovascular risk factors in patients with type 2 diabetes mellitus. J Intern Med 1994;235:253-61. Liu GC, Coulston AM, Lardinois CK, Hollenbeck CB, Moore JG, Reaven GM. Moderate weight loss and sulfonylurea treatment of non-insulin-dependent diabetes mellitus. Arch Intern Med 1985;145:665-9. Lopes-Virella MFL, Stone PG, Colwell JA. Serum high density lipoprotein in diabetic patients. Diabetologia 1977;13:285-91.

207

Lu W, Resnick HE, Jablonski KA, Jones KL, Jain AK, Howard WJ, Robbins DC, Howard BV. Non-HDL cholesterol as a predictor of cardiovascular disease in Type 2 diabetes. The Strong Heart Study. Diabetes Care 2003;26:16-23. Lucas CP, Patton S, Stepke T, Kinhal V, Darga LL, Carroll-Michals L, Spafford TR, Kasim S. Achieving therapeutic goals in insulin-using diabetic patients with non-insulin-dependent diabetes mellitus. A weight reduction-exercise-oral agent approach. Am J Med 1987;83(Suppl 3A):3-9. Ludvik B, Nolan JJ, Baloga J, Sacks D, Olefsky J. Effects of obesity on insulin resistance in normal subjects and patients with NIDDM. Diabetes 1995;44:1121-5. Liu DP, Molyneaux L, Chua E, Wang YZ, Wu CR, Jing H, Hu LN, Liu YJ, Xu ZR, Yue DK. Retinopathy in a Chinese population with Type 2 diabetes: factors affecting the presence of complications at diagnosis of diabetes. Diabetes Res Clin Prac 2002;56:125-31. Luo J, Rizkalla SW, Vidal H, Oppert JM, Colas C, Boussairi A, Guerre-Millo M, Chapuis AS, Chevalier A, Durand G, Slama G. Moderate intake of n-3 fatty acids for 2 months has no detrimental effect on glucose metabolism and could ameliorate the lipid profile in type 2 diabetic men. Diabetes Care 1998;21:717-24. Mani UV, Iyer U, Mani I, Desikachar HSR. Long-term effect of cereal-pulse mix (diabetic mix) supplementation on serum lipid profile in non-insulin-dependent diabetes mellitus patients. J Nutr Environ Med 1997;7:163-8. Mann JI. The role of nutritional modifications in the prevention of macrovascular complications of diabetes. Diabetes 1997;46:(Suppl 2):125-30. Manzato E, Crepaldi G. Dyslipoproteinaemia in manifest diabetes. J Intern Med 1994;236:27-31. Marangou AG, Weber KM, Boston RC, Aitken PM, Heggie JCP, Kirsner RLG, Best JD, Alford FP. Metabolic consequences of prolonged hyperinsulinemia in humans. Evidence for induction of insulin insensitivity. Diabetes 1986;35:1383-9. Martinez-Triguero M-L, Salvador A, Samper M-J, Almela M, Vega L, Mora A, Martinez-Diago V. Lipoprotein (a) and other risk factors in patients with non-insulin-dependent diabetes mellitus. Coron Artery Dis 1994;5:755-60. Maxwell SRJ, Thomason H, Sandler D, LeGuen C, Baxter MA, Thorpe GHG, Jones AF, Barnett AH. Poor glycaemic control is associated with reduced serum free radical scavenging (antioxidant) activity in non-insulin-dependent diabetes mellitus. Ann Clin Biochem 1997;34:638-44. McCarron DA, Oparil S, Chait A, Haynes B, Kris-Etherton P, Stern JS, Resnick LM, Clark S, Morris CD, Hatton DC, Metz JA, McMahon M, Holcomb S, Snyder GW, Pi-Sunyer FX. Nutritional management of cardiovascular risk factors. A randomized clinical trial. Arch Intern Med 1997;157:169-77. McColl AJ, Kong C, Nimmo L, Collins J, Elkeles RS, Richmond W. Total antioxidant status, protein glycation, lipid hydroperoxides in non insulin dependent diabetes mellitus. Biochem Soc Trans 1997;25:660. McGrath LT, Brennan GM, Donnelly JP, Johnston GD, Hayes JR, McVeigh GE. Effect of dietary fish oil supplementation on peroxidation of serum lipids in patients with non-insulin dependent diabetes mellitus. Atheroslerosis 1996;121:275-83. McIntosh A, Hutchinson A, Feder G, Home P (2001). Clinical guidelines for Type 2 diabetes: Lipid management. London, RCGP. McKenney JM. Understanding and treating dyslipidemia associated with noninsulin-dependent diabetes mellitus and hypertension. Pharmacotherapy 1993;13:340-52. McManus RM, Jumpson J, Finegood DT, Clandinin MT, Ryan EA. A comparison of the effects of n-3 fatty acids from linseed oil and fish oil in well-controlled Type II diabetes. Diabetes Care 1996;19:463-7. Meade T, Zuhrie R, Cook C, Cooper J. Bezafibrate in men with lower extremity arterial disease: randomised controlled trial. BMJ 2002;325:1139-43.

208

Mero N, Syvanne M, Taskinen MR. Postprandial lipid metabolism in diabetes. Atherosclersis 1998;141(Suppl 1):S53-5. Merrin PK, Feher MD, Elkeles RS. Diabetic macrovascular disease and serum lipids: is there a connection? Diab Med 1992;9:9-14. Miccoli R, Bertolotto A, Giovannitti MG, Tedesco I, Manfredi S, Galantini G, Navalesi R. Simvistatin for lipid lowering cholesterol levels in non-insulin-dependent diabetes mellitus and in primary hypercholesterolemia. Curr Ther Res 1992;51:66-74. Miccoli R, Giovannitti MG, Ceraudo A, Anichini R, Dolci A, Trifiro R, Navalesi R. Effects of pravastatin treatment on lipoprotein levels and composition in patients with Type 2 diabetes mellitus and hypercholesterolaemia. Curr Ther Res Clin Exp 2000;61:107-18. Michailidou G, Perea D, Katsilambros N. Monounsaturated fat and postprandial triglycerides levels in non-insulin-dependent diabetic persons. Diabet Med 1997;14:406-7. Mikhail N. The use of niacin in diabetes mellitus. Arch Intern Med 2003;163:369-70. Mikhailidis DP, Mathur S, Barradas MA, Dandona P. Bezafibrate retard in type II diabetic patients: effects on hemostasis and glucose homeostasis. J Cardiovasc Pharmacol 1990;16(Suppl 9):26-9. Miki E, Lu M, Lee ET, Keen H, Bennett PH, Russell D, Fuller J. The incidence of visual impairment and its determinants in the WHO multinational study of vascular disease in diabetes. Diabetologia 2001;44(Suppl 2):S31-6. Mogensen CE. Natural history of cardiovascular and renal disease in patients with type 2 diabetes: effect of therapeutic interventions and risk modification. Am J Cardiol 1998;82(9B):R4-8. Mohan V, Deepa R, Haranath SP, Premalatha G, Rema M, Sastry NG, Enas EA. Lipoprotein (a) is an independent risk factor for coronary artery disease in NIDDM patients in South India. Diabetes Care 1998;21:1819-23. Mohan V, Deepa R, Rani SS, Premalatha G; Chennai Urban Population Study (CUPS No.5). Prevalence of coronary artery disease and its relationship to lipids in a selected population in South India: The Chennai Urban Population Study (CUPS No. 5). J Am Coll Cardiol 2001;38:682-7. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003;289:76-9. Molnar GD, Berge KG, Rosevear JW, McGuckin WF, Achor RW. The effect of nicotinic acid in diabetes mellitus. Metabolism 1964;13:181-90. Monk A, Barry B, McClain K, Weaver T, Cooper N, Franz MJ. Practice guidelines for medical nutrition therapy provided by dietitians for persons with non-insulin-dependent diabetes mellitus. J Am Diet Assoc 1995;95:999-1006. Mooradian AD. Increased serum conjugated dienes in elderly diabetic patients. J Am Geriatr Soc 1991;39:571-4. Morgan WA, Raskin P, Rosenstock J. A comparison of fish oil or corn oil supplements in hyperlipidemic subjects with NIDDM. Diabetes Care 1995;18:83-6. Mori TA. Fish oils, dyslipidaemia and glycaemic control in diabetes. Pract Diabetes Int 1999;16:223-6. Mori TA, Vandongen R, Masarei JR, Rouse IL, Dunbar D. Comparison of diets supplemented with fish oil or olive oil on plasma lipoproteins in insulin-dependent diabetics. Metabolism 1991;40:241-6. Morisaki N, Yokote K, Tashiro J, Inadera H, Kobayashi J, Kanzaki T, Saito Y, Yoshida S. Lipoprotein(a) is a risk factor for diabetic retinopathy in the elderly. J Am Geriatr Soc 1994;42:965-7.

209

Morrish NJ, Stevens LK, Fuller JH, Jarrett RJ, Keen H. Risk factors for macrovascular disease in diabetes mellitus: the London follow-up to the WHO Multinational Study of Vascular Disease in Diabetics. Diabetologia 1991;34:590-4. Murakami T, Yamada N, Kawakubo K, Oku J, Mizushima Y, Iino S, Sugimoto T. Lipoprotein abnormalities in non-insulin dependent diabetic patients with ischemic heart disease. Artery 1997;22:206-32. Myers J, Atwood JE, Froelicher V. Active lifestyle and diabetes. Circulation 2003;107:2392-4. Nagi DK, Yudkin JS. Effect of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. Diabetes Care 1993;16:621-9. Nakata H, Horita K, Eto M. Alterations of lipoprotein(a) concentration with glycemic control in non-insulin-dependent diabetic subjects without diabetic complications. Metabolism 1993;42:1323-6. Nash DT. Statins: Evidence of effectiveness in older patients. Geriatrics 2003;58:35-42. Nathan DM, Meigs J, Singer DE. The epidemiology of cardiovascular disease in type 2 diabetes mellitus: How sweet it is...or is it? Lancet 1997;350(Suppl 1):SI4-9. National Cholesterol Education Program Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Arch Intern Med 1988;148:36-68. National Heart Foundation. www.heartfoundation.com.au. 2001. National Institutes of Health Consensus Development Panel. Treatment of hypertriglyceridemia. NIH Consensus Development Conference summary. Arteriosclerosis 1984;4:296-301. Nicholl JP, Coleman P, Brazier JE. Health and healthcare costs and benefits of exercise. Pharmacoeconomics 1994;5:109-22. Nielsen FS, Rossing P, Gall MA, Skott P, Smidt UM, Parving HH. Long-term effects of lisinopril and atenolol on kidney function in hypertensive NIDDM subjects with diabetic nephropathy. Diabetes 1997;46:1182-8. Niort G, Gambino R, Cassader M, Pagano G. Bezafibrate affects lipid, lipo- and apolipoprotein pattern in non-insulin-dependent diabetic patients. Horm Metab Res 1993;25:372-4. Notarbartolo A, Galletti F, Averna MR, Barbagallo CM, Piliego T. Effects of gemfibrozil in hyperlipidemic patients with or without diabetes. Curr Ther Res 1993;53:381-93. Nourooz-Zadeh J, Tajaddini-Sarmadi J, McCarthy S, Betteridge DJ, Wolff SP. Elevated levels of authentic plasma hydroperoxides in NIDDM. Diabetes 1995;44:1054-8. O'Brien SF, Watts GF, Playford DA, Burke V, O'Neal DN, Best JD. Low-density lipoprotein size, high-density lipoprotein concentration, and endothelial dysfunction in non-insulin-dependent diabetes. Diabet Med 1997;14:974-8. O'Brien T, Nguyen TT, Hallaway BJ, Hodge D, Bailey K, Kottke BK. HDL subparticles and coronary artery disease in NIDDM. Atherosclerosis 1996;121:285-91. O'Brien T, Nguyen TT, Zimmerman BR. Hyperlipidemia and diabetes mellitus. Mayo Clin Proc 1998;73:969-76. Oh JY, Barrett-Connor E, Wedick NM, Wingard DL. Rancho Bernardo Study. Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabetes Care 2002;25:55-60. Ohrvall M, Lithell H, Johansson J, Vessby B. A comparison between the effects of gemfibrozil and simvastatin on insulin sensitivity in patients with non-insulin-dependent diabetes mellitus and hyperlipoproteinemia. Metabolism 1995;44:212-7.

