Lipids: Is Lower Better For Diabetic Patients?

Prof. Samir Helmy Assaad -KhalilDepartment of Internal Medicine

Unit of Diabetes, Lipidology & Metabolism

Alexandria University, Alexandria, Egypt

MGSD Morocco; Friday, April 29, 2011

Agenda

Epidemiological data EBM derived from clinical trials Evidence in patients with T2DM What is Desirable Cholesterol?

Elevated Cholesterol Is a Risk Factor for Cardiovascular Disease (CVD)

Elevated serum cholesterol is associated with increasedrisk of1–3

CHD Reinfarction CVD mortality4

All-cause CHD Stroke

CHD=coronary heart disease; MRFIT=Multiple Risk Factor Intervention Trial.

1. Kannel WB. Am J Cardiol. 1995;76:69C–77C; 2. Anderson KM et al. JAMA. 1987;257:2176–2180; 3. Kannel WB et al. Ann Intern Med. 1971;74:1–12; 4. Neaton JD et al. Arch Intern Med. 1992;152:1490–1500.

0

10

20

30

40

50

<160(4.13)

160–199(4.13–5.14)

200–239(5.17–6.18)

240(6.20)

CV

D M

ort

alit

y R

atea

MRFIT (N=350,977)4

Serum Cholesterol,

mg/dL (mmol/L)

Correlation Between LDL-C & Cardiovascular

Mortality: The Framingham Study1

aNs refer to person-years.1. Wilson PWF et al. Circulation. 1998;97:1837–1847.

<130 mg/dL(<3.4 mmol/L)

(n=11,142a) (n=10,384a) (n=8,628a)(n=15,835a) (n=10,455a) (n=11,767a)

7.3

2.3

0

5

10

15

20

Ag

e A

dju

sted

10-

Yea

r D

eath

R

ates

, %

of

Po

pu

lati

on

Men

Women

130–159 mg/dL(3.4–4.11 mmol/L)

≥160 mg/dL(≥4.14 mmol/L)

11.3

6.5

17.3

10.6

Log Linear Relationship Between LDL-C and Relative Risk of CHD1

CHD=coronary heart disease.

Log-linear relationship between LDL-C levels and relative risk of CHD. This relationship is consistent with a large body of epidemiologic data and with data available from clinical trials of LDL-lowering therapy. These data suggest that for every 30 mg/dL change in LDL-C, the relative risk of CHD is changed in proportion by about 30%. The relative risk is set at 1.0 for LDL-C=40 mg/dL.

1. Grundy SM et al. Circulation. 2004;110:227–239.

Reprinted with permission ©2004, American Heart Association, Inc.

Rel

ativ

e R

isk

of

CH

D,

Lo

g S

cale

0

3.7

2.9

2.2

1.3

1.7

LDL-C, mg/dL (mmol/L)

40(1.0)

100(2.6)

130(3.4)

160(4.1)

190(4.9)

70(1.8)

1.0

Is Lower LDL-C Better?1

CHD=coronary heart disease.

1. Grundy SM et al. Circulation. 2004;110:227–239.

Reprinted with permission ©2004, American Heart Association, Inc.

1

3.7

2.9

2.2

1.3

1.7

Rel

ativ

e R

isk

of

CH

D,

Lo

g S

cale –30 mg/dL

–30% CHD risk

40(1.0)

100(2.6)

130(3.4)

160(4.1)

190(4.9)

70(1.8)

LDL-C, mg/dL (mmol/L)

Correlation Between LDL-C Lowering & Decreased CHD Risk in Primary & Secondary Prevention Trials With Statins1–3

Reproduced from Rosenson. (2004).1

CHD=coronary heart disease; Atv=atorvastatin; Pra=pravastatin; Sim=simvastatin; PROVE-IT=Pravastatin or AtorVastatin Evaluation and Infection Therapy; IDEAL=Incremental Decrease in Endpoints through Aggressive Lipid Lowering; ASCOT=Anglo-Scandinavian Cardiac Outcomes Trial; AFCAPS=Air Force Coronary Atherosclerosis Prevention Study; 4S=Scandinavian Simvastatin Survival Study; CARE=Cholesterol And Recurrent Events Trial; HPS=Heart Protection Study; LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; TNT=Treating to New Targets: WOSCOPS=West of Scotland Coronary Prevention Study.

