1. VBWG Insulin Resistance and Cardiovascular Disease: New Perspectives From Vascular Biology

2. VBWG I.CV disease and insulin resistance: Challenges and opportunities II.New perspectives in cardioprotection: Focus on PPAR  activation III.Insulin sensitizers: Surrogate and clinical outcomes studies IV.Identifying and treating patients with insulin resistance Contents

3. VBWG Cardiovascular Disease and Insulin Resistance: Challenges and Opportunities

4. VBWG The majority of Americans do not follow a healthy lifestyle 24 59.9 76.7 77.8 0 20 80 100 2000 Behavioral Risk Factor Surveillance System; N = 153,805 % Respondents Smokers Reeves MJ, Rafferty AP. Arch Intern Med. 2005;165:854-7. BMI ≥25 kg/m 2 Consumes fruits/vegetables <5x/day Infrequent exercise (<5x/week) 60 40

5. VBWG Numbers of persons with diabetes will more than double by 2030 0 10 20 30 40 2002 118% increase US population with diabetes (millions) AHA. Heart Disease and Stroke Statistics–2005 Update. Wild S et al. Diabetes Care. 2004;27:1047-53. 2030 13.9 30.3 Year

6. VBWG Increasing problem of obesity and diabetes among US adults *Jan–SepCDC. 2005 NHIS. www.cdc.gov/nchs/nhis/released200603.htm. Accessed April 2006. Obesity (BMI ≥30 kg/m 2 ) US adults (%) 30 0 8 0 Diabetes 31% increase 36% increase 19.4 1997 25.4 2005* 5.3 1997 7.2 2005* 154

7. VBWG Cumulative lifetime risk for diagnosis of diabetes Adapted from Narayan et al. JAMA. 2003;290:1884-90. 55 Risk of diagnosis of diabetes (%) 0 50 45 40 35 30 25 20 15 10 5 0 2030405060708090100 Hispanic males Non–Hispanic black males Non–Hispanic white males Hispanic females Non–Hispanic black females Non–Hispanic white females Age (years)

8. VBWG Cardiac rehabilitation Savage PD et al. Am Heart J. 2005;149:627-31. Milani RV, Lavie CJ. Am J Cardiol. 2003;92:50-4. Curran PJ et al. J Am Coll Cardiol. 2004;43(suppl A):249A. Over half of patients referred to cardiologists have insulin resistance syndrome N = 1912 Savage, 2005 Patients with insulin resistance syndrome (%) 50 58 59 0 20 40 60 N = 235 Milani, 2003 N = 85 Curran, 2004 Acute MI

9. VBWG Patients (%) Norhammar A et al. Lancet. 2002;359:2140-4. Undiagnosed diabetes 66 Almost 70% of patients with first MI have IGT or undiagnosed diabetes N = 181 consecutive patients admitted to CCU 35 31 0 10 30 50 70 Impaired glucose tolerance (IGT) Glucose tolerance test results

10. VBWG Role of obesity in insulin resistance Adapted from Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9. Visceral Obesity  Caloric intake Sedentary lifestyle Genetic factors  Free fatty acids  Glucose  Lipids Oxidative stress Inflammation Insulin resistance

11. VBWG Elevated glucose increases risk in elderly patients with acute MI Kosiborod M et al. Circulation. 2005;111:3078-86. Cooperative Cardiovascular Project 1994–1996; N =141,680 0 20 40 60 80 100 110>110–140>140–170>170–240>240 Glucose groups (mg/dL) Without diabetesWith diabetes Mortality rate (%) ≤

12. VBWG Insulin resistance associated with coronary vasomotor abnormalities Myocardial blood flow (MBF) response to cold pressor test Insulin sensitiveInsulin resistant 0 25 50 75  MBF* (%) P = 0.003 Quiñones MJ et al. Ann Intern Med. 2004;140:700-8. *vs baseline

13. VBWG Insulin resistance to diabetes: Coronary vasomotor abnormalities progressively worsen Prior JO et al. Circulation. 2005;111:2291-8. *vs baseline † P < 0.05 vs insulin sensitive Cold pressor test Insulin sensitive Insulin resistant IGT Diabetes + Hypertension –10 0 10 20 30 40 14 7 Diabetes 10 –2 44  MBF* (%) † † † †

14. VBWG Patients (%) Leoncini G et al. J Intern Med. 2005;257:454-60. Insulin resistance increases risk of target organ damage in hypertension 10 40 19 59 0 15 30 45 60 Microalbuminuria* LV hypertrophy With insulin resistance syndrome* Without insulin resistance syndrome* *Modified ATP III definition P = 0.04 P = 0.003 N = 354 with untreated hypertension

15. VBWG Clinical manifestations of insulin resistance Type 2 diabetes and glycemic disorders Dyslipidemia – Low HDL – Small, dense LDL – Hypertriglyceridemia Hypertension Endothelial dysfunction/ inflammation (hsCRP) Impaired thrombolysis  PAI-1 Visceral Obesity Insulin resistance Glucotoxicity Lipotoxicity  Adiponectin Atherosclerosis Courtesy of Selwyn AP, Weissman PN.