210

Oi K, Komori H. Escape phenomenon with pravastatin during long-term treatment of patients with hyperlipidemia associated with diabetes mellitus. Curr Ther Res 1998;59:130-8. Okada S, Ishii K, Hamada H, Tanokuchi S, Ichiki K, Ota Z. The effect of an alpha-glucosidase inhibitor and insulin on glucose metabolism and lipid profiles in non-insulin-dependent diabetes mellitus. J Int Med Res 1996;24:438-47. Okada S, Ishii K, Tanokuchi S, Hamada H, Ichiki K, Ota Z. Effect of alpha-glucosidase inhibitor in combination with sulphonylurea compounds on lipid profile in patients with non-insulin-dependent diabetes mellitus. J Int Med Res 1995;23:492-6. Okada S, Miyai Y, Ichiki K, Sato K, Masaki Y, Higuchi T, Ogino Y, Ota Z. Clinofibrate therapy raises high-density lipoprotein levels and lowers atherogenic index in diabetes mellitus patients. J Int Med Res 1989;17:521-5. Okubo M, Murase T. Hypertriglyceridemia and low HDL cholesterol in Japanese patients with NIDDM. Diabetes 1996;45(Suppl 3):S123-5. O'Neal DN, Lewicki J, Ansari MZ, Matthews PG, Best JD. Lipid levels and peripheral vascular disease in diabetic and non-diabetic subjects. Atherosclerosis 1998;136:1-8. Onuma T, Kikuchi T, Tsutsui M, Shimura S, Matsui J, Boku A, Takebe K. High incidence of diabetic nephropathy in non-insulin-dependent diabetic patients with heterozygous familial hypercholesterolemia. Curr Ther Res 1994;55:532-6. Orchard TJ. Dyslipoproteinemia and diabetes. Endocrinol Metab Clin North Am 1990;19:361-80. Orloff DG, Blazing MA, O'Connor CM. Atherosclerosis disease in non-insulin-dependent diabetes mellitus: role of abnormal lipids and the place for lipid-altering therapies. Am Heart J 1999;138:S406-12. Ostgren CJ, Lindblad U, Bog-Hansen E, Ranstam J, Melander A, Rastam L. Differences in treatment and metabolic abnormalities between normo- and hypertensive patients with Type 2 diabetes: the Skaraborg Hypertension and Diabetes Project. Diabetes Obes Metab 1999;1:105-12. Owens D, Stinson J, Collins P, Johnson A, Tomkin GH. Improvement in the regulation of cellular cholesterologenesis in diabetes: the effect of reduction in serum cholesterol by simvastatin. Diabet Med 1991;8:151-6. Ozdemirler G, Mehmetcik G, Oztezcan S, Toker G, Sivas A, Uysal M. Peroxidation potential and antioxidant activity of serum in patients with diabetes mellitus and myocardial infarction. Horm Metab Res 1995;27:194-6. Page RCL, Harnden KE, Walravens NKN, Onslow C, Sutton P, Levy JC, Hockaday DTR, Turner RC. 'Healthy living' and sulphonylurea therapy have different effects on glucose tolerance and risk factors for vascular disease in subjects with impaired glucose tolerance. Quart J Med 1993;86:145-54. Paisey R, Elkeles RS, Hambley J, Magill P. The effects of chlorpropamide and insulin on serum lipids, lipoproteins and fractional triglycerides removal. Diabetelogia 1978;15:81-5. Paisey RB, Harvey P, Rice S, Belka I, Bower L, Dunn M, Taylor P, Paisey RM, Frost J, Ash I. An intensive weight loss programme in established type 2 diabetes and controls: effects on weight and atherosclerosis risk factors at 1 year. Diabet Med 1998;15:73-9. Paisey RB, Frost J, Harvey P, Paisey A, Bower L, Paisey RM, Taylor P, Belka I. Five year results of a prospective very low calorie diet or conventional weight loss programme in type 2 diabetes. J Hum Nutr Dietet 2002;15:121-7. Palin SL, Kumar S, Sturdee DW, Barnett AH. HRT in women with diabetes - review of the effects on glucose and lipid metabolism. Diabetes Res Clin Pract 2001;54:67-77. Palumbo PJ. Metformin: effects on cardiovascular risk factors in patients with non-insulin-dependent diabetes mellitus. J Diabetes Complications 1998;12:110-9.

211

Pan XR, Walden CE, Warnick GR, Hu SX, Albers JJ, Cheung M, Bierman EL. Comparison of plasma lipoproteins and apoproteins in Chinese and American non-insulin-dependent diabetic subjects and controls. Diabetes Care 1986;9:395-400. Paolisso G, Sgambato S, De Riu S, Gambardella A, Verza M, Varricchio M, D'Onofrio F. Simvastatin reduces plasma lipid levels and improves insulin action in elderly, non-insulin dependent diabetics. Eur J Clin Pharmacol 1991;40:27-31. Papadakis JA, Milionis HJ, Press M, Mikhailidis DP. Treating dyslipidaemia in non-insulin-dependent diabetes mellitus - a special reference to statins. J Diabetes Complications 2001;15:211-26. Parfitt VJ, Hopton M, Taberner J, Bolton C, Hartog M. The effects of high monounsaturated and polyunsaturated fat diets on vascular endothelium and the coagulation system in non-insulin dependent diabetes mellitus--related to changes in lipid peroxidation? Biochem Soc Trans 1993;21:S103. Parillo M, Rivellese AA, Ciardullo AV, Capaldo B, Giacco A, Genovese S, Riccardi G. A high-monounsaturated-fat/low-carbohydrate diet improves peripheral insulin sensitivity in non-insulin-dependent diabetic patients. Metabolism 1992;41:1373-8. Parving HH, Gall MA, Nielsen FS. Dyslipidaemia and cardiovascular disease in non-insulin-dependent diabetic patients with and without diabetic nephropathy. J Intern Med 1994;236(Suppl 736):89-94. Pascale RW, Wing RR, Butler BA, Mullen M, Bononi P. Effects of a behavioral weight loss program stressing calorie restriction versus calorie plus fat restriction in obese individuals with NIDDM or a family history of diabetes. Diabetes Care 1995;18:1241-8. Patel J, Anderson RJ, Rappaport EB. Rosiglitazone monotherapy improves glycaemic control in patients with type 2 diabetes: a twelve-week, randomized, placebo-controlled study. Diabetes Obes Metab 1999;1:165-72. Patti L, Maffettone A, Iovine C, Marino LD, Annuzzi G, Riccardi G, Rivellese AA. Long-term effects of fish oil on lipoprotein subfractions and low density lipoprotein size in non-insulin-dependent diabetic patients with hypertriglyceridemia. Atherosclerosis 1999;146:361-7. Pauciullo P, Mancini M. Treatment challenges in hypercholesterolemia. Cardiovasc Drugs Ther 1998;12:325-37. Pekkanen J, Linn S, Heiss G, Suchindran CM, Leon A, Rifkind BM, Tyroler HA. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med 1990;322:1700-7. Pelikanova T, Kohout M, Valek J, Kazdova L, Base J. Metabolic effects of omega-3 fatty acids in type 2 (non-insulin-dependent) diabetic patients. Ann NY Acad Sci 1993;683:272-8. Perez A, Carreras G, Caixas A, Castellvi A, Caballero A, Bonet R, Ordonez-Llanos J, DeLeiva A. Plasma lipoprotein (a) levels are not influenced by glycemic control in Type 1 diabetes. Diabetes Care 1998;21:1517-20. Perriello G, Misericordia P, Volpi E, Santucci A, Santucci C, Ferrannini E, Ventura MM, Santeusanio F, Brunetti P, Bolli GB. Acute antihyperglycemic mechanisms of metformin in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose production. Diabetes 1994;43:920-8. Peterson DB, Fisher K, Carter RD, Mann J. Fatty acid composition of erythrocytes and plasma triglyceride and cardiovascular risk in Asian diabetic patients. Lancet 1994;343:1528-30. Pfeffer MA, Keech A, Sacks FM, Cobbe SM, Tonkin A, Byington RP, Davis BR, Friedman CP, Braunwald E. Safety and tolerability of pravastatin in long-term clinical trials. Prospective Pravastatin Pooling (PPP) Project. Circulation 2002;105:2341-6. Pfeifer MA, Brunzell JD, Best JD, Judzewitsch RG, Halter JB, Porte D Jr. The response of plasma triglycerides, cholesterol, and lipoprotein lipase to treatment in non-insulin-dependent diabetic subjects without familial hypertriglyceridemia. Diabetes 1983;32:525-31.

212

Phillips LS, Grunberger G, Miller E, Patwardhan R, Rappaport EB, Salzman A; Rosiglitazone Clinical Trials Study Group. Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes. Diabetes Care 2001;24:308-15. Picard S, Talussot C, Serusclat A, Ambrosio N, Berthezene F. Minimally oxidised LDL as estimated by a new method increase in plasma of type 2 diabetic patients with atherosclerosis or nephropathy. Diabetes Metab 1996;22:25-30. Pitt B, Waters D, Brown WV, van Boven AJ, Schwartz L, Title LM, Eisenberg D, Shurzinske L, McCormick LS. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus Revascularization Treatment Investigators. N Engl J Med 1999;341:70-6. Pontiroli AE, Calderara A, Bonisolli L, De Pasqua A, Maffi P, Margonato A, Radaelli G, Gallus G, Pozza G. Risk factors for micro- and macroangiopathic complications in Type 2 diabetes: lack of association with acetylator phenotype, chlorpropamide alcohol flush and ABO and Rh blood groups. Diabete Metab 1987;13:444-9. Pontrelli L, Parris W, Adeli K, Cheung RC. Atorvastatin treatment beneficially alters the lipoprotein profile and increases low-density lipoprotein particle diameter in patients with combined dyslipidemia and impaired fasting glucose/type 2 diabetes. Metabolism 2002;51:334-42. Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997;336:153-62. Prince MJ, Deeg MA. Do n-3 fatty acids improve glucose tolerance and lipemia in diabetics? Curr Opin Lipidol 1997;8:7-11. Purnell JQ, Brunzell JD. Effect of intensive diabetes therapy on diabetic dyslipidemia. Diabetes Rev 1997;5:434-44. Pyorala K, Steiner G. Will correction of dyslipoproteinaemia reduce coronary heart disease risk in patients with non-insulin-dependent diabetes? Need for trial evidence. Ann Med 1996;28:357-62. Rabkin SW, Boyko E, Streja DA. Changes in high density lipoprotein cholesterol after initiation of insulin therapy in non-insulin-dependent diabetes mellitus: relationship to changes in body weight. Am J Med Sci 1983;285:14-20. Raeini-Sarjaz M, Vanstone CA, Papamandjaris AA, Wykes LJ, Jones PJ. Comparison of the effect of dietary fat restriction with that of energy restriction on human lipid metabolism. Am J Clin Nutr 2001;73:262-7. Rains SG, Wilson GA, Richmond W, Elkeles RS. The reduction of low density lipoprotein cholesterol by metformin is maintained with long-term therapy. J Roy Soc Med 1989;82:93-4. Rainwater DL, MacCluer JW, Stern MP, VandeBerg JL, Haffner SM. Effects of NIDDM on lipoprotein (a) concentration and apolipoprotein (a) size. Diabetes 1994;43:942-6. Ramirez LC, Arauz-Pacheco C, Lackner C, Albright G, Adams BV, Raskin P. Lipoprotein (a) levels in diabetes mellitus: relationship to metabolic control. Ann Intern Med 1992;117:42-7. Raskin P, Ganda OP, Schwartz S, Willard D, Rosenstock J, Lodewick PA, Cressman MD, Phillipson B, Weiner B, McGovern ME. Norton JM, Cucinotta GG, Behounek BD. Efficacy and safety of pravastatin in the treatment of patients with type 1 or type 2 diabetes mellitus and hypercholesterolemia. Am J Med 1995;99:362-9. Raskin P, Rappaport EB, Cole ST, Yan Y, Patwardhan R, Freed MI. Rosiglitazone short-term monotherapy lowers fasting and post-prandial glucose in patients with type 2 diabetes. Diabetologia 2000;43:278-84. Rasmussen OW, Thomsen C, Hansen KW, Vesterlund M, Winther E, Hermansen K. Effects on blood pressure, glucose, and lipid levels of a high-monounsaturated fat diet compared with a high-carbohydrate diet in NIDDM subjects. Diabetes Care 1993;16:1565-71. Ravid M, Neumann L, Lishner M. Plasma lipids and the progression of nephropathy in diabetes mellitus type II: effect of ACE inhibitors. Kidney Int 1995;47:907-10.

