1. CVD Critical Pathways Group 2006 Teleconferences This activity is supported by an educational grant from the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. October 11, 2006

5. Diabetes and Metabolic Syndrome in Patients Hospitalized With CVD Gregg C. Fonarow, MD

7. Diagnose by presence of 3 or more risk factors Adapted with permission from Grundy SM, et al. Circulation. 2005;112:2735-2752. AHA/NHLBI-Modified ATP III Criteria for the Metabolic Syndrome Risk Factor Defining Level Abdominal obesity Waist circumference* Men >40 in Women >35 in Triglycerides, mg/dL  150 HDL-C, mg/dL Men <40 Women <50 BP, mm Hg  130/≥85 Fasting glucose, mg/dL  100 *Lower cutpoints for Asian Americans.

9. 1 in 4 Adults Have Diabetes or the Metabolic Syndrome ~ 64 14.6 6.2 Undiagnosed diabetes* Diagnosed diabetes* Metabolic syndrome † Population at risk (millions) 12 8 4 0 35 15 5 0 25 Diagnosed diabetes Metabolic syndrome White Black Hispanic Other White Black Hispanic Other Prevalence, %, age ≥18 yrs Prevalence, %, age ≥20 yrs Mokdad AH, et al. JAMA . 2003;289:76-79. Ford ES, et al. JAMA . 2002;287:356-359. Ford ES, et al. Diabetes Care . 2004;27:2444-2449. 10 6 2 30 20 10 *2005 US data, NIDDK, NIH. † Based on revised NCEP/ATP III definition (NHANES 2000 data).

10. Risk Factors Associated With the Metabolic Syndrome (NHANES 1999-2000) 90.9 73.9 77.0 41.5 73.9 15.1 36.6 14.9 24.9 7.2 26.5 5.6 0 20 40 60 80 100 High Waist Circumference High Triglycerides Low HDL-C High Fasting Glucose High BP CVD History Percentage Metabolic syndrome Without metabolic syndrome Adapted from Ford ES, et al. JAMA. 2002;287:356-359.

11. Metabolic Syndrome Predicts Incidence of Diabetes Independently of Impaired Glucose Tolerance San Antonio Heart Study (N = 1734 ) Lorenzo C, et al. Diabetes Care . 2003;26:3153-3156. *ATP III definition. 60 50 40 30 20 10 0 No Yes Metabolic syndrome* Diabetes, % P = .018 P <.0001 P <.0001 Impaired Glucose Tolerance Yes No

12. Cardiovascular Disease Mortality and the Metabolic Syndrome Follow-up, Years Cumulative Hazard, % RR = 3.55 (95% CI, 1.96-6.43) 866 288 852 279 834 234 292 100 Yes No Metabolic Syndrome?* Metabolic Syndrome Controls *Based on factor analysis; men in highest quarter of distribution of the metabolic syndrome factor were considered to have metabolic syndrome. Reproduced with permission from Lakka HM, et al. JAMA. 2002;288:2709-2716. 12 10 8 6 4 2 0 0 5 10 15

13. Clustering of Risk Factors Increases Mortality in Post-CABG Patients: 8-Year Follow-up Obesity, Diabetes, Hypertension, Hypertriglyceridemia Sprecher DL, Pearce GL. J Am Coll Cardiol. 2000;36:1159-1165. 50 45 40 35 30 25 20 15 10 5 0 0 1 2 3 4 Number of Risk Factors Mortality, % P <.001 for relationship of increasing number of risk factors to mortality Men Women N = 6428; deaths = 860.

