Metabolic Syndrome, Diabetes, and Cardiovascular Disease: Implications

for Preventive Cardiology

Nathan D. Wong, PhD, FACC, FAHA

Professor and Director

Heart Disease Prevention Program

Division of Cardiology

University of California, Irvine

Overview of Diabetes in the United States

Diabetes Prevalence, 1990-1998

Age-adjusted prevalence of physician-diagnosed diabetes in Adults age 18 and older by race/ethnicity and sex (NHANES: 1999-2004). Source: NCHS and NHLBI. NH – non-Hispanic.

6.75.6

10.7

13.2

11.0 10.9

0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

Men Women

Per

cen

t o

f P

op

ula

tio

n

NH Whites NH Blacks Mexican Americans

Risk of Cardiovascular Events in Diabetics Framingham Study

Age-adjusted

Biennial Rate Age-adjusted

Per 1000 Risk Ratio

Cardiovascular Event Men Women Men Women

Coronary Disease 39 21 1.5** 2.2***

Stroke 15 6 2.9*** 2.6***

Peripheral Artery Dis. 18 18 3.4*** 6.4***

Cardiac Failure 23 21 4.4*** 7.8***

All CVD Events 76 65 2.2*** 3.7***

Subjects 35-64 36-year Follow-up **P<.001,***P<.0001

_________________________________________________________________

_________________________________________________________________

Insulin Resistance

Hyperglycemia in Type 2 Diabetes Results From Three

Major Metabolic Defects

Relationship Between Obesity and

Insulin Resistance and Dyslipidemia

Insulin Resistance: Associated Conditions

New Cases of ESRD in the United States

New Cases of ESRD in the United States

by Cause and Ethnicity, 1998

Microalbuminuria

Cardiovascular Disease and Diabetes

Probability of Death From CHD in Patients With Type 2 Diabetes With

or Without Previous MI

Framingham Heart Study 30-Year Follow-Up:CVD Events in Patients With Diabetes (Ages 35-64)

109

20

11

9 63819

3*

30

0

2

4

6

8

10

Age-adjusted annual rate/1,000

Men Women

Total CVD

CHD Cardiac failure

Intermittent claudication

Stroke

Riskratio

P<0.001 for all values except *P<0.05.

Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease.Ruderman N et al, eds. Oxford; 1992.

The Metabolic Syndrome

InsulinResistance

Hypertension

Type 2 Diabetes

DisorderedFibrinolysis

ComplexDyslipidemia

TG, LDL

HDL

EndothelialDysfunction

SystemicInflammation

Athero-sclerosis

VisceralObesity

Adapted from the ADA. Diabetes Care. 1998;21:310-314;Pradhan AD et al. JAMA. 2001;286:327-334.

Revised ATP III Metabolic Syndrome Oct 2005

*Diagnosis is established when 3 of these risk factors are present.†Abdominal obesity is more highly correlated with metabolic risk factors than is BMI. ‡Some men develop metabolic risk factors when circumference is only marginally increased.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497; Updated AHA/NHLBI Statement Oct 18, 2005: Grundy et al. Circulation 2005; 112 (epub).

<40 mg/dL<50 mg/dL or Rx for ↓ HDL

MenWomen

>102 cm (>40 in)>88 cm (>35 in)

MenWomen

100 mg/dL or Rx for ↑ glucoseFasting glucose130/85 mm Hg or on HTN RxBlood pressure

HDL-C150 mg/dL or Rx for ↑ TGTG

Abdominal obesity† (Waist circumference‡)

Defining LevelRisk Factor

International Diabetes Federation Definition:

Abdominal obesity plus two other components: elevated BP, low HDL, elevated TG, or impaired fasting glucose

Back

Visceral AT

Subcutaneous AT

Front

Intra-abdominal (Visceral) FatThe dangerous inner fat!

Prevalence of the Metabolic Syndrome Among US Adults NHANES 1988-1994Prevalence of the Metabolic Syndrome Among US Adults NHANES 1988-1994

Pre

vale

nc

e (

%)

P

reva

len

ce

(%

)

05

10

15

2025

3035

40

45

20-29 30-39 40-49 50-59 60-69 > 70

MenMenWomenWomen

Age (years)Age (years)Ford E et al. JAMA. 2002(287):356.Ford E et al. JAMA. 2002(287):356.