213

Raz I, Hauser E, Bursztyn M. Moderate exercise improves glucose metabolism in uncontrolled elderly patients with non-insulin-dependent diabetes mellitus. Isr J Med Sci 1994;30:766-70. Reavan GM. Beneficial effect of moderate weight loss in older patients with non- insulin dependent diabetes mellitus poorly controlled with insulin. J Am Geriatr Soc 1985;33:93-5. Reaven GM. Effect of metformin on various aspects of glucose, insulin and lipid metabolism in patients with non-insulin-dependent diabetes mellitus with varying degrees of hyperglycemia. Diabetes Metab Rev 1995;11(Suppl 1):97-108. Reaven P. Dietary and pharmacologic regimens to reduce lipid peroxidation in non-insulin-dependent diabetes mellitus. Am J Clin Nutr 1995;62(Suppl 6):S1483-9. Reaven P, Grasse B, Barnett J. Effect of antioxidants alone and in combination with monounsaturated fatty acid-enriched diets on lipoprotein oxidation. Arterioscler Thromb Vasc Biol 1996;16:1465-72. Reaven GM, Johnston P, Hollenbeck CB, Skowronski R, Zhang JC, Goldfine ID, Chen YD. Combined metformin-sulfonylurea treatment of patients with noninsulin-dependent diabetes in fair to poor glycemic control. J Clin Endocrinol Metab 1992;74:1020-6. Relimpio F, Pumar A, Losada F, Molina J, Maynar A, Acosta D, Astorga R. Urinary albumin excretion rate and cardiovascular disease in Spaniard type 2 diabetic patients. Diabetes Res Clin Pract 1997;36:127-34. Relimpio F, Pumar A, Losada F, Montilla C, Morales F, Acosta D, Astorga R. Lack of association of lipoprotein (a) with coronary heart disease in Spaniard type 2 diabetic patients. Diabetes Res Clin Pract 1997;35:135-41. Reverter JL, Senti M, Rubies-Prat J, Lucas A, Salinas I, Pizarro E, Pedro-Botet J, Romero R, Sanmarti A. Relationship between lipoprotein profile and urinary albumin excretion in type II diabetic patients with stable metabolic control. Diabetes Care 1994;17:189-94. Riccardi G, Genovese S, Saldalamacchia G, Patti L, Marotta G, Postiglione A, Rivellese A, Capaldo B, Mancini M. Effects of bezafibrate on insulin secretion and peripheral insulin sensitivity in hyperlipidemic patients with and without diabetes. Atherosclerosis 1989;75:175-81. Riccardi G, Parillo M. Comparison of the metabolic effects of fat-modified vs low fat diets. Ann NY Acad Sci 1993;683:192-8. Riccardi G, Rivellese AA. Effects of dietary fiber and carbohydrate on glucose and lipoprotein metabolism in diabetic patients. Diabetes Care 1991;14:1115-25. Riegger G, Abletshauser C, Ludwig M, Schwandt P, Widimsky J, Weidinger G, Welzel D. The effect of fluvastatin on cardiac events in patients with symptomatic coronary artery disease during one year of treatment. Atherosclerosis 1999;144:263-70. Ritz E. Why are lipids not predictive of cardiovascular death in the dialysis patient? Miner Electrolyte Metab 1996;22:9-12. Rivellese AA, Auletta P, Marotta G, Saldalamacchia G, Giacco A, Mastrilli V, Vaccaro O, Riccardi G. Long term metabolic effects of two dietary methods of treating hyperlipidaemia. BMJ 1994;308:227-31. Rivellese AA, De Natale C, Lilli S. Type of dietary fat and insulin resistance. Ann NY Acad Sci 2002;967:329-35. Rivellese AA, Giacco R, Genovese S, Patti L, Marotta G, Pacioni D, Annuzzi G, Riccardi G. Effects of changing amount of carbohydrate in diet on plasma lipoproteins and apolipoproteins in Type II diabetic patients. Diabetes Care 1990;13:446-8. Rivellese AA, Maffettone A, Iovine C, Di Marino L, Annuzzi G, Mancini M, Riccardi G. Long-term effects of fish oil on insulin resistance and plasma lipoproteins in NIDDM patients with hypertriglyceridemia. Diabetes Care 1996;19:1207-13.

214

Robins SJ, Rubins HB, Faas FH, Schaefer EJ, Elam MB, Anderson JW, Collins D; Veterans Affairs HDL Intervention Trial (VA-HIT). Insulin resistance and cardiovascular events with low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT). Diabetes Care 2003;26:1513-7. Robinson AC, Burke J, Robinson S, Johnston DG, Elkeles RS. The effects of metformin on glycemic control and serum lipids in insulin-treated NIDDM patients with suboptimal metabolic control. Diabetes Care 1998;21:701-5. Romano G, Patti L, Innelli F, Di Marino L, Annuzzi G, Iavicoli M, Coronel GA, Riccardi G, Rivellese AA. Insulin and sulfonylurea therapy in NIDDM patients. Are the effects on lipoprotein metabolism different even with similar blood glucose control?. Diabetes 1997;46:1601-6. Roselli della Rovere G, Lapolla A, Sartore G, Rossetti C, Zambon S, Minicuci N, Crepaldi G, Fedele D, Manzato E. Nutr Metab Cardiovasc Dis 2003;13:46-51. Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity. Diabetes Care 1990;13:610-30. Rubies-Prat J, Reverter JL, Senti M, Pedro-Botet J, Salinas I. Lucas A, Nogues X, Sanmarti A. Calculated low-density lipoprotein cholesterol should not be used for management of lipoprotein abnormalities in patients with diabetes mellitus. Diabetes Care 1993;16:1081-6. Rubinstein A, Maritz FJ, Soule SG, Markel A, Chajek-Shaul T, Maislos M, Tal S, Stolero D. Efficacy and safety of cerivstatin for type 2 diabetes and gypercholesterolaemia. Hyperlipidaemia in Diabetes Mellitus investigators. J Cardiovasc Risk 1999;6:399-403. Ruderman N, Horton E, Kemmer F, Berger M. The lost symposium. Diabetes and exercise 1990. Diabetes Care 1993;16:959-60. Rustemeijer C, Schouten JA, Janssens EN, Spooren PF, van Doormaal JJ. Pravastatin in diabetes-associated hypercholesterolemia. Acta Diabetol 1997;34:294-300. Salonen R, Nyyssonen K, Porkkala E, Rummukainen J, Belder R, Park JS, Salonen JT. Kuopio Atherosclerosis Prevention Study (KAPS). A population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation 1995;92:1758-64. Saloranta C, Groop L, Ekstrand A, Franssila-Kallunki A, Eriksson J, Taskinen MR. Different acute and chronic effects of acipimox treatment on glucose and lipid metabolism in patients with type 2 diabetes. Diabet Med 1993;10:950-7. Samaras K, Hayward CS, Sullivan D, Kelly RP, Campbell LV. Effects of postmenopausal hormone replacement therapy on central abdominal fat, glycaemic control, lipid metabolism, and vascular factors in Type 2 diabetes. A prospective study. Diabetes Care 1999;22:1401-7. Sarkkinen ES, Uusitupa MI, Gylling H, Miettinen TA. Fat-modified diets influence serum concentrations of cholesterol precursors and plant sterols in hypercholesterolemmic subjects. Metabolism 1998;47:744-50. Sarlund H, Pyorala K, Penttila I, Laakso M. Early abnormalities in coronary heart disease risk factors in relatives of subjects with non-insulin-dependent diabetes. Atheroscler Thomb 1992;12:657-63. Sartor G, Ursing D, Nilsson-Ehle P, Wahlin-Boll E, Melander A. Lack of primary effect of sulphonylurea (glipizide) on plasma lipoproteins and insulin action in former Type 2 diabetics with attenuated insulin secretion. Eur J Clin Pharmacol 1987;33:279-82. Sasaki A, Horiuchi N, Hasegawa K, Uehara M. Mortality from coronary heart disease and cerebrovascular disease and associated risk factors in diabetic patients in Osaka District, Japan. Diabetes Res Clin Pract 1995;27:77-83. Sattar N, McKenzie J, MacCuish AC, Jaap AJ. Hormone replacement therapy in type 2 diabetes mellitus: a cardiovascular perspective. Diabet Med 1998;15:631-3. Sawayama Y, Shimizu C, Maeda N, Tatsukawa M, Kinukawa N, Koyanagi S, Kashiwagi S, Hayashi J. Effects of probucol and pravastatin on common carotid atherosclerosis in patients with asymptomatic hypercholesterolemia. Fukuoka Atherosclerosis Trial (FAST). J Am Coll Cardiolo 2002;39:610-6.

