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

Faculty Gregg C. Fonarow, MD Eliot Corday Professor of Medicine and Cardiovascular Science Director, Ahmanson-UCLA Cardiomyopathy Center UCLA Division of Cardiology UCLA Medical Center Los Angeles, California

Gregg C. Fonarow, MD

Eliot Corday Professor of Medicine

and Cardiovascular Science

Director, Ahmanson-UCLA Cardiomyopathy Center

UCLA Division of Cardiology

UCLA Medical Center

Los Angeles, California

Disclosure Statement The Network for Continuing Medical Education requires that CME faculty disclose, during the planning of an activity, the existence of any personal financial or other relationships they or their spouses/partners have with the commercial supporter of the activity or with the manufacturer of any commercial product or service discussed in the activity.

The Network for Continuing Medical Education requires that CME faculty disclose, during the planning of an activity, the existence of any personal financial or other relationships they or their spouses/partners have with the commercial supporter of the activity or with the manufacturer of any commercial product or service discussed in the activity.

Faculty Disclosure Statement Gregg C. Fonarow, MD , has served as a consultant to and has received research support and honoraria from Bristol-Myers