1999-2002 Prevalence by IDF vs. NCEP Definitions (Ford ES, Diabetes Care 2005; 28: 2745-9) (unadjusted, age 20+)NCEP : 33.7% in men and 35.4% in women IDF: 39.9% in men and 38.1% in women

0%

10%

20%

30%

40%

Prevalence of the NCEP Metabolic Syndrome: NHANES III by Sex and Race/Ethnicity

Pre

vale

nce

, %

MenFord ES et al. JAMA 2002;287:356-359.

Women

WhiteAfrican AmericanMexican AmericanOther

25%25%

16%16%

28%28%

21%21%23%23%

26%26%

36%36%

20%20%

Cardiovascular Disease (CVD) and Total Mortality: US Men and Women Ages 30-74

(age, gender, and risk-factor adjusted Cox regression) NHANES II Follow-Up (n=6255)(Malik and Wong, et al., Circulation 2004; 110: 1245-1250)

0

1

2

3

4

5

6

7

Rel

ativ

e R

isk

CHD Mortality CVD Mortality Total Mortality

None

MetS

Diabetes

CVD

CVD+Diabetes

* p<.05, ** p<.01, **** p<.0001 compared to none

*

***

***

***

**

***

***

***

******

***

Metabolic Syndrome, CVD Events, and Mortality

• European cohort studies (6156 men and 5356 women): Modified WHO definition of MetS associated with all-cause mortality (RR=1.44 [1.17-1.84] in men and 1.38 [1.02-1.87] in women) and CVD mortality (RR=2.26 [1.61-3.17] in men and 2.78 [1.57-4.94 in women) (Hu et al. Arch Intern Med 2004; 164: 1066-76)

• Atherosclerosis Risk in Communities (ARIC) study (12,089 men and women): 11 year follow-up, ATP III MetS associated with 1.5-2-fold greater likelihood of developing CHD and stroke, but MetS did not improve prediction over FRS (McNeill et al. Diab Care 2005; 28: 385-90)

• Cardiovascular Health Study (CHS) (2,175 elderly subjects): ATP III definition associated with 38% increased risk (p<0.01) of coronary/cerebrovascular events (Scuteri et al., Diab Care 2005; 28: 882-7)

Evidence Supporting Aggressive Glycemic

Control

Treatment of Type 2 Diabetes

Sites of Action of Therapeutic Options for

Type 2 Diabetes

DCCT: Effects of Intensive vs Conventional Glycemic Control

UKPDS: Design

UKPDS: Effects of Intensive (Sulfonylurea/Insulin) Treatment

UKPDS: Effects of Intensive (Metformin)

Treatment*

UKPDS: Effects of Glycemia Exposure

Over Time

UKPDS: Risk Reduction in Diabetes-

Related Complications (A1c)

Diabetes Prevention Program: Protocol Design

Diabetes Prevention Program: Reduction in Diabetes Incidence

Structures of Thiazolidinediones

Thiazolidinediones: Mechanism of Insulin

Sensitization

PPAR α vs. gamma

• PPAR α (fibrates) work mostly in the liver and lower VLDL triglycerides and increase HDL-C but do not affect FFA, glucose, or insulin sensitivity

• PPAR gammas (TZDs such as rosiglitazone or pioglitazone) promote new fat cells in subcutaneous tissue and decrease intramuscular and visceral fat.

Thiazolidinediones:Rationale for Type 2 Diabetes

Therapy

ACTOS, an Insulin Sensitizer

Reduced Insulin Resistance Suggested by HOMA Analysis of

Pioglitazone Therapy

Improved β-Cell Response Suggested by HOMA Analysis of

Pioglitazone Therapy

Changes in A1c From Baseline in All Treated Patients

Endpoint Changes in Patients With

Lower Baseline A1c (Mean 9.0%)*

Change in FPG From Baseline in All Treated Patients

Change in Lipid Profile at Endpoint:

ACTOS 26-Week Monotherapy

DREAM Study for Prevention of Diabetes• 5,269 persons with pre-diabetes randomized to

rosiglitazone (8 mg daily) vs. placebo and ramipril vs. placebo for median of 3 years

• 10.6% of those on rosiglitazone progressed to type 2 diabetes vs. 25% on placebo, a 62% risk reduction (p<0.0001).

• Primary endpoint of development of diabetes or death from any cause reduced by 60%

• 51% of those on rosiglitazone vs. 30% on placebo returned to normal blood sugar

• No significant difference in future cardiovascular events, but higher rate of new heart failure in those on rosiglitazone (0.5%) vs. placebo (0.1%). Body weight increased 2.2kg more in the rosiglitazone vs. placebo group.

The DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096-105.

PERISCOPE:Comparison of Pioglitazone vs.

Glimepirideon Progression of Coronary

Atherosclerosisin Patients with Type 2 Diabetes

Steve E. Nissen, MDCleveland Clinic FoundationCleveland, Ohio

ACC Scientific Sessions, Late BreakerMonday March 31, 2008Chicago, Illinois

PERISCOPEBackground

Background• Cardiovascular disease is the leading cause of death in patients with diabetes• Few studies have compared outcomes for diabetes medications beyond their

glucose lowering efficacy• Sought to compare coronary disease progression measured by intravascular

ultrasound for two alternative treatment strategies:–Glimepiride (an insulin secretagogue) –Pioglitazone (an insulin sensitizer)

Hypothesis• To directly compare the effectiveness of these 2 alternative approaches, an

insulin-providing vs an insulin-sensitizing strategy, in reducing progression of atherosclerosis in patients with type 2 diabetes and coexisting coronary artery disease

Nissen S. JAMA.2008;299(13):1561-1573

543 patients with type 2 diabetes undergoing angiography for clinical indications

Glimepiride 1-4mg(titrated to maximally

tolerated dose)

Repeat Intravascular Ultrasonography Examination at 16 weeks

Primary Outcome Measure: Change in percent atheroma volume (PAV) from baseline to study completion

Pioglitazone 15-45mg(titrated to maximally

tolerated dose)

PERISCOPEStudy Design

Nissen S. JAMA.2008;299(13):1561-1573

Pioglitazone

PERISCOPEPrimary Efficacy Parameter

Change in Percent Atheroma Volume (%)

-0.3

-0.1

0.1

0.3

0.5

0.7

0.9 Glimepiride (n=181)

Pioglitazone (n=179)

P<0.001

P=0.44

Change in PAV(%)

0.73

-0.16

Difference between groups P=0.002

Nissen S. JAMA.2008;299(13):1561-1573

0.0

-1.0

-2.0

-3.0

-4.0

-5.0

-6.0

-1.5

-5.5

Glimepiride Pioglitazone

Atheroma Thickness (mm) Atheroma Volume (mm3) Most Disease 10mm (mm3)

PERISCOPE

Intravascular Ultrasound. Secondary Endpoints

0.011

-0.011

0.015

0.01

0.005

0

-0.005

-0.01

-0.015

0.0

-0.5

-2.0

-3.0

-4.0

-5.0

-6.0

-2.1-2.0

P=0.006 P=0.06 P=0.93

Nissen S. JAMA.2008;299(13):1561-1573

PERISCOPEOther Adverse Events

Glimepiride (n=273)

Pioglitazone (n=270)

P Value

Hypoglycemia 37.0% 15.2% <0.001

Edema 11.0% 17.8% 0.02

Angina 12.1% 7.0% 0.05

BUN >30 mg/dL

4.8% 10.7% 0.01

Creatinine > 2.0 mg/dL

0.7% 1.1% 0.69

Hypertension 8.8% 4.8% 0.07

Bone Fractures 0% 3.0% 0.004

Change in Body Weight

+1.6kg +3.6kg <0.001

Nissen S. JAMA.2008;299(13):1561-1573

UKPDS: Effects of Tight vs Less-Tight Blood Pressure

Control

ACCORD: Is too aggressive lowering of HbA1c harmful?

• NHLBI-sponsored ACCORD study of approx. 10,000 T2DM pts with CHD or 2+ risk factors tested control of HbA1c to <6% vs. standard strategy for HbA1c 7-7.9%.

• Median HbA1c achieved 6.4% vs. 7.5%• The trial was stopped early (Feb 6, 2008) due to more

deaths in intensive arm (257, or 14/1000 person years) vs. standard arm (203, or 11/1000 person years).

• There were, however, 10% fewer MIs in intensive arm and no link to any particular medication causing increases in deaths was noted.

• No change in general recommendation by ADA to achieve for HbA1c <7% in most diabetics; in older diabetics with prior CHD or other risk factors like in ACCORD population, less stringent goals of around 7% might be appropriate.

ADVANCE and VADT• In light of ACCORD, a larger study, ADVANCE, in

progress of 11,140 pts with T2DM also did an interim analysis reported February 14 but did not find any evidence of increased risks.