215

Scanu AM. Genetic basis and pathophysiological implications of high plasma Lp(a) levels. J Intern Med 1992;231:679-83. Schaper NC. Early atherogenesis in diabetes mellitus. Diabet Med 1996;13(Suppl):S23-5. Schartl M, Bocksch W, Koschyk DH, Voelker W, Karsch KR, Kreuzer J, Hausmann D, Beckmann S, Gross M. Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease. Circulation 2001;104:387-92. Schectman G, Kaul S, Cherayil GD, Lee M, Kissebah A. Can the hypotriglyceridemic effect of fish oil concentrate be sustained? Ann Intern Med 1989;110:346-52. Schectman G, Kaul S, Kissebah AH. Effect of fish oil concentrate on lipoprotein composition in NIDDM. Diabetes 1988;37:1567-73. Schernthaner G. Cardiovascular mortality and morbidity in type-2 diabetes mellitus. Diabetes Res Clin Pract 1996;31(Suppl 1):S3-13. Schleiffer T, Hellstern P, Freitag M, Brass H. Plasminogen activator inhibitor 1 activity and lipoprotein(a) in nephropathic patients with non-insulin-dependent diabetes mellitus versus patients with nondiabetic nephropathy. Haemostasis 1994;24:49-54. Schonfeld G. Hypertriglyceridemia in noninsulin dependent diabetes mellitus. Semin Thromb Hemost 1988;14:184-8. Schranz AG. Abnormal glucose tolerance in the Maltese. A population-based longitudinal study of the natural history of NIDDM and IGT in Malta. Diabetes Res Clin Pract 1989;7:7-16. Schwandt P. Very low density lipoproteins in Type II diabetes mellitus and risk of atherosclerosis. Horm Metab Res 1985;15:80-3. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischaemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;285:1711-8. Schwenke DC, D'Agostino RB Jr, Goff DC Jr, Karter AJ, Rewers MJ, Wagenknecht LE. Insulin resistance atherosclerosis study. Differences in LDL oxidizability by glycemic status: the insulin resistance atherosclerosis study. Diabetes Care 2003;26:1449-55. Scott RS, Florkowski CM, Lipid and Diabetes Research Group. Noninsulin dependent diabetes mellitus: the importance of dyslipidaemia. NZ Med J 1994;107:155-6. Seghieri G, Alviggi L, De Giorgio LA, Breschi C, Gironi A, Niccolai M, Bartolomei GC. Serum lipids and lipoproteins in Type 2 diabetic patients with persistent microalbuminuria. Diabet Med 1990;7:810-4. Serruys PW, Foley DP, Jackson G, Bonnier H, Macaya C, Vrolix M, Branzi A, Shepherd J, suryapranata H, de Feyter PJ, Melkert R, van Es GA, Pfister PJ. A randomised placebo-controlled trial of fluvastatin for prevention of restenosis after successful coronary bollon angioplasty. Euro Heart J 1999;20:58-69. Sheffield JVL. General medicine update: NIDDM, prevention of CAD, and risks and benefits of hormone replacement therapy. Compr Ther 1997;23:303-9. Shen DC, Fuh MM, Shieh SM, Chen YD, Reaven GM. Effect of gemfibrozil treatment in sulphonylurea-treated patients with non-insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1991;73:503-10. Shepherd J, Packard CJ, Patsch JR, Gotto AM Jr, Taunton OD. Effects fo dietary polyunsaturated and saturated fat on the properties of high-density lipoprotein and the metabolism of apoliporotein A-1. J Clin Invest 1978;61:1582-92.

216

Shih KC, Kwok CF, Hwu CM, Hsiao LC, Li SH, Liu YF, Ho LT. Acipimox attenuates hypertriglyceridemia in dyslipidemic noninsulin dependent diabetes mellitus patients without perturbation of insulin sensitivity and glycemic control. Diabetes Res Clin Pract 1997;36:113-9. Simonson DC, Kourides IA, Feinglos M, Shamoon H, Fischette CT. Efficacy, safety, and dose-response characteristics of glipizide gastrointestinal therapeutic system on glycemic control and insulin secretion in NIDDM. Results of two multicenter, randomized, placebo-controlled clinical trials. The Glipizide Gastrointestinal Therapeutic System Study Group. Diabetes Care 1997;20:597-606. Simopoulos A. n-3 fatty acids in the prevention-management of cardiovascular disease. Can J Physiol Pharmacol 1997;75:234-9. Simpson RW, Mann JI, Hockaday TD, Hockaday JM, Turner RC, Jelfs R. Lipid abnormalities in untreated maturity-onset diabetes and the effect of treatment. Diabetologia 1979;16:101-6. Sinha R, Ismail A, Herbert S, Hoyte R, Gill G. Effect of diet and fenofibrate on lipid and glycaemic control in type 2 diabetes. Pract Diabetes Int 2001;18:269-73. Sironi AM, Vichi S, Gastaldelli A, Pecori N, Anichini R, Foot E, Seghieri G, Ferrannini E. Effects of troglitazone on insulin action and cardiovascular risk factors in patients with non-insulin-dependent diabetes. Clin Pharmacol Ther 1997;62:194-202. Sirtori CR, Crepaldi G, Manzato E, Mancini M, Rivellese A, Paoletti R, Pazzucconi F, Pamparana F, Stragliotto E. One-year treatment with ethyl esters of n-3 fatty acids in patients with hypertriglyceridemia and glucose intolerance: reduced triglyceridemia, total cholesterol and increased HDL-C without glycemic alterations. Atherosclerosis 1998;137:419-27. Smellie WSA, Sandler D, O'Donnell J. Hyperlipidaemia and diabetes. Ann Clin Biochem 1993;30:331-2. Smellie WS, Sandler D, O'Donnell J, MacCuish AC. Screening and treatment for hyperlipidaemia in non-insulin-dependent diabetes: a prospective assessment of 350 patients. Br J Clin Pract 1995;49:83-5. Smud R, Sermukslis B. Bezafibrate and fenofibrate in type II diabetics with hyperlipoproteinaemia. Curr Med Res Opin 1987;10:612-24. Sobel BE. Altered fibrinolysis and platelet function in the development of vascular complications of diabetes. Curr Opin Endocrinol Diabetes 1996;3:355-60. Solomon CG. Reducing cardiovascular risk in Type 2 diabetes. N Engl J Med 2003;348:457-9. Solomon CG, Hu FB, Stampfer MJ, Colditz GA, Speizer FE, Rimm EB, Willett WC, Manson JE. Moderate alcohol consumption and risk of coronary heart disease among women with type 2 diabetes mellitus. Circulation 2000;102:494-9. Sosenko JM, Kato M, Soto R, Goldberg RB. Plasma lipid levels at diagnosis in Type 2 diabetic patients. Diabet Med 1993;10:814-9. Sotaniemi EA, Haapakoski E, Rautio A. Ginseng therapy in non-insulin-dependent diabetic patients. Effects on psychophysical performance, glucose homeostasis, serum lipids, serum aminoterminalpropeptide concentration, and body weight. Diabetes Care 1995;18:1373-5. Sprecher DL, Watkins TR, Behar S, Brown WV, Rubins HB, Schaefer EJ. Importance of high-density lipoprotein cholesterol and triglyceride levels in coronary heart disease. Am J Cardiol 2003;91:575-80. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915-24. Steiner G. The Diabetes Atherosclerosis Intervention Study (DAIS): A study conducted in cooperation with the World Health Organization. Diabetologia 1996;39:1655-61. Steiner G. Altering triglycerides concentrations changes insulin-glucose relationships in hypertriglyceridemic patients. Double-blind study with gemfibrozil with implications for atherosclerosis. Diabetes Care 1991;14:1077-81.

217

Steiner G. Intermediate-density lipoproteins, diabetes and coronary artery disease. Diabetes Res Clin Pract 1998;40(Suppl 1):S29-33. Steiner G. Risk factors for macrovascular disease in Type 2 diabetes. Diabetes Care 1999;22(Suppl 3):C6-9. Steiner G, Stewart D, Hosking JD. Baseline characteristics of the study population in the Diabetes Atherosclerosis Intervention Study (DAIS). World Health Organization Collaborating Centre for the Study of Atherosclerosis in Diabetes. Am J Cardiol 1999;84:1004-10. Steiner G, Tkac I, Uffelman KD, Lewis GF. Important contribution of lipoprotein particle number to plasma triglycerides concentration in type 2 diabetes. Atherosclerosis 1998;137:211-4. Stern MP. Diabetes and cardiovascular disease. The "Common Soil" hypothesis. Diabetes 1995;44:369-74. Stern MP, Haffner SM. Dyslipidemia in type II diabetes. Implications for therapeutic intervention. Diabetes Care 1991;14:1144-59. Stewart JM, Kilpatrick ES, Cathcart S, Small M, Dominiczak MH. Low-density lipoprotein particle size in type 2 diabetic patients and age matched controls. Ann Clin Biochem 1994;31:153-9. Stewart MW, Dyer RG, Alberti KGMM, Laker MF. The effects of lipid lowering drugs on metabolic control and lipoprotein composition in type 2 diabetic patients with mild hyperlipidaemia. Diabet Med 1995;12:250-7. Stewart MW, Laker MF, Alberti KGMM. The contribution of lipids to coronary heart disease in diabetes mellitus. J Int Med 1994;236(Suppl 736):41-6. Stewart MW, Laker MF, Dyer RG, Game F, Mitcheson J, Winocour PH, Alberti KG. Lipoprotein compositional abnormalities and insulin resistance in type II diabetic patients with mild hyperlipidemia. Arterioscler Thromb 1993;13:1046-52. Steyn K, Weich HFH, Bonnici F, Kotze TJW, Stander I, Vermaak WJH, Lourens W, Van Lathem J, Omar MAK, Fourie J. Simvastatin in non-insulin-dependent diabetic patients with hypercholesterolaemia. S Afr Med J 1992;82:402-6. Storm H, Thomsen C, Pedersen E, Rasmussen O, Christiansen C, Hermansen K. Comparison of a carbohydrate-rich diet and diets rich in stearic or palmitic acid in NIDDM patients: Effects on lipids, glycemic control, and diurnal blood pressure. Diabetes Care 1997;20:1807-13. Syvanne M, Taskinen MR. Lipids and lipoproteins as coronary risk factors in non-insulin-dependent diabetes mellitus. Lancet 1997;350(Suppl 1):SI20-3. Syvanne M, Vuorinen-Markkola H, Hilden H, Taskinen MR. Gemfibrozil reduces postprandial lipemia in non-insulin-dependent diabetes mellitus. Arteriosclerosis Thrombosis 1993;13:286-95. Tallis GA, Beng C, Popplewell P, Phillips P. Sugar and fat, a recipe for disaster. New guidelines for the pharmacological management of diabetic dyslipidaemia. Aust Fam Phys 1995;24:1638-49. Tan CE, Chew LS, Tai ES, Chio LF, Lim HS, Loh LM, Shepherd J. Benefits of micronised fenofibrate in Type 2 diabetes mellitus subjects with good glycaemic control. Atherosclerosis 2001;154:469-74. Tan CE, Chew LS, Chio LF, Tai ES, Lim HS, Lim SC, Jayakumar L, Eng HK, Packard CJ. Cardiovascular risk factors and LDL subfraction profile in Type 2 diabetes mellitus subjects with good glycaemic control. Diabetes Res Clin Prac 2001;51:107-14. Tan KC, Cooper MB, Ling KL, Griffin BA, Freeman DJ, Packard CJ, Shepherd J, Hales CN, Betteridge DJ. Fasting and postprandial determinants for the occurrence of small dense LDL species in non-insulin-dependent diabetic patients with and without hypertriglyceridaemia: the involvement of insulin, insulin precursor species and insulin resistance. Athersclerosis 1995;113:273-87. Tan KC, Shiu SW, Wong Y. Plasma phospholipid transfer protein activity and small, dense LDL in type 2 diabetes mellitus. Eur J Clin Invest 2003;33:301-6.

