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Identifying and Treating Patients with

Insulin Resistance

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Diagnosis of diabetes, IFG, and IGT

≥200

–

140 to 199 (ADA)

>140 to <200 (AACE)

Casual Fasting 2-hr postload*

Plasma glucose (mg/dL)

*Following equivalent of 75 g anhydrous glucose in water

ADA. Diabetes Care. 2005;28(suppl 1):S4-36.AACE. Endocr Pract. 2003;9:240-52.

Diabetes

Impaired fasting glucose (IFG)

Impaired glucose tolerance (IGT)

≥200

–

–

≥126

100 to 125 (ADA)

>110 to ≤126 (AACE)

–

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Metabolic syndrome diagnosis: ATP III emphasizes clinical practice

Risk factor Defining level

• Abdominal obesity (in) Waist:Men >40Women >35

• Triglycerides (mg/dL) ≥150

• HDL-C (mg/dL)Men <40Women <50

• BP (mm Hg) ≥130/≥85

• Fasting glucose (mg/dL) ≥110 (ADA ≥100)NCEP ATP III. JAMA. 2001;285:2486-97.

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• Plasma triglycerides >150 mg/dL*• HDL-C <40 mg/dL*• BP 140/90 mm Hg*• Fasting glucose 100 mg/dL or

previously diagnosed type 2 diabetes

*Or receiving specific treatment for this abnormality www.idf.org. Accessed August 2005.

Metabolic syndrome diagnosis: IDF emphasizes central obesity

Central obesity

Plus any 2 of the following:

• Defined according to waist circumference (ethnic- and gender-specific)

International Diabetes Federation

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European 37 32Sub-Saharan AfricanMiddle Eastern

South Asian 35 32South/Central American

Chinese 35 32

Japanese 34 35

Waist circumference (inches)

Men Women

IDF ethnic- and gender-specific criteria for central obesity

www.idf.org. Accessed August 2005.

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Metabolic syndrome diagnosis: WHO emphasizes central role of insulin resistance

Grundy SM et al. Circulation. 2004;109:433-8.Adapted from Alberti KG, Zimmet PZ. Diabet Med.1998;15:539-53.

Insulin resistance

•Type 2 diabetes, or

•Impaired fasting glucose, or

•If fasting glucose <110 mg/dL, glucose uptake below lowest quartile

Plus any 2 of the following:

•Antihypertensive medication and/or BP ≥140/90 mm Hg

•Plasma triglycerides ≥150 mg/dL

•HDL-C <35 mg/dL (men) or <39 mg/dL (women)

•BMI >30 kg/m2 and/or waist-hip ratio >0.9 (men); >0.85 (women)

•Urinary albumin excretion rate ≥20 µg/min or albumin-creatinine ratio ≥30 mg/g

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Other markers of insulin resistance

• Family history of type 2 diabetes or CAD

• Overactive sympathetic nervous system

Uric acid

Cohn GS et al. Am J Hypertens. 2005;18:1099-103.

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Adapted from Cohen JD. Lancet. 2001;357:972-3.

B Beta-blockadeBlood pressure control

A AspirinACE inhibitionA1C control

C Cholesterol management

D DietDon’t smoke

E Exercise

ABCs of coronary prevention

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Multidisciplinary consensus on managingmetabolic syndrome

Grundy SM et al. Circulation. 2004;109:551-6.

• Modify lifestyle (weight loss, physical activity)

• Assess risk

– Framingham Risk Score

– CRP (optional)

• Reduce risk factors (ATP III, JNC 7, ADA)

– Lipids, BP, thrombosis, glucose

AHA / NHLBI / ADA

“There is growing interest in the possibility that drugs that reduceinsulin resistance will delay onset of type 2 diabetes and will reduce

CVD risk when the metabolic syndrome is present.”

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DPP Research Group. N Engl J Med. 2002;346:393-403.

0

0

10

20

30

40

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Year

N = 3234, no diabetesAge 50 207 lbsGlucose 107

• Lose 5–10 lbs

• Exercise 2.5 hrs/wk

Placebo

Metformin

LifestyleCumulativeincidence of

diabetes(%)

31%

58%

P

< 0.001

< 0.001

DPP: Impact of lifestyle intervention or metformin on diabetes

DPP = Diabetes Prevention Program

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UKPDS: Comparison of tight control of BP vs glycemia on risk of diabetes complications

UKPDS Group. BMJ. 1998;317:703-13.