• These pts achieved the same HbA1c of 6.4% as achieved in the ACCORD intensive therapy arm, but ADVANCE pts had less severe diabetes--duration shorter (8 vs. 10 years) and somewhat lower HbA1c at baseline.

• It is possible that it is the intensity of treatment or rather than the HbA1c achieved which is the problem but that will need to be examined further.

• The U.S. VA Diabetes Trial, also examining the relation of intensive glycemic control to cardiovascular outcomes will report its results soon.

• The ADA plans to evaluate the results from all these studies before making further recommendations.

Collaborative Atorvastatin Diabetes Study (CARDS)

• 2838 patients aged 40-75 with type 2 diabetes, no prior CVD, but at least 1 of the following: retinopathy, albuminuria, smoking, or hypertension

• Randomization to 10 mg atorvastatin or placebo• Mean follow-up 3.9 years• Reduction in all CVD events of 37% (p=0.001),

all cause mortality 27% (p=0.059). CHD events reduced 36% and stroke 48%.

Colhoun HM et al., The Lancet 2004; 364: 685-696

Relative Risk of Eventsin 4S Study

Adapted from Haffner et al. Arch Intern Med. 1999;159:2661.

RR = 0.6895% CI = 0.59-0.79

P <0.001 n = 1631/1606

RR = 0.62 95% CI = 0.46-0.85 P <0.003 n = 335/343

NFG IFG DMRR = 0.58 95% CI = 0.41-0.80P <0.001 n = 232/251

RR = 0.67 95% CI = 0.55-0.80P <0.001 n = 1631/1606

RR = .57 95% CI = 0.37-.87P <0.01 n = 335/343

RR = 0.52 95% CI = 0.32-0.82P <0.005 n = 232/251

RR = 0.72 95% CI = 0.57-0.90P <0.005 n = 1631/1606

RR = 0.57 95% CI = 0.35-0.93 P <0.02 n = 335/343

16.4

7.7 7.312.810.4 13.1

05

10152025

RR = 0.79 95% CI = 0.49-1.27P <0.34 n = 232/251

NFG IFG DM

NFG IFG DM

Patients (%)

CAD Events

Revascularization

Total Mortality

21.1

11.5 10.2 11.616.6 16.7

05

10152025

Patients (%)

30.437.5

18.6 19.523.526.2

010203040

Patients (%)

Placebo Simvastatin

Reduction in CHD Event Rates With Statin Treatment

(WOSCOPS)

Sattar N, et al. Circulation. 2003;108:414-419

10.4

6.2

7.7

4.4

0

2

4

6

8

10

12

CH

D e

ven

t ra

te (

%)

Patients WithMetabolic Syndrome

Patients WithoutMetabolic Syndrome

PlaceboPravastatin

Are LDL and HDL Effects Additive?

R2 = 0.8512

0

20

40

60

80

100

0 10 20 30 40 50 60 70 80

% Absolute Change in LDL+HDL

% C

V E

ven

t R

RR

HATS

FATS

FATS F/U

4SVA HIT DAIS

BIP

AFCAPS/TexCAPS

WOSCOPS

LIPIDCARE, HPS

HHS

CDP

ASCOT

ALLHAT

PROSPER

2nd Order Relationship

Hypertension Optimal Treatment (HOT): Outcomes in Patients

With Diabetes

Most CHD Events May be Preventable by Control of Blood Pressure, HDL-C, LDL-C to “Optimal” Levels in

Persons with the Metabolic Syndrome (Wong et al., Am J Cardiol 2003; 91: 1421-26)

28.2

51.2 50.646.2

38.1

80.5 82.1

45.1

0

10

20

30

40

50

60

70

80

90

Men Women

Pro

po

rtio

n o

f C

HD

Ev

en

ts P

rev

en

ted

(P

AR

%)

BP only HDL-C only LDL-C only All 3 factors

***

* p<0.05, ** p<0.01 compared to men

The endocannabinoid system

• An endogenous signaling system which contributes to physiologic regulation of energy balance, food intake, and lipid and glucose metabolism through both central and peripheral effects

Effects of cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular

risk factors over 1 year: RIO Europe Study

• 1,507 pts with BMI >=30 or >27 with dyslipidemia and/or hypertension randomized to placebo, 5mg or 20 mg rimonabant, w/hypocaloric diet

• Weight loss at 1 year: -3.4 kg w/5mg, -6.6 kg w/10 mg rimonabant vs. placebo (-1.8 kg)