218

Taskinen MR. Hyperlipidaemia in diabetes. Baillieres Clin Endocrinol Metab 1990;4:743-75. Taskinen MR. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia 2003;46:733-49. Taskinen MR. Quantitative and qualitative lipoprotein abnormalities in diabetes mellitus. Diabetes 1992;41(Suppl 2):12-7. Taskinen MR. Criteria for metabolic control and intervention in diabetes. Diabetes 1996;45(Suppl 3):S120-2. Taskinen MR. Triglycerides is the major atherogenic lipid in NIDDM. Diabetes Metab Rev 1997;13:93-8. Taskinen MR, Beltz WF, Harper I, Fields RM, Schonfeld G, Grundy SM, Howard BV. Effects of NIDDM on very-low-density lipoprotein triglycerides and apolipoprotein B metabolism. Studies before and after sulfonylurea therapy. Diabetes 1986;35:1268-77. Taskinen MR, Lahdenpera S, Syvanne M. New insights into lipid metabolism in non-insulin-dependent diabetes mellitus. Ann Med 1996;28:335-40. Taskinen MR, Smith U. Lipid disorders in NIDDM: implications for treatment. J Intern Med 1998;244:361-70. Taskinen MR, Kuusi T, Helve E, Nikkila EA, Yki-Jarvinen H. Insulin therapy induces antiatherogenic changes of serum lipoproteins in noninsulin-dependent diabetes. Arteriosclerosis 1988;8:168-77. Taskinen MR, Packard CJ, Shepherd J. Effect of insulin therapy on metabolic fate of apolipoprotein B-containing lipoproteins in NIDDM. Diabetes 1990;39:1017-27. Temelkova-Kurktschiev T, Hanefeld M, Leonhardt W. Small dense low-density lipoprotein (LDL) in non-insulin-dependent diabetes mellitus (NIDDM). Impact of hypertriglyceridemia. Ann NY Acad Sci 1997;827:279-86. Tetrault GA, Miller WG, Chinchilli VM, Brown B, Balby T, Rooney P, Bennett S, Seckman V, Dickens M, Johnson J, Ligon D, Hull B, Carpenter R, Steinmetz W, Mason L, Freude K, St Charles C, Huffington B, Rosendale AM. Regional interlaboratory standardization of determinations of cholesterol, high-density lipoprotein cholesterol, and triglycerides. Clin Chem 1990;36:145-9. The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary heart disease. The Bezafibrate Prevention (BIP) study. Circulation 2000;102:21-7. Thorburn AW, Crapo PA, Beltz WF, Wallace P, Witztum JL, Henry RR. Lipid metabolism in non-insulin-dependent diabetes: Effects of long-term treatment with fructose-supplemented mixed meals. Am J Clin Nutr 1989;50:1015-22. Tian H, Han L, Ren Y, Li X, Liang J. Lipoprotein(a) level and lipids in Type 2 diabetic patients and their normoglycaemic first-degree relatives in Type 2 diabetic pedigrees. Diabetes Res Clin Pract 2003;59:63-9. Tilly-Kiesi M, Syvanne M, Kuusi T, Lahdenpera S, Taskinen M-R. Abnormalities of low density lipoproteins in normolipidemic type II diabetic and nondiabetic patients with coronary artery disease. J Lipid Res 1992;33:333-42. Tilly-Kiesi M, Knudsen P, Groop L, Taskinen M-R, Nissen M, Forsen B, Snickars B, Ehrnstrom B-O, Isomaa B, Lahti K, Forsblom C, Tuomi T, Lehto M, Haggblom M, Akerma L, Eklof G, Paulaharju S, Gullstrom M, Stenbeck I- B. Hyperinsulinemia and insulin resistance are associated with multiple abnormalities of lipoprotein subclasses in glucose-tolerant relatives of NIDDM patients. J Lipid Res 1995;37:1569-78. Tomlinson BT, Mak TWL, Tsui JYY, Woo J, Shek CC, Critchley JAJH, Masarei JRL. Effects of Fluvastatin on lipid profile and apolipoproteins in Chinese patients with hypercholesterolemia. Am J Cardiol 1995;76:136-9. Tonolo G, Ciccarese M, Brizzi P, Puddu L, Secchi G, Calvia P, Atzeni MM, Melis MG, Maioli M. Reduction of albumin excretion rate in normotensive microalbuminuric Type 2 diabetic patients during long-term simvastatin treatment. Diabetes Care 1997;20:1891-5.

219

Torjesen PA, Birkeland KI, Anderssen SA, Hjermann I, Holme I, Urdal P. Lifestyle changes may reverse development of the insulin resistance syndrome: the Oslo Diet and Exercise Study: a randomized trial. Diabetes Care 1997;20:26-31. Torremocha F, Hadjadj S, Carrie F, Rosenberg T, Herpin D, Marechaud R. Prediction of major coronary events by coronary risk profile and silent myocardial ischaemia: Prospective follow-up study of primary prevention in 72 diabetic. Diabetes Metab 2001;27:49-57. Tschope W, Koch M, Thomas B, Ritz E. Serum lipids predict cardiac death in diabetic patients on maintenance hemodialysis. Results of a prospective study. Nephron 1993;64:354-8. UKPDS 13. United Kingdom Prospective Diabetes Study (UKPDS) 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ 1995;310:83-8. UKPDS 27. UK Prospective Diabetes Study 27. Plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex. Diabetes Care 1997;20:1683-7. UKPDS 28. UKPDS 28: A randomised trial of efficacy of early addition of metformin in sulfonylurea-treated Type 2 diabetes. Diabetes Care 1998;21:87-92. Umeda F, Watanabe J, Inoue K, Hisatomi A, Mimura K, Yamauchi T, Sako Y, Kunisaki M, Tajiri Y, Nawata H. Effect of pravastatin on serum lipids, apolipoproteins and lipoprotein (a) in patients with non-insulin dependent diabetes mellitus. Endocrinol Japan 1992;39:45-50. Uusitupa M, Laakso M, Sarlund H, Majander H, Takala J, Penttila I. Long term effects of a very low calorie diet on metabolic control and cardiovascular risk factors in the treatment of obese non-insulin dependent diabetics. Int J Obes 1989;13(Supp 2):163-4. Uusitupa M, Laitinen J, Siitonen O, Vanninen E, Pyorala K. The maintenance of improved metabolic control after intensified diet therapy in recent type 2 diabetes. Diabetes Res Clin Pract 1993;19:227-38. Uusitupa M, Siitonen O, Pyorala K, Aro A, Hersio K, Penttila I, Voutilainen E. The relationship of cardiovascular risk factors to the prevalence of coronary heart disease in newly diagnosed type 2 (non-insulin-dependent) diabetes. Diabetologia 1985;28:653-9. Uusitupa MIJ. Fructose in the diabetic diet. Am J Clin Nutr 1994;59(Suppl 1):S753-7. Uusitupa MIJ, Laakso M, Sarlund H, Majander H, Takala J, Penttila I. Effects of a very-low-calorie diet on metabolic control and cardiovascular risk factors in the treatment of obese non-insulin-dependent diabetics. Am J Clin Nutr 1990;51:768-73. Uusitupa MIJ, Niskanen LK, Siitonen O, Voutilainen E, Pyorala K. 5-Year incidence of atherosclerotic vascular disease in relation to general risk factors, insulin level, and abnormalities in lipoprotein composition in non-insulin-dependent diabetic and nondiabetic subjects. Circulation 1990;82:27-36. Uusitupa MIJ, Niskanen LK, Siitonen O, Voutilainen E, Pyorala K. Ten year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in Type 2 (non-insulin-dependent) diabetic and non-diabetic subjects. Diabetologia 1993;36:1175-84. Vaag AA, Beck-Nielsen H. Effects of prolonged acipimox treatment on glucose and lipid metabolism and on in vivo insulin sensitivity in patients with non-insulin dependent diabetes mellitus. Acta Endocrinol 1992;127:344-50. Vakkilainen J, Steiner G, Ansquer JC, Perttunen-Nio H, Taskinen MR. Fenofibrate lowers plasma triglycerides and increases LDL particle diameter in subjects with Type 2 diabetes. Diabetes Care 2002;25:627-8 Valmadrid CT, Klein R, Moss SE, Klein BEK, Cruickshanks KJ. Alcohol intake and the risk of coronary heart disease mortality in persons with older-onset diabetes mellitus. JAMA 1999;282:239-46. Vaverkova H, Chlup R, Ficker L, Novotny D, Bartek J. Complimentary insulin therapy improves blood glucose and serum lipid parameters in type 2 (non-insulin-dependent) diabetic patients. II. Effects on serum lipids, lipoproteins and apoproteins. Exp Clin Endocrinol Diabetes 1997;105(Suppl 2):74-7.

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Velazquez E, Winocour PH, Kesteven P, Alberti KGMM, Laker MF. Relation of lipid peroxides to macrovascular disease in Type 2 diabetes. Diabet Med 1991;8:752-8. Velussi M. Long-term (18-month) efficacy of atorvastatin therapy in Type 2 diabetics at cardiovascular risk. Nutr Metab Cardiovasc Dis 2002;12:29-35. Verity LS, Ismail AH. Effects of exercise on cardiovascular disease risk in women with NIDDM. Diabetes Res Clin Pract 1989;6:27-35. Vessby B. Effects of omega 3 fatty acids on glucose and lipid metabolism in non-insulin-dependent diabetes mellitus. World Rev Nutr Diet 1991;66:407-16. Vessby B, Boberg M. Dietary supplementation with n-3 fatty acids may impair glucose homeostasis in patients with non-insulin-dependent diabetes mellitus. J Intern Med 1990;228:165-71. Vignati L, Anderson JH Jr, Iversen PW. Efficacy of insulin lispro in combination with NPH human insulin twice per day in patients with insulin-dependent or non-insulin-dependent diabetes mellitus. Clin Ther 1997;19:1408-21. Vlajinac H, Ilic M, Marinkovic J. Cardiovascular risk factors and prevalence of coronary heart disease in Type 2 (non-insulin-dependent) diabetes. Eur J Epidemiol 1992;8:783-8. Walden CE, Knopp RH, Wahl PW, Beach KW, Strandness E Jr. Sex differences in the effect of diabetes mellitus on lipoprotein tryglyceride and cholesterol concentrations. N Engl J Med 1984;311:953-9. Walker WG. Relation of lipid abnormalities to progression of renal damage in essential hypertension, insulin-dependent and non insulin-dependent diabetes mellitus. Miner Electolyte Metab 1993;19:137-43. Wallberg-Henriksson H, Rincon J, Zierath JR. Erratum: Exercise in the management of non-insulin-dependent diabetes mellitus. Sports Med 1998;25:25-35. Wasada T, Kuroki H, Arii H, Maruyama A, Aoki K, Katsumori K, Saito S, Hanada H, Omori Y. Relationship between insulin resistance and risk factors for cardiovascular disease in Japanese non-insulin-dependent diabetic patients. Diabetes Res Clin Pract 1994;25:191-8. Wassef N, Sidhom G, Zakareya el-K, Mohamed el-K. Lipoprotein (a) in android obesity and NIDDM. Diabetes Care 1997;20:1693-6. Watanabe J, Kobayashi K, Umeda F, Yamauchi T, Mimura K, Nakashima N, Masakado M, Hiramatsu S, Nawata H. Apolipoprotein E polymorphism affects the response to pravastatin on plasma apolipoproteins in diabetic patients. Diabetes Res Clin Pract 1993;20:21-7. Watts NB, Spanheimer RG, DiGirolamo M, Gebhart SS, Musey VC, Siddiq YK, Phillips LS. Prediction of glucose response to weight loss in patients with non- insulin dependent diabetes mellitus. Arch Intern Med 1990;150:803-6. Weber P, Schrezenmeir J, Fenselau S, Ausieker S, Probst R, Zuchhold HD, Prellwitz W, Beyer J. Prolonged postprandial increment in triglycerides and decreased postprandial response of very low density lipoproteins in type 2 diabetics following an oral lipid load. Ann NY Acad Sci 1993;683:315-21. Weintraub WS, Boccuzzi SJ, Klein JL, Kosinski AS, King III SB, Ivanhoe R, Cedarholm JC, Stillabower ME, Talley JD, DeMaio SJ, O'Neill WW, Frazier II JE, Cohen-Bernstein CL, Robbins DC, Brown III CL, Alexander RW, Mitchel YB, Hirsch JJ, Melino MR. Lack of effect of lovastatin on restenosis after coronary angioplasty. N Engl J Med 1994;331:1331-7. Westerveld HT, de Graaf JC, van Breugel HH, Akkerman JW, Sixma JJ, Erkelens DW, Banga JD. Effects of low-dose EPA-E on glucemic control, lipid profile, lipoprotein (a), platelet aggregation, viscosity, and platelet and vessel wall interaction in NIDDM. Diabetes Care 1993;16:683-8. Wilson PWF. Lower diabetes risk with hormone replacement therapy: An encore for estrogen? Ann Intern Med 2003;138:69-70.