14. Overweight and Obesity Increase the Risk of Cardiovascular Disease Mortality Overweight Data are from 1 million men and women (average age, 57 years) followed for 16 years who never smoked and had no history of disease at enrollment. Calle EE, et al. N Engl J Med. 1999;341:1097-1105. Normal weight Obese Relative Risk of Cardiovascular Disease Mortality 0.6 3.0 2.6 2.2 1.8 1.4 1.0 >18 25 30 > 40 BMI, kg/m 2 Women Men

15. The Ticking Clock:  CV Risk Before  Glucose Nurses’ Health Study; 20-year follow-up of 117,629 women Hu FB, et al. Diabetes Care . 2002;25:1129-1134. Relative risk of MI or stroke No diabetes throughout study Risk of event prior to diabetes diagnosis Risk of event after diabetes diagnosis Diabetes at baseline 5.0 3.7 2.8 1.0 6 4 2 0

17. Waist Circumference Correlates With BP and Insulin Resistance 768 men with fasting glucose ≤126 mg/dL (≤7 mmol/L) Siani A, et al. Am J Hypertens . 2002;15:780-786. P <.001 for trend in each parameter. 50 40 30 20 10 0 50 40 30 20 10 0 High blood pressure Insulin resistance Quintiles of Waist Circumference % I II III IV V I II III IV V

18. Link Between Hyperglycemia and Poor Hospital Outcomes Clement S et al. Diabetes Care. 2004;27:553-591. Metabolic stress response  Stress hormones and peptides Prolonged hospital stay Disability Death  Glucose  Insulin  FFA  Ketones  Lactate Immune dysfunction Infection dissemination  Reactive O 2 species  Transcription factors  Secondary mediators Cellular injury/apoptosis Inflammation Tissue damage Altered tissue/wound repair Acidosis Infarction/ischemia

19. Increasing Glucose Levels Increase Long-Term Mortality in ACS Bhadriraju S, et al. Am J Cardiol. 2006;97:1573-1577. OPUS-TIMI 16 trial; 10,288 patients with ACS Quartile 1=<101 mg/dL Quartile 2=101–120.6 mg/dL Quartile 3=120.6–157 mg/dL Quartile 4=>157 mg/dL 1 .95 .9 .85 Days of Follow-up Cumulative Survival 0 100 200 300 P for trend across group=0.006 Quartile 1 Quartile 2 Quartile 3 Quartile 4

20. Hyperglycemia Increases In-Hospital Complications and Long-Term Mortality 1. Foo K, et al. Heart . 2003;89:512-516. 2. Kosiborod M, et al. Circulation. 2005;111:3078-3086. N=2,127 patients with AMI or unstable angina 1 Q 1= ≤5.8 mmol/L; Q2= ≤7.2; Q3=≤10.0; Q4=>10.0. Cooperative Cardiovascular Project; N=141,680 elderly patients hospitalized with AMI 2 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 70 120 170 220 270 320 370 Glucose (mg/dl) Mortality Rate Diabetes: No P <.001 for interaction Diabetes: Yes One-Year Mortality <.0001 2.80 (1.74 to 4.50) Q4 1.73 (1.06 to 2.83) Q3 1.10 (0.66 to 1.86) Q2 1.00 Q1 Glucose P Value Odds Ratio Comparison Variable Multivariate Predictors of Left Ventricular Failure

23. Management of Cardiovascular Risk in Patients With Abdominal Obesity Hypertension Type 2 diabetes Dyslipidemia Risk factors Coronary heart disease Treat the complications? Manage coronary heart disease risk Adapted with permission from Després JP, et al. BMJ . 2001;322:716-720. Treat the cause Abdominally obese patient at increased cardiometabolic risk

24. Effect of Interventions on Weight Change and Risk of Diabetes and Metabolic Syndrome Knowler WM, et al; Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403. Diabetes Prevention Program -8 -0.1 Weight Change, kg -6 -4 -2 0 PB (n = 1082) LS (n = 1079) MET (n = 1073) -5.6* -2.1* *P <.001 vs placebo % Reduction in Incidence of Diabetes -60 -40 -20 MET LS -58* -31 *P <.05 vs metformin -50 -40 -30 -20 -10 0 MET LS Reduction in Risk of Metabolic Syndrome, % -17% † -41%* Risk of developing metabolic syndrome n=1523 LS = lifestyle intervention; MET = metformin; PB = placebo. Orchard TJ, et al; Diabetes Prevention Program Research Group. Ann Intern Med . 2005;142:611-619. * P <.001; † P = .03

