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

Natural History of Type 2 Diabetes

Development of Type 2 Diabetes

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

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

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

Thiazolidinediones:Rationale for Type 2 Diabetes

Therapy

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.

PROACTIVE Study: Secondary Prevention of Macrovascular Events in

Persons with Diabetes from Pioglitazone 5238 patients with type 2 diabetes who had evidence of

macrovascular disease assigned to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), taken w/existing drugs.

Primary endpoint: combined all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle.

Over an average of 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group achieved the primary endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095).

Lancet 2005; 366: 1279-89

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

UKPDS: Effects of Tight vs Less-Tight Blood Pressure

Control

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)

ADA 2007 Algorithm for Glycemic Management of Type 2 DM (Diabetes Care, 2007)

Rationale for the ADA Goal of HbA1c <7%: DCCT and UKPDS Results

• On the basis of the DCCT and UKPDS, the ADA recommended the HbA1c goal to be <7% for most adults with diabetes

• DCCT involving Type 1 diabetes patients showed an approximately 60% reduction in development or progression of diabetic retinopathy, nephropathy, and neuropathy between intensively treated pts (goal A1c<6%, mean achieved 7%) and standard group (A1c=9%) over 6.5 Years (NEJM 1993; 329: 977-986). A 9-year follow-up of this cohort has now shown a 42% reduction (p=0.02) in CVD outcomes and a 57% reduction (p=0.02) in risk of nonfatal MI, stroke, or CVD death compared to those in the standard arm (NEJM 2005; 353: 2643-2653).

Rationale for HbA1c<7% goal and Trials to Examine Effect of Intensive

Glycemic Control• The UKPDS involving newly diagnosed patients with Type

2 diabetes followed for 10 years showed microvascular complications to be reduced by 25% in the intensive control (mean A1c=7%) vs. conventional arm (mean A1c=7.9%). There was a nonsignificant (p=0.052) reduction in cardiovascular complications (Lancet 1998; 352: 854-65).

• Epidemiologic analysis of the UKPDS cohort showed, however, that for every percentage point reduction in A1c level, there was a statistically significant 18% reduction in CVD events with no glycemic threshold.

• Several large-scale clinical trials have since been launched to better address the question of intensive glycemic control on CVD outcomes.

ACCORD: Is too aggressive lowering of HbA1c harmful?

• NHLBI-sponsored ACCORD study randomized 10,251 participants with T2DM with hx of CVD, significant CVD risk or 2+ risk factors and tested control of HbA1c to <6% vs. standard strategy for HbA1c 7-7.9%.

• Median HbA1c achieved 6.4% vs. 7.5%.• The primary outcome of MI, stroke, or CVD death was

reduced in the intensive vs. control group due to fewer nonfatal MIs, but was not significant (HR=0.90, p=0.16)

• But the trial was stopped early due to increased all-cause mortality (5.0% vs. 4.0%, HR=1.2, p<0.05) and death from CVD (2.6% vs. 1.8%) in the intensive arm, despite a reduction in non-fatal MI (3.6% vs. 4.6%). Major hypoglycemia requiring assistance was also significantly higher (3.1% vs. 1.0%).

ACCORD (cont.)

• But in those without a prior CVD event and who had a baseline HbA1c <8% had a significant reduction in the primary CVD outcome suggesting a possible benefit of intensive therapy this subgroup of T2DM pts.

• In both arms of the study, those with vs. without severe hypoglycemia had a higher mortality.

NEJM 2008; 358: 2545-9

ADVANCE• A larger study, ADVANCE, in 11,140 pts with T2DM done in

Europe, Australia/NZ, Canada, and Asia did not find an increased risk (8.9% vs. 9.6% for total deaths, 4.5 vs. 5.2% for CVD death).

• The primary intensive therapy was the sulfonylurea gliclizide with addl medications to achieve HbA1c<6.5%

• 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 8 vs. 10 years and somewhat lower HbA1c at baseline.

• A significant reduction in the primary endpoint of combined microvascular and macrosvascular events was achieved (HR=0.90, p=0.01) mainly due to reduction in microvascular outcomes (macrovascular endpoints not reduced, HR=0.94,p=0.32)

• This study also showed those without prior macrovascular disease to show a benefit (14% risk reduction, p<0.05) from the intensive therapy. No benefit seen in those with prior disease.

NEJM 2008; 358: 2560-2572)

ACCORD vs. ADVANCE• One possible explanation of the difference in

findings between the two studies was that the rate of HbA1c reduction was much greater in ACCORD (1.4% reduction within 4 months than in ADVANCE 0.5% at 6 months and 0.6% at 12 months).

• Experts speculate that more aggressive treatment can more likely lead to hypoglycemia requiring attention, as was clearly the case in ACCORD.

VA Diabetes Trial (VADT)• 1,791 veterans, 97% men, 62% white, mean age

60 years), 7.5 year intervention

• Intensive HbA1c <7% vs. standard control.

• Baseline glycemic control worst of the recent trials at 9.5%; 40% had prior CVD events, 80% had HTN, 50% had dyslpidemia, most were obese

N Engl J Med. 2009 Jan 8;360(2):129-39

VADT (cont.)• No significant difference in primary outcome of

CVD events: 263 in standard control and 231 in intensive control, HR=0.88, p=0.12.

• More CVD deaths in the intensive arm compared to the standard arm (38 vs. 29, n.s.)

• Most important finding was that severe hypoglycemia (impairment/loss of consciousness within prior 3 months) was a power predictor of CVD events (HR=2.1, p=0.02) and occurred in 21% of intensive control and 10% of standard control subjects.

• An ancillary study showed that the primary CVD endpoint was significantly reduced in those with low, but not high baseline coronary calcium scores.

Why no benefit from these trials?• Other CVD risk factors were treated to a moderate or high

degree, so had lower overall rates of CVD in the standard arm than originally predicted.

• The additive benefits of intensive glycemic control may be smaller and more difficult to show in the background of aggressive treatment of other risk factors.

• The three trials compared intensive vs. conventional treatment in the flatter part of the observational glycemic-CVD risk curve.

• The trials were also conducted in persons with established diabetes in combination whether with CVD or multiple risk factors; subset analyses of the 3 trials suggested a significant benefit in those without known CVD, or with a shorter duration of diabetes or lower A1c upon entry.

Circulation 2009; 119: 351-357

ADA / AHA / ACC Statement Recommendations(Circulation 2009; 119: 351-357)

• Findings from ACCORD, ADVANCE, and VADT do not suggest need for major changes in targets, but additionally clarification for individualizing therapy.

• General goal of <7% HbA1c remains reasonable for non-complicated DM pts based on benefits seen from DCCT and UKPDS for microvascular disease (ACC/AHA Class Ia – Level of Evidence A) and based on follow-up of these trials, macrovascular disease (ADA B-Level, ACC/AHA Class IIb - A).

• An additional benefit for microvascular disease may be obtained from even lower goals if they can be achieved without significant hypoglycemia (ADA B-Level, ACC/AHA, Class IIa – C).

• Less stringent goals may be appropriate for those with a hx of severe hypoglycemia, difficult to control DM pts, and those with advanced micro or macrovascular complications or major comorbidities (ADA, C-level recommendation, ACC/AHA, Class IIa – C).