1. Rosenson RS. Expert Opin Emerg Drugs. 2004;9(2):269–279; 2. LaRosa JC et al. N Engl J Med. 2005;352(14):1425–1435; 3. Pedersen TR et al. JAMA. 2005;294(19):2437–2445.

Eve

nt,

%

0

30

25

20

15

10

5

StatinPlacebo

Mean Treatment LDL-C at Follow-up, mg/dL (mmol/L)

0 80(2.1)

140(3.6)

200(5.2)

100(2.6)

40(1.0)

120(3.1)

180(4.7)

60(1.6)

160(4.1)

4S

4S

CARE

HPS

LIPID

HPS

CARELIPID

PROVE-IT (Atv)

PROVE-IT (Pra)

ASCOT

AFCAPS

ASCOT

AFCAPS

WOSCOPS

WOSCOPS

SecondaryPrevention

PrimaryPrevention

IDEAL (Atv)

IDEAL(Sim)

TNT(Atv

80 mg)

TNT (Atv 10 mg)

NCEP 2001

NCEP 2004

Correlation Between LDL-C Lowering & Decreased CHD Risk According to Treatment Modality in a Meta-Regression Analysis1,a

Reprinted from Journal of the American College of Cardiology, 46(10), Robinson JG, Smith B, Maheshwari N, et al, Pleiotropic effects of statins: benefits beyond cholesterol reduction? A meta-regression analysis, 1855–1862, Copyright © (2005), with permission from Elsevier.

CHD=coronary heart disease; MI=myocardial infarction; MRC=Medical Research Council; LRC=Lipid Research Clinics; NHLBI=National Heart, Lung, and Blood Institute; POSCH=Program on the Surgical Control of the Hyperlipidemias; 4S=Scandinavian Simvastatin Survival Study; WOSCOPS=West of Scotland Coronary Prevention Study; CARE=Cholesterol And Recurrent Events Trial; LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; AF/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; HPS=Heart Protection Study; ALERT=Assessment of LEscol in Renal Transplantation; PROSPER=PROspective Study of Pravastatin in the Elderly at Risk; ASCOT-LLA=Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm; CARDS=Collaborative Atorvastatin Diabetes Study.aAnalysis included 19 trials of high-risk primary prevention and secondary prevention (CHD, cardiovascular disease, renal transplant, diabetes) patients; bStatin trials.

Robinson JG et al. J Am Coll Cardiol. 2005;46(10):1855–1862.

No

nfa

tal M

I an

d C

HD

Dea

th

Rel

ativ

e R

isk

Red

uct

ion

, %

–20

100

80

60

40

20

0

LDL-C Reduction, %

25 3015 35 4020

London

Oslo

MRC

Los Angeles

Upjohn

LRC

NHLBI

POSCH

4Sb

WOSCOPSb

CAREb

LIPIDb

AF/TexCapsb

HPSb

ALERTb

PROSPERb

ASCOT-LLAb

CARDSb

Each LDL-C Reduction of 1 mmol/L (39 mg/dL) Reduced CHD Risk by Over 20% in a MetaAnalysis1,a

CHD=coronary heart disease.aMeta-analysis of 62 randomized, controlled clinical studies that included 216,616 patients with CHD (secondary prevention), without CHD (primary prevention), or with or without CHD.bFatal or nonfatal myocardial infarction.

1. Gould AL et al. Clin Ther. 2007;29(5):778–794.

Rel

ativ

e R

isk

Red

uct

ion

, %

–26.6

–28.0–28.8

–27.5

–26.5

–25.5

0CHD Eventsb CHD Mortality

–26.0

–27.0

–28.0

Each LDL-C Reduction of 1 mmol/L (39 mg/dL) Reduced Major Coronary Eventsa by 23% in a Meta-Analysisb of Statin Trials1

Each 1 mmol/L (39 mg/dL) reduction also reduced

All-cause mortality (P<0.0001)

CHD mortality (P<0.0001)

Nonvascular mortality (P=NS)

CHD=coronary heart disease.aMajor coronary event=nonfatal myocardial infarction or death due to CHD. bMeta-analysis of 14 trials of patients with CHD (47%), history of diabetes (21%), and history of hypertension (55%).cIn the 14 trials analyzed, the control group was placebo in 11 trials, lower statin doses in 1 trial, no treatment in 1 trial, and usual care in 1 trial.

1. Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet. 2005;366:1267–1278.

Pooled Statin Groups

(n=45,054)

Pooled Controlc Groups

(n=45,002)

P<0.001

Statin vs Control

7.4

9.8

0

2

4

6

8

10

12

Pat

ien

ts W

ith

Maj

or

Co

ron

ary

Eve

nts

, %

Reducing LDL-C by 1 mmol/L Continued to Reduce IHDa Risk During Each Year of Treatment in a Meta Analysis1,b

IHD=ischemic heart disease.aIHD death and nonfatal myocardial infarction.bMeta-analysis of 58 trials.

1. Law MR et al. BMJ. 2003;326:1423–1427.

Ris

k R

edu

ctio

n,

%

–11

–33–40

–30

–20

–10

0

–24

–36

Year 1 Year 2 Years 3–5Year 6

and After

Years of Treatment

The 4S Diabetes Sub-study

(n=202)

P=0.087 P=0.002 P=0.018

The Role of Lipid-lowering Therapy in Preventing CHD in

Patients with Type 2 Diabetes : A Meta-analysis

D.G. Karalis. Clin. Cardiol. 31, 6, 2008: 241–248

The Role of Lipid-lowering Therapy in Preventing CHD in

Patients with Type 2 Diabetes : A Meta-analysis (continued)

D.G. Karalis. Clin. Cardiol. 31, 6, 2008: 241–248

An Ideal Level of LDL Cholesterol should be between 40-70 mg/dL

What Is the Ideal Level of LDL Cholesterol

“Normal” Plasma Cholesterol

What is Desirable Cholesterol?

Evolution of NHLBI Supported Guidelines

Intensive LDL-C Goals for High Risk Patients

* And other forms of atherosclerotic disease.2

† Factors that place a patient at very high risk: established cardiovascular disease plus: multiple major risk factors (especially diabetes); severe and poorly controlled risk factors (e.g., cigarette smoking); metabolic syndrome (triglycerides ≥200 mg/dL + non–HDL-C ≥130 mg/dL with HDL-C <40 mg/dL); and acute coronary syndromes.1

1. Grundy SM et al. Circulation 2004;110:227–239.2. Smith SC Jr et al. Circulation 2006; 113:2363–2372.

<100 mg/dL

<70 mg/dL

Recommended LDL-C treatment goals

If it is not possible to attain LDL-C <70 mg/dL because of a high baseline LDL-C, it generally is possible to achieve LDL-C reductions of >50% with more intensive LDL-C lowering therapy, including drug

combinations.

ATP IIIUpdate 20041

<100 mg/dL:Patients with CHD or CHD risk equivalents(10 year risk >20%)1

<70 mg/dL:Therapeutic option for very high risk

patients1

AHA/ACC guidelinesfor patients with

CHD*,2

<100 mg/dL:Goal for all

patients with CHD†,2

<70 mg/dL:A reasonable goal

for all patients with CHD2

-1

-0.5

0

0.5

1

1.5

2

50 60 70 80 90 100 110 120

ASTEROID3 rosuvastatin

A-Plus2 placebo

ACTIVATE1 placebo

CAMELOT4 placebo

REVERSAL5 pravastatin

REVERSAL5 atorvastatin

Mean LDL-C (mg/dL)

The relationship between mean LDL-C and change in

percent atheroma volume (PAV) in IVUS studies†

Change in

Percent Atheroma

Volume*(%)

†ASTEROID and REVERSAL investigated active statin treatment; A-PLUS, ACTIVATE AND CAMELOT investigated non-statin therapies but included placebo arms who received background statin therapy (62%, 80% and 84% respectively).

*Median change in PAV from ASTEROID and REVERSAL; LS mean change in PAV from A-PLUS, ACTIVATE AND CAMELOT

1 Nissen S et al. N Engl J Med 2006;354:1253-1263. 2 Tardif J et al. Circulation 2004;110:3372-3377. 3 Nissen S et al. JAMA 2006;295 (13):1556-1565 4 Nissen S et al. JAMA 2004;292: 2217–2225. 5 Nissen S et al. JAMA 2004; 291:1071–1080

Progression

Regression

Conclusion

Epidemiological data Findings in other species EBM derived from clinical trials Evidence in patients with T2DM Studies aiming at regression of atheroma volume

All support the view of: “The lower the better in the context of lipids in patients with diabetes”

Thank You!