221

Wing RR, Shoemaker M, Marcus MD, McDermott M, Gooding W. Variables associated with weight loss and improvements in glycemic control in type II diabetic patients in behavioral weight control programs. Int J Obes 1990;14:495-503. Wing RR, Epstein LH, Nowalk MP, Koeske R, Hagg S. Behaviour changes, weight loss and physiological improvements in Type II diabetic patients. J Consult Clin Psychol 1985;53:111-22. Wing RR, Koeske R, Epstein LH, Nowalk MP, Gooding W, Becker D. Long-term effects of modest weight loss in type II diabetic patients. Arch Intern Med 1987;147:1749-53. Winocour PH, Bhatnagar D, Ishola M, Arrol S, Durrington PN. Lipoprotein (a) and microvascular disease in type 1 (insulin-dependent) diabetes. Diabet Med 1991;8:922-7. Wirta O, Pasternack A, Mustonen J, Laippala P. Renal and cardiovascular predictors of 9-year total and sudden cardiac mortality in non-insulin-dependent diabetic subjects. Nephrol Dial Transplant 1997;12:2612-17. Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest 1991;88:1785-92. Wolever TM, Jenkins DJ, Vuksan V, Jenkins AL, Buckley GC, Wong GS, Josse RG. Beneficial effect of a low glycaemic index diet in Type 2 diabetes. Diabet Med 1992;9:451-8. Wolffenbuttel BH, Gomis R, Squatrito S, Jones NP, Patwardhan RN. Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in Type 2 diabetic patients. Diabet Med 2000;17(1):40-7. Wolffenbuttel BH, Leurs PB, Sels JP, Rondas-Colbers GJ, Menheere PP, Nieuwenhuijzen Kruseman AC. Improved blood glucose control by insulin therapy in type 2 diabetic patients has no effect on lipoprotein(a) levels. Diabet Med 1992;10:427-30. Wolffenbuttel BH, Sels JP, Heesen BJ, Menheere PP, Kruseman AC. Lipoprotein (a) levels and diabetes control. Diabetes Care 1992;15:941. Wolffenbuttel BH, Weber RF, Van Koetsveld PM, Verschoor L. Limitations of diet therapy in patients with non- insulin dependent diabetes mellitus. Int J Obes 1989;13:173-82. Wollesen F, Dahlen G, Berglund L, Berne C. Peripheral atherosclerosis and serum lipoprotein (a) in diabetes. Diabetes Care 1999;22:93-8. Wu M-S, Johnston P, Sheu WH-H, Hollenbeck CB, Jeng C-Y, Goldfine ID, Chen Y-DI, Reaven GM. Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care 1990;13:1-8. Yamada N, Yoshinaga H, Gotoda T, Harada K, Shimada M, Ohsuga J-C, Akanuma Y, Murase T. Plasma lipid abnormalities and risk factors for coronary artery disease in Japanese subjects with diabetes mellitus and glucose intolerance. Diabetes Res Clin Pract 1994;24(Suppl 1):S215-20. Yamamoto M, Egusa G, Yamakido M. Carotid atherosclerosis and serum lipoprotein(a) concentrations in patients with NIDDM. Diabetes Care 1997;20:829-31. Yoshinari M, Asano T, Kaori S, Shi AH, Wakisaka M, Iwase M, Fujishima M. Effect of gemfibrozil on serum levels of prostacyclin and precursor fatty acids in hyperlipidemic patients with Type 2 diabetes. Diabetes Res Clin Pract 1998;42:149-54. Yoshinari M, Yamamoto M, Wakisaka M, Iwase M, Takano K, Fujishima M. Effect of bezafibrate on hypercoagulability assessed by fluorogenic prothrombin time in hyperlipidemic patients with non-insulin-dependent diabetes mellitus. Thrombosis Res 1997;86:443-51. Yoshino G, Hirano T, Kazumi T. Dyslipidemia in diabetes mellitus. Diabetes Res Clin Pract 1996;33:1-14. Yoshino G, Kazumi T, Iwai M, Matsushita M, Matsuba K, Uenoyama R, Iwatani I, Baba S. Long-term treatment of hypercholesterolemic non-insulin dependent diabetics (NIDDM) with pravastatin (CS-514). Atherosclerosis 1989;75:67-72. Yudkin JS. Lipids, thrombosis and cardiovascular disease in diabetes. Proc Nutr Soc 1997;56:273-80.

222

Zambon S, Friday KE, Childs MT, Fujimoto WY, Bierman EL, Ensinck JW. Effect of glyburide and omega3 fatty acid dietary supplements on glucose and lipid metabolism in patients with non-insulin-dependent diabetes mellitus. Am J Clin Nutr 1992;56:447-54. Zambon S, Lapolla A, Sartore G, Gherardingher C, Cortella A, Manzato E, Crepaldi G, Fedele D. Long-term treatment with simvastatin in hypercholesterolemic non-insulin-dependent diabetic patients. Curr Ther Res 1992;52:221-9. Zierath JR, Wallberg-Henriksson H. Exercise training in obese diabetic patients. Special considerations. Sports Med 1992;14:171-89. Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation 1979;60:473-85. Zimetbaum P, Frishman WH, Kahn S. Effects of gemfibrozil and other fibric acid derivatives on blood lipids and lipoproteins. J Clin Pharmacol 1991;31:25-37.

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2.5 Lipid Guideline Search Strategy and Yield Electronic Databases Searched: Medline EMBASE CINAHL Cochrane

Terms used to search the databases: Detailed within the table below.

Search Inclusion Criteria: Where possible the searches were limited by the English language and human research. The databases were searched for the following years of publication: Medline 1985 - August 2003; EMBASE 1988 - August 2003; CINAHL 1985 - August 2003; Cochrane 1993 - August 2003. Unless other year ranges are specified on the table.

Other searching: Reference lists at the end of review articles of particular relevance were hand searched. Relevant articles were solicited from expert colleagues and organisations. Local and international clinical practice guidelines were reviewed for relevant references.

Abbreviations: The database searched has been indicated next to each set of keywords using the following abbreviations. M= Medline, EM= EMBASE, CO= Cochrane and CI= CINAHL. All EMBASE and Medline searches were done using English language En.La and human as a limit. Other abbreviations used were NIDDM= non-insulin-dependent diabetes mellitus; CVD = cardiovascular disease; CBD = cerebrovascular disease; MI = myocardial infarction; CHD = coronary heart disease; CAD = coronary artery disease; dh = diet therapy; dt = drug therapy; th = therapy, ae = adverse effects, du = diagnostic use, st = standards, cl = classification, co = complications, di = diagnosis, TG = triglycerides; HRT = hormone replacement therapy; FA = fatty acid/s; LDL = low density lipoprotein; HDL = high density lipoprotein; VLDL = very low density lipoprotein; Identified = number of articles which matched the MeSH terms listed OR contained the text terms in each particular database. Relevant = those articles considered relevant to the questions being asked after viewing titles OR abstracts. Articles identified by other strategies = articles identified by hand searching, other searches for other questions, OR from colleagues. Total for Review = Those articles which were relevant to the question, contained original data OR were systematic reviews of original articles and met the following criteria.

224

Criteria used to determine the suitability of articles for review 1. Appropriate patient population for question being addressed (epidemiology, specific diet) 2. The paper was published in the English language 3. Articles with original data 4. Review articles on lipids where diabetes is a major focus OR on diabetes where lipids are a major focus 5. Review articles that cover lipids in patients with diabetes 6. Articles based on human studies not those with hypothesis/mechanism/in vitro study/ animal study, detailed compositional analysis of lipids/lipoproteins or genetic studies that are clinically

inapplicable 7. Articles were obtained from journals able to be accessed within our Library network, ordered through an interlibrary loan or obtained via other sources.

225

QUESTIONS KEY WORDS NO. ARTICLES IDENTIFIED

NO RELEVANT ARTICLES

ARTICLES IDENTIFIED BY OTHER STRATEGIES

TOTAL FOR REVIEW

LEVEL I LEVEL II LEVEL III

LEVEL IV

TOTAL NO. REVIEWED AND GRADED

HIGHEST LEVELOF EVIDENCE

1. What lipid abnormalities are associated with Type 2 diabetes and what are the consequences?

Total for Question NIDDM/ AND (Lipids/ OR hypercholesterolemia/ OR TG/ OR hyperlipidemia/ OR cholesterol/ OR lipoproteins/) CI 85-03 AND limit to review articles M 85-99 AND limit to review articles OR RCT/ OR meta-analysis/ OR cohort/ M 99-03 (Lipoproteins/ae,du OR Lipoproteins, HDL cholesterol/ae,st,du OR Lipoproetins, LDL cholesterol/ae,st,du, OR hypercholesterolemia/cl,co,di,th OR hyperlipidemia/cl, di OR Lipids/ae,st,du OR cholesterol/ae,st,du) AND (Diagnostic tests, routine/ OR chemistry, clinical/ OR hematologic tests/ OR risk assessment/ OR methods/) AND frequency.mp M, CI 85-03 (Lipoproteins/ OR Lipoproteins, HDL cholesterol/ OR Lipoproetins, LDL cholesterol/ OR hypercholesterolemia/ OR hyperlipidemia/ OR Lipids/ OR cholesterol/ OR triglycerides/) AND (Diagnosis, laboratory/ OR chemistry, clinical/ OR hematologic tests/ OR risk assessment/ OR sampling methods/) AND frequency.mp M, CI 85-03

20479

278

220

294

84 (M) 5 (CI)

176 (M) 9 (CI)

362 25 260 2 7 77 0 86 I

226




TOTAL FOR REVIEW


LEVEL IV




(Lipoproteins/ OR Lipoproteins, HDL cholesterol/ OR Lipoproetins, LDL cholesterol/ OR hypercholesterolemia/ OR hyperlipidemia/ OR Lipids/ OR cholesterol/ OR triglycerides/) AND (laboratory techniques and procedures/ OR chemistry, clinical/ OR hematologic tests/ OR risk assessment/ OR sampling methods.mp) AND frequency.mp M 99-03 (Laboratory assessment.mp OR predictive value of tests/ OR diagnostic tests, routine/ OR clinical chemistry tests/ OR hematologic tests/ OR risk assessment/ OR methods/) AND (lipids/ OR cholesterol/ OR hypercholesterolemia/ OR hyperlipidemia/ OR triglycerides/ OR lipoproteins/) M, CI 85-03 AND limit review articles M 85-99 (Laboratory assessment.mp OR predictive value of tests/ OR diagnostic tests, routine/ OR clinical chemistry tests/ OR hematologic tests/ OR risk assessment/ OR methods/) AND (lipids/ OR cholesterol/ OR hypercholesterolemia/ OR hyperlipidemia/ OR triglycerides/ OR lipoproteins/) AND

10

585 (M) 445 (CI)

45 (M)

91

227




TOTAL FOR REVIEW


LEVEL IV




NIDDM/ M 85-03 NIDDM/ AND: TG/ Cholesterol/ Dyslipid emia/ High density cholesterol/ Hyperlipidemia/ Lipid/ Lipid blood level/ Low density lipoprotein/ Lipid metabolism/ EM 88-99 limit to review/ OR metaanalysis/ OR cohort analysis/ OR cohort study.mp systematic review.mp EM 99-03 Freguency AND (Lipoprotein/ OR LDL/ OR HDL/ OR Triacylglycerol/ OR hypercholesterolemia/ OR hyperlipidemia/ OR lipid/ OR cholesterol/) EM 88-99, CI 85-99 AND NIDDM/ EM 99-03 Diabetes mellitus.mp AND Lipids.mp CO 93-03 Risk assessment.mp AND lipid.mp CO 93-03 NIDDM.mp AND: TG.mp Cholesterol.mp Hypercholesterolemia.mp (Hyperlipidaemia.mp OR Hyperlipidemia.mp) Lipids.mp Lipoproteins.mp CO 93-99