0

–10

–20

–30

–40

–50

–60

%Patients

Any diabetes-related

outcome

Diabetes-relateddeath

Micro-vascular Retinopathy Stroke

Coronaryheart failure

Tight BP (144/82 vs 154/87 mm Hg)

Tight glucose (A1C 7% vs 7.9%)

UKPDS = UK Prospective Diabetes Study

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HPS and CARDS: Benefits of lowering LDL-C in diabetes

HPS Collaborative Group. Lancet. 2003;361:2005-16.Colhoun HM et al. Lancet. 2004;364:685-96.

Δ LDL-C(mg/dL)*

34.8

46.4

Statinbetter

Placebobetter

All diabetes

HPS

CARDS

Relative risk

0.5 0.7 0.9 1

<0.0001

0.0003

0.001

Event rate (%)

12.6

13.5

9.0

Placebo

9.4

9.3

5.8

Statin

0.63

0.67

0.73

P

Diabetes, no CVD

1.7

*Statin vs placeboHPS = Heart Protection StudyCARDS = Collaborative Atorvastatin Diabetes Study

34.8

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ASCOT-LLA: Atorvastatin reduces CV events in patients with diabetes and hypertension N = 2532, baseline LDL-C 128 mg/dL

Nonfatal MI, CV mortality, UA, stable angina, arrhythmias, stroke, TIA, PAD, retinal vascular thrombosis, revascularization ASCOT-LLA = Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm

Sever PS et al. Diabetes Care. 2005;28:1151-7.

%

14.0

12.0

10.0

8.0

6.0

4.0

2.0

0.00.50.0 1.0 1.5 2.0 2.5 3.0 3.5 Years

Number at risk

Placebo 12311258 1209 1191 1171 1065 699 370

Atorvastatin 12371274 1219 1200 1175 1058 714 375

Atorvastatin 10 mg

Placebo

HR = 0.77 (0.61–0.98)

23% Risk reductionP = 0.036

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HOPE Study Investigators. Lancet. 2000;355:253-9.Daly CA et al. Eur Heart J. 2005;26:1369-78.

PERSUADE(N = 1502)

CV death/MI/cardiac arrest

MICRO-HOPE(N = 3577)

CV death/MI/stroke

MICRO-HOPE, PERSUADE: Reduction in primary outcome with ACEI

Placebo

Ramipril10 mg

25

20

15

10

5

0

%

Follow-up (years)

0 1 2 3 4 5

25% Risk reductionRR 0.75 (0.64–0.88)

P = 0.000420

15

10

5

00 1 2 3 4 5

Follow-up (years)

Placebo

Perindopril8 mg

19% Risk reductionP = 0.131

25

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Steno-2 supports aggressive multifactorial intervention in type 2 diabetes

Gæde P et al. N Engl J Med. 2003;348:383-93.

Objective: Target-driven, long-term, intensified interventionaimed at multiple risk factors compared withconventional therapy

Design: N = 160 patients with type 2 diabetes and microalbuminuria

Intensive treatment targets: BP <130/80 mm Hg

A1C <6.5%

Total-C <175 mg/dL

Triglycerides <150 mg/dL

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Steno-2: Effects of multifactorial intervention on CV outcomesN = 160 with type 2 diabetes and microalbuminuria

Gæde P et al. N Engl J Med. 2003;348:383-93.

53% risk reductionP = 0.01

Follow-up (months)

Primary composite outcome*

(%)

*CV death, MI, stroke, revascularization, amputation

Conventional

Intensive

60

50

40

30

20

10

00 12 24 36 48 60 72 84 96

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Summary

• The majority of patients seen in cardiology practices have insulin resistance

• Synergistic interaction of risk factors associated with insulin resistance places patients at high risk for CV disease

• Current guidelines recommend aggressive multi-factorial treatment in patients with diabetes or prediabetes

• PPAR modulation is a potentially important strategy for improving insulin sensitivity and blunting atherosclerosis progression