26. Most Widely Prescribed Drugs for Treating Obesity *Approved for OTC use in January 2006. Adapted from Yanovski SZ, Yanovski JA. N Engl J Med. 2002;346:591-602. Phentermine Year Approved Approved Use DEA Schedule 1997 Long term IV 1973 Short term IV 1999 Long term None Generic Name Sibutramine Orlistat*

27. Current Therapies Often Address Individual Risk Factors  Waist circumference  Blood pressure  Blood glucose  Triglycerides  HDL-cholesterol  LDL-cholesterol Insulin resistance  Thrombotic risk NCEP ATP III definition of the metabolic syndrome Antiplatelet agents Lipid modifiers Insulin sensitizers Antihypertensives Oral antidiabetic agents

29. R imonabant I n O verweight/ O besity Trials 1 year 1045 Obese or overweight with type 2 diabetes RIO-Diabetes 1 year 1036 Obese or overweight with untreated dyslipidemia (diabetes excluded) RIO-Lipids 2 years 1507 Obese or overweight with/without comorbidities (except diabetes) RIO-Europe 1+1 year Re-randomized 3045 Obese or overweight with/without comorbidities (except diabetes) RIO-North America Design Population Study N

31. RIO-North America: Change in Metabolic Syndrome Status Pi-Sunyer FX, et al. JAMA. 2006;295:761-775. Baseline 1-Year Treatment ITT, LOCF Patients, % 31.7% 34.8% 29.2% 21.2% 0 10 20 30 40 Placebo Rimonabant 20 mg P <.001

32. Pooled RIO Studies: Overall Safety Year 1 Year 2 Subjects discontinued due to adverse event Subjects with any serious adverse event* Subjects with any adverse event 4.7% 5.4% 77.0% 4.5% 4.7% 74.4% 4.7% 4.5% 76.7% 86.0% 82.9% 81.8% 13.8% 8.8% 7.2% 5.9% 5.4% 4.2% (n = 466) Placebo (n = 663) Rimonabant 5 mg (n = 688) Rimonabant 20 mg Rimonabant 20 mg (n = 2503) (n = 1602) (n = 2520) Rimonabant 5 mg Placebo Includes all deaths occurring in all four RIO studies: 4 on placebo, 3 on rimonabant 5 mg, 4 on rimonabant 20 mg. RIO- North America RIO- Europe RIO- Lipids RIO- Diabetes RIO- North America RIO- Europe Scheen A, et al. Presented at: American Diabetes Association 65th Annual Scientific Sessions; June 12, 2005; San Diego, Calif.

34. Featured Institution Cleveland Clinic Foundation Cleveland, Ohio

36. Progress Checklist: Immediate Goals Circulate discharge plan and other tools to all cardiology, ED, and CV nursing staff for comments  Circulate pathways to all cardiology, ED, and CV nursing staff for comments  Develop draft pathways  Assemble team and set up meeting of working group 

37. Progress Checklist: Short-term Goals/Activities Grand rounds/conference: Cardiology/IM  Grand rounds/conference: Emergency Dept.  Grand rounds/conference: Nursing  Circulate memo  Launch critical pathways  Finalize critical pathways 

38. Progress Checklist: Long-term Goals/Activities  NRMI  AHA Get With the Guidelines  ACC National Cardiovascular Data Registry  CRUSADE  GRACE  REACH  Other Monitor data: Which registry? 

39. Question-and-Answer Session

40. Concluding Remarks Gregg C. Fonarow, MD Next Program Highlights From the 2006 Transcatheter Cardiovascular Therapeutics (TCT) Conference Christopher P. Cannon, MD Wednesday, November 8, 2006 12:00 Noon Eastern Time (9:00 AM Pacific Time)