806 557 221 315 137 672 303 229 458

767 (EM)

604 (EM) 43 (CI)

72

854

75

180 236 19 25

132 121

228




TOTAL FOR REVIEW


LEVEL IV




NIDDM.mp AND (TG.mp OR Cholesterol.mp OR Hypercholesterolemia.mp OR Hyperlipidaemia.mp OR Hyperlipidemia.mp OR Lipids.mp OR Lipoproteins.mp) CO 99-03 (Lipids.mp OR lipoproteins-LDL-cholesterol.mp OR triglycerides.mp OR lipoproteins.mp) AND: (diagnostic-techniques-and-procedures.mp OR risk-assessment.mp OR diagnostic-tests-routine.mp OR chemical-test.mp OR diagnostic-tests.mp OR clinical-chemistry-test.mp) Frequency CO 93-99 (Lipids.mp OR lipoproteins-LDL-cholesterol.mp OR triglycerides.mp OR lipoproteins.mp) AND (diagnostic-techniques-and-procedures.mp OR risk-assessment.mp OR diagnostic-tests-routine.mp OR chemical-test.mp OR diagnostic-tests.mp OR clinical-chemistry-test.mp) Frequency CO 99-03 NIDDM/ AND (cholesterol/ OR hypercholesterolemia/ OR hyperlipidemia/ OR TG/ OR lipoproteins/) CI 85-03 AND limit to review articles M 85-99 AND (RCT/ OR meta-analysis/ OR cohort/) M 99-03

306

8

229

82

278

220

294

229




TOTAL FOR REVIEW


LEVEL IV




NIDDM/ AND Lipids.mp/ AND (coronary disease/ OR coronary heart disease.mp OR CBD.mp/ OR PVD.mp/) M 91-03 NIDDM/ AND (cholesterol/ OR hypercholesterolemia/ OR hyperlipidemia/ OR TG/ OR lipoproteins/) AND (CBD/ OR myocardial ischemia/ OR coronary disease/ OR CVD/ OR vascular disease/ OR MI/) M, CI 85-03 NIDDM/ AND (cholesterol/ OR hypercholesterolemia/ OR hyperlipidemia/ OR TG/ OR lipoproteins/) AND (diabetic retinopathy/ OR diabetic neuropathies/ OR diabetic nephropathies/ OR neuropathy.mp/ OR retinopathy.mp/ OR nephropathy.mp/) M, CI 85-03 NIDDM/ AND: Lipid/ Cholesterol/ Dyslipidemia/ High density cholesterol/ Hyperlipidemia/ Lipid blood level/ Lipid metabolism/ Low density lipoprotein/ TG/ CHD/ CVD lipid/ Cholesterol risk factor/ Coronary risk/ Cerebrovascular disease/ HRT Lipid/ Ischemic heart disease/ Risk assessment/

165

558 (M) 80 (CI)

288 (M) 20 (CI)

672 557 221 315 137 303 458 229 806

3 152 17

177 53 3

199 199

230




TOTAL FOR REVIEW


LEVEL IV




Stroke/ Vascular/ EM 88-99 AND review/ OR randomised controlled trial/ OR meta-analysis/ EM 99-03 NIDDM/ AND (cholesterol/ OR hypercholesterolemia/ OR hyperlipidemia/ OR TG/ OR lipoproteins/) AND (heart infarction/ OR ischemic heart disease/ OR retinopathy/ OR myocardial ischemia.mp OR diabetic neuropathy/ OR diabetic retinopathy/ OR neuropathy/ OR MI.mp OR diabetic nephropathy/ OR coronary disease.mp OR CVD/ OR nephropathy.mp OR vascular disease/ OR microvascular.mp) EM 88-03 Diabetes mellitus.mp AND Lipids.mp CO 93-03 NIDDM.mp AND: TG.mp Cholesterol.mp Hypercholesterolemia.mp (Hyperlipidaemia.mp OR Hyperlipidemia.mp) Lipoproteins.mp CO NIDDM.mp AND (TG.mp OR Cholesterol.mp OR Hypercholesterolemia.mp OR Hyperlipidaemia.mp OR Hyperlipidemia.mp OR Lipoproteins.mp) CO 93-03 NIDDM.mp AND lipids.mp AND: Cardiovascular disease.mp

190 140 978

958

854

180 236 19 25

121

306

132

15

231




TOTAL FOR REVIEW


LEVEL IV




Cerebrovascular disease.mp Coronary heart disease.mp Diabetic nephropathies.mp Diabetic neuropathies.mp Diabetic retinopathy.mp Macrovascular.mp Myocardial infarction.mp Myocardial ischemia.mp Nephropathy.mp Neuropathy.mp Retinopathy.mp Stroke.mp Vascular disease.mp CO 93-99 NIDDM.mp AND lipids.mp AND (Cardiovascular disease.mp OR Cerebrovascular disease.mp OR Coronary heart disease.mp OR Diabetic nephropathies.mp OR Diabetic neuropathies.mp OR Diabetic retinopathy.mp OR Macrovascular.mp OR Myocardial infarction.mp OR Myocardial ischemia.mp OR Nephropathy.mp OR Neuropathy.mp OR Retinopathy.mp OR Stroke.mp OR Vascular disease.mp) CO 99-03

2 10 3 0 4 3 6 1 4 4 4 3 0

181 (CO)

232




TOTAL FOR REVIEW


LEVEL IV



2. What are the effects of diet and exercise on lipids in people with Type 2 diabetes?

Total for Questions NIDDM/ AND (Cholesterol/ OR Hypercholesterolemia/ OR Hyperlipidemia/ OR TG/ OR Lipoproteins/) CI 85-03 AND limit to review articles M 85-99 AND (RCT/ OR cohort/ OR metaanalysis/) M99-03

Phytosterols/ AND (Cholesterol/ OR Lipoprotien, hdl cholesterol/ OR Lipoprotein., ldl cholesterol/ OR Lipoproteins, vldl cholesterol/) M 85-99, EM 88-99 Phytosterols/ AND (Cholesterol/ OR Lipoprotien, hdl cholesterol/ OR Lipoprotein., ldl cholesterol/ OR Lipoproteins, vldl cholesterol/) AND NIDDM/ M 99-03 NIDDM/ AND lipids.mp/ AND Antioxidants.mp/ M (99-03) NIDDM/ AND (Cholesterol/ OR hypercholesterolemia/ OR hyperlipidemia/ OR TG/ OR lipoproteins/) AND (diabetic diet/ OR exercise/ OR diet/ OR exercise therapy/ OR diet therapy/ OR antioxidants/) M, CI 85-03

7603

278

220

294

109 (M) 117 (EM)

105

17

270 (M) 42 (CI)

491 10 208 4 80 42 3 129 I

233




TOTAL FOR REVIEW


LEVEL IV




NIDDM/ AND: (Dietary fats/ OR saturated fat.mp) AND (Cholesterol/ OR HDL cholesterol OR LDL cholesterol) M 85-03 (Dietary fats/ OR fatty acids, saturated/) AND (Cholesterol/ OR HDL cholesterol OR LDL cholesterol) CI 85-03 (Fat intake/ OR saturated fatty acid/) AND (cholesterol/ OR HDL cholesterol/ OR LDL cholesterol/ OR VLDL cholesterol/) EM 88-99 Saturated fat.mp AND cholesterol.mp CO 93-03 NIDDM/ AND triglycerides/ AND: Alcohol drinking/ OR alcoholic beverages/ OR ethanol/ M 85-99 Alcoholic beverages/ OR alcohol drinking/ CI 85-03 Alcohol/ OR alcohol consulmption/ EM 88-99 Alcohol/ CO 93-03 Phytosterols.mp CI 85-03, CO 93-03

63

12

59

12

23

16

21

22

20 (CI) 350 (CO)

234




TOTAL FOR REVIEW


LEVEL IV




NIDDM.mp AND: TG.mp Cholesterol.mp Hypercholesterolemia.mp (Hyperlipidaemia.mp OR Hyperlipidemia.mp) Lipoproteins.mp CO 93-99 Diabetes mellitus.mp AND Lipids.mp CO 93-99 NIDDM/ AND : TG/ Cholesterol/ Dyslipidemia/ Hidensity cholesterol/ Hyperlipidemia/ Lipid/ Lipid blood level/ Lipid metabolism/ Low density lipoprotein/ Antioxidant/ Diet/ Diet and lipid/ CO 93-99 Exercise/ EM 88-99 AND review/ or randomised controlled trial/ or meta-analysis/ or systematic review.mp EM 99-03 NIDDM AND LIPIDS: Antioxidant/ Diet/ Exercise/ Glycaemic control/ Glycemic control/ CO 93-99 NIDDM AND (LIPIDS OR Antioxidant/ OR Diet/ OR Exercise/ OR Glycaemic control/ OR Glycemic control/ ) CO 93-99

180 236 19 25

121

385

806 557 221 315 137 672 303 458 229 27

122 245

104 ??

132 0 56 9 10 49

135

235




TOTAL FOR REVIEW


LEVEL IV



3. What is the effect of improved blood glucose control on lipids in Type 2 diabetes?

Total for Question NIDDM/ AND (cholesterol/ OR hypercholesterolemia/ OR hyperlipidaemia/ OR HDL OR Hyperlipidemia/ OR TG/) CI 85-03 Limit to review articles M 85-99 OR RCT/ OR metaanalysis/ OR cohort/ M 99-03 As Above AND (glycemic control.mp OR glycaemic control.mp OR blood glucose/ OR hemoglobin a, glycosylated/ OR insulin/ OR hypoglycemic agents/) M, CI 85-03 NIDDM.mp AND Lipids.mp AND: Diet.mp Glycaemic control.mp Glycemic control.mp CO 93-99 diabetes mellitus non-insulin dependent/ AND (lipids/ OR diet/) CO 99-03 NIDDM/ AND: Lipid/ Cholesterol/ Dyslipidemia/ High density cholesterol/ Hyperlipidemia/ Lipid blood level/ Lipid metabolism/ Low density lipoprotein/ TG/ Antioxidant/ EM 88-99 (antibiabetic agent/ OR glycosylated hemoglobin/ OR glucose blood level/ OR hemoglobin A1C/) EM 99-03

8487

278 (CI)

220 (M)

294 (M)

1543 (M) 117 (CI)

132

56 10

188

672 557 221 315 137 303 458 229 806 27

958

276 21 107 0 31 21 13 65 I

236




TOTAL FOR REVIEW


LEVEL IV



3. What is the effect of improved blood glucose control on lipids in Type 2 diabetes?

Diabetes Mellitus.mp AND Lipids.mp CO 93-99 NIDDM.mp AND: TG.mp Hypercholesterolemia.mp (Hyperlipidaemia.mp OR Hyperlipidemia.mp) Lipoproteins.mp Cholesterol.mp CO 93-99

385

180 19 25

121 236

4. What are the effects on lipids of treatment with lipid modifying agents and HRT in Type 2 diabetes?

Total For Question NIDDM/dh,dt,th, AND (lipids OR hypercholesterolemia/ OR hypertriglyceridemia/ OR TG/ OR hyperlipidaemia/ OR hyperlipidemia/ OR cholesterol/) M, CI 85-03 NIDDM/ AND (cholesterol/ OR hypercholesterolemia/ OR hyperlipidaemia/ OR TG/ OR hypertriglyceridemia/ OR hyperlipidemia/ CI 85-99 (Limit to review articles) M 85-99 (hypercholesterolemia/ OR TG/ OR hypertriglyceridemia/OR hyperlipidaemia/ OR hyperlipidemia/ OR cholesterol/ OR lipids/) AND NIDDM/ AND Antilipemic agents/ M, CI 85-03, EM 88-99 NIDDM/ AND HRT/ M 85-99, CI 85-03, EM 88-99