• Rimonabant 20 mg produced greater improvements in waist circumference, HDL-C, triglycerides, LDL-C, insulin, and prevalence of metabolic syndrome (reduced by 34% w/placebo vs. 64.8% with rimonabant)

Van Gaal LF, et al. Lancet 2005; 365: 1389-97

Metabolic Syndrome: Lifestyle Management

• Obesity / weight management: low fat – high fiber diet resulting in 500-1000 calorie reduction per day to provide a 7-10% reduction on body weight over 6-12 mos, ideal goal BMI <25

• Physical activity: at least 30, pref. 60 min moderate intensity on most or all days of the week as appropriate to individual

• Nutritional recommendations per ATP III guidelines: low intake of saturated fats, trans fats, and cholesterol, reduced consumption of simple sugars, and increased intakes of fruits, vegetables, and whole grains are reasonable

Grundy SM, Hansen B, Smith SC, et al. Clinical management of metabolic syndrome. Report of the American Heart Association / National Heart, Lung, and Blood Institute / American Diabetes Association Conference on Scientific Issues Related to Management. Circulation 2004; 109: 551-556

Therapeutic Lifestyle ChangesNutrient Composition of TLC Diet

Nutrient Recommended Intake• Saturated fat Less than 7% of total calories• Polyunsaturated fat Up to 10% of total calories• Monounsaturated fat Up to 20% of total calories• Total fat 25–35% of total calories• Carbohydrate 50–60% of total calories• Fiber 20–30 grams per day• Protein Approximately 15% of total calories• Cholesterol Less than 200 mg/day• Total calories (energy) Balance energy intake and

expenditure to maintain desirable body weight/prevent weight gain

Effect of Mediterranean-style diet in the metabolic syndrome

• 180 pts with metabolic syndrome randomized to Mediterranean-style vs. prudent diet for 2 years

• Those in intervention group lost more weight (-4kg) than those in the control group (+0.6kg) (p<0.01), and significant reductions in CRP and Il-6.

• After 2 years, 40 pts in intervention group still had features of metabolic syndrome compared to 78 pts in the control group

Esposito K et al. JAMA 2004; 292(12): 1440-6.

Therapeutic Goals and Recommendations for Clinical Management of Metabolic Syndrome

(Grundy et al. Circulation 2005; 112 (epub) Oct 18)

Dyslipidemia

LDL-C, HDL-C, TG, non-HDL-C

Elevated Blood Pressure

Elevated Glucose

Prothrombotic and Proinflammatory States

ABC’s of Metabolic Syndrome Management

Intervention Goals / Treatment

A Antiplatelet agent Treat all high-risk patients with low-dose aspirin (or clopidogrel in those with CVD if aspirin is contraindicated) and consider low-dose aspirin in moderately high-risk patients.

B BP Control Aim for BP <130/85 mm Hg, or <130/80 mm Hg for type 2 diabetes. Consider ACE-I or ARBs and low dose diuretics in combination rx.

ABC’s of Metabolic Syndrome ManagementIntervention Goals

C Cholesterol Management

LDL-C targets, ATP III guidelines

–High Risk: CHD, CHD risk equivalents (incl. >20% 10-year risk): <100 mg/dL (option <70 mg/dl if CVD present)

– Moderately High Risk (10-20% risk or subclinical disease) 2 RF: <130 mg/dL, option <100 mg/dL

– Moderate Risk (2+ RF, <10%) <130 mg/dL

-- Low Risk: 0-1 RF: <160 mg/dL

Non-HDL-C targets 30 mg/dL higher

HDL-C: >40 mg/dL (men)

>50 mg/dL (women)

TG: <150 mg/dL

Cigarette Smoking

Long term smoking cessation

Goals for Elevated Glucose

• For IFG delay progression to type 2 diabetes; for diabetes, HgbA1c <7.0%

• For IFG encourage weight reduction and increased physical activity

• For type 2 diabetes, lifestyle therapy and if necessary, pharmacologic therapy to achieve near normal HgbA1c <7%; modify other risk factors and behaviors.

• Limited clinical trial data on treatment to reduce CVD events; neither metformin or thiazolidinediones recommended just for prevention of diabetes because cost-effectiveness and long-term safety not yet documented.

Grundy et al. AHA/NHLBI scientific statement on diagnosis and management of metabolic syndrome. Circulation Oct 18, 2005; 112 (e pub)