8018

827 (M) 95 (CI)

101

220

149 (M) 11 (CI) 7 (EM)

0 (M) 18 (CI) 4 (EM)

660 9 164 2 72 14 9 97 I

237




TOTAL FOR REVIEW


LEVEL IV




HRT/ M, CI 85-99 NIDDM/ AND Antilipemic agents/ AND Lipids/ M, CI 85-99 (Bezafibrate/ OR gemfibrozil/ OR fibric acid.mp/ OR acipimox.mp/ OR nicotinic acid.mp/ OR niacin/ OR hydroxymethylglutaryl-coa reductase inhibitors/ OR bile acid sequestrants.mp/ OR statins.mp OR atorvastatin.mp/ OR fish oils/ OR cholestyramine/ OR FA, omega-3/ OR fluvastatin.mp/ OR cholestipol.mp/ OR Lovastatin/ OR pravastatin/ OR probucol/) M, CI 85-03 NIDDM/ AND (Acipimox.mp/ OR antilipedic agents/ OR HRT/ OR niacin/ OR bezafibrate/ OR gemfibrozil/ OR fibric acid.mp/ OR hydroxymethylglutaryl-coa reductase inhibitors/ OR nicotinic acid.mp/ OR cholestyramine/ OR bile acid sequestrants.mp/ OR probucol/ OR fluvastatin.mp/ OR fish oils/ OR statins.mp OR atorvastatin.mp/ OR lovastatin/ OR cholestipol.mp/ OR FA, omega-3/ OR pravastatin/)

7 (M) 39 (CI)

23 (M) 0 (CI)

220 (M) 21 (CI)

148 (M) 9 (CI)

238




TOTAL FOR REVIEW


LEVEL IV




AND (Hemoglobin a, glycosylated/ OR hypoglycemic agents/ OR insulin/ OR glycaemic control.mp. OR glycemic control.mp OR blood glucose/) M, CI 85-99 NIDDM/ AND (fishes/ OR fish.mp) AND (Cholesterol/ OR lipoproteins, hdl cholesterol/ OR lipoproteins ldl cholesterol/ OR Lipoproteins, vldl cholesterol/) M 85-03 NIDDM/ AND (lipoproteins, HDL cholesterol/ OR cholesterol/ lipoproteins, LDL cholesterol/) AND (fish/ or fish oils/) CI 85-03, EM 88-03 NIDDM.mp AND fish.mp AND cholesterol.mp CO 93-99 NIDDM/ AND : Cholesterol/ Dyslipidemia/ High density cholesterol/ Hyperlipidemia/ Lipid/ Lipid blood level/ Lipid metabolism/ Low density lipoprotein/ TG/ Estrogen/ (probucol/ OR acipimox/ OR pravastatin/ OR colestyramine/ OR atorvastatin/ OR lovastatin.mp OR colestipol/ OR

30

8 (CI) 35 (EM)

25

557 221 315 137 672 303 458 229 806 51

149

239




TOTAL FOR REVIEW


LEVEL IV




hydroxymethylglutaryl-Co A reductase inhibitors.mp OR fluindostatin/ OR statin/) EM 88-99 NIDDM/ AND (Cholesterol/ OR Dyslipidemia/ OR High density cholesterol/ OR Hyperlipidemia/ OR Lipid/ OR Lipid blood level/ OR Lipid metabolism/ OR Low density lipoprotein/ OR TG/ OR Estrogen/) EM 99-03 hudroxymethyglutaryl-co A reductase inhibitors/ AND (RCT/ OR review/ OR meta-analysis/ OR systematic review.mp EM 99-03 NIDDM/ AND (Antidiabetic agent/ OR blood glucose monitoring/ OR oral antidiabetic agent/ OR glycemic control.mp OR glucose/ OR glucose blood level/ OR glycaemic control.mp OR insulin/) AND: Antilipemic agents/ HRT.mp. (Fibric acid.mp OR bezafibrate/ OR gemfibrozil/ OR bile acid sequestrant/ OR fish oil/ OR omega 3 FA/ OR nicotinic acid/ OR niacin.mp. OR probucol/ OR acipimox/ OR pravastatin/ OR colestyramine/ OR atorvastatin/ OR

81

214

61 5

203

240




TOTAL FOR REVIEW


LEVEL IV




lovastatin.mp OR colestipol/ OR hydroxymethylglutaryl-Co A reductase inhibitors.mp OR fluindostatin/ OR statin/) EM 88-99 NIDDM/ AND (hyperlipidemia/ OR hypercholesterolemia/ OR hyperlipidaemia/ OR cholesterol/ OR hypertriglyceridemia/ OR TG/) AND: (bezafibrate/ OR gemfibrozil/ OR nicotinic acid/ OR niacin.mp OR fibric acid.mp OR acipimox/ OR colestyramine/ OR Omega 3 FA/ OR hydroxymethylglutaryl-coa reductase inhibitors.mp OR bile acid sequestrant/ OR statin/ OR probucol/ OR colestipol/ OR atorvastatin/ OR fish oil/ OR pravastatin/ OR fluindostatin/ OR lovastatin.mp) EM 88-99 NIDDM/ AND (hyperlipidemia/ OR hypercholesterolemia/ OR cholesterol/ OR hyperlipidaemia/ OR hypertriglyceridemia/ OR TG/) AND Antilipemic agents/ EM 88-99 NIDDM.mp AND Antilipemic agents.mp AND: Lipids.mp Cholesterol.mp TG.mp Hyperlipidemia.mp

208

49

9 14 14 7

241




TOTAL FOR REVIEW


LEVEL IV




Hypercholesterolemia.mp Hypertriglyceridemia.mp Glycaemic.mp OR glycemic control.mp Estrogen.mp CO 93-99 Diabetes mellitus.mp AND Lipids.mp CO 93-99 NIDDM.mp AND HRT.mp AND:Lipids.mp Cholesterol.mp (TG.mp OR glycaemic.mp OR glycemic control.mp OR hyperlipidemia.mp OR hypercholesterolemia.mp OR hypertriglyceridemia.mp) CO 93-99 Diabetes mellitus.mp AND Lipids.mp CO 93-99 NIDDM.mp AND lipids.mp AND: Cholesterol.mp Glycaemic control.mp Glycemic control.mp CO 93-99 NIDDM.mp AND: TG.mp Cholesterol.mp Hypercholesterolemia.mp Lipoproteins.mp (Hyperlipidaemia.mp OR Hyperlipidemia.mp) CO 93-99

3 1 5

2

1 1 0

385

132 98 10 49

180 236 19

121 25

242




TOTAL FOR REVIEW


LEVEL IV



5. Does treatment with lipid modifying agents or HRT improve outcomes in Type 2 diabetes

Total For Question NIDDM/ AND (hyperlipidemia/ OR hyperlipidaemia/ OR lipids/ OR hypercholesterolemia/ OR TG/ OR hypertriglyceridemia/ cholesterol/) CI 85-99 limit to review articles M 85-99 (hypercholesterolemia/ OR TG/ OR hyperlipidaemia/ OR hyperlipidemia/ OR cholesterol/ OR hypertriglyceridemia/ OR lipids/) AND (CVD/ OR Coronary disease/ OR Risk/) AND: NIDDM/ M, CI 85-03, EM 88-99 (triglycerides.mp OR triaclyglycerol/ OR lipid/ OR coronary artery disease/ OR cardiovascular risk/ OR coronary risk/) AND (review/ OR RCT/ OR meta-analysis/ OR clinical trial/) EM 99-03 NIDDM/dh,dt,th, M 85-03, CI 85-99, EM 88-03 NIDDM AND: Cholesterol/ Hypercholesterolemia/ (Hyperlipidaemia OR Hyperlipidemia/) Lipoproteins/ TG/ CO 93-99

7976

101 (CI)

220 (M)

325(M) 2 (CI)

81 (EM)

269

128 (M) 5 (CI)

382 (EM)

236 19 25

121 180

81 32 93 6 46 9 0 60 I

243




TOTAL FOR REVIEW


LEVEL IV




NIDDM/ AND (hyperlipidemia/ OR hypercholesterolemia/ OR hypertriglyceridemia/ OR TG/ OR hyperlipidaemia/ OR cholesterol/) AND: Antilipemic agents/ M, CI 85-99 HRT/ M 85-99, CI 85-03, EM 94-99 estrogen therapy/ OR HRT.mp EM 99-03 (bezafibrate/ OR gemfibrozil/ OR nicotinic acid/ OR niacin.mp. OR fibric acid.mp OR acipimox/ OR colestyramine/ OR Omega 3 FA/ OR hydroxymethylglutaryl-coa reductase inhibitors.mp. OR bile acid sequestrant/ OR statin/ OR probucol/ OR colestipol/ OR atorvastatin/ OR fish oil/ OR pravastatin/ OR fluindostatin/ OR lovastatin.mp) M, CI 85-99 NIDDM/ AND Antilipemic agents/ AND HRT/ AND (bezafibrate/ OR gemfibrozil/ OR nicotinic acid/ OR niacin.mp. OR fibric acid.mp OR acipimox/ OR colestyramine/ OR Omega 3 FA/ OR hydroxymethylglutaryl-coa reductase inhibitors.mp. OR bile acid sequestrant/ OR statin/ OR probucol/ OR

56 (M) 6 (CI)

0(M) 5(CI)

4 (EM) 24 (EM)

137(M) 6(CI)

32

244




TOTAL FOR REVIEW


LEVEL IV




colestipol/ OR atorvastatin/ OR fish oil/ OR pravastatin/ OR fluindostatin/ OR lovastatin.mp) M 85-99 NIDDM/ AND : TG/ Cholesterol/ Dyslipidemia/ High density cholesterol/ Hyperlipidemia/

Lipid/

Lipid blood level/ Lipid metabolism/ Low density lipoprotein/ CHD/ CVD lipid/ Cholesterol risk factor/ Coronary risk/ Cerebrovascular disease/ HRT Lipid/ Ischemic heart disease/ Risk assessment/ Stroke/ Vascular/ EM 93-99 NIDDM AND coronary risk/ EM 99-03 Diabetes Mellitus AND Lipids/ CO 93-99

806 557 221 315 137

672

303 458 229 3

152 17

177 53 3

199 128 190 140

96

385

245




TOTAL FOR REVIEW


LEVEL IV




NIDDM/ AND Lipids/ AND: Cholesterol/ Cardiovascular disease/ Cerebrovascular disease/ Coronary heart disease/ Diabetic nephropathies/ Diabetic neuropathies/ Diabetic retinopathy/ Macrovascular/ Myocardial infarction/ Myocardial ischemia/ Nephropathy/ Neuropathy/ Retinopathy/ Stroke/ Vascular disease/ Estrogen/ CO 93-99 NIDDM.mp AND cardiovascular diseases.mp AND: HRT.mp Antilipemic agents.mp CO 93-03 NIDDM/ AND estrogen/ CO 93-03 NIDDM/ AND hydroxymethylglutaryl-CoA reductase inhibitors/ AND (costs and cost analysis/ OR cost-benefit analysis OR cost-effectiveness.mp) M 85-03 NIDEM/ AND statins/ AND (cost benefit analysis OR cost.mp) CI 85-03

132 98 15 2 10 3 0 4 3 6 1 4 4 4 3 0 2

41

14

3

2

246




TOTAL FOR REVIEW


LEVEL IV




NIDDM/ AND (statins.mp OR hydroxymethylglutaryl-CoA reductase inhibitors/) AND (cost benefit analysis/ OR cost effectiveness analysis/ OR cost/) EM 88-03 NIDDM.mp AND (statins.mp OR hydroxymethylglutaryl-CoA reductase inhibitors/) AND (cost effectiveness.mp OR cost.mp OR cost-benefit analysis/) CO 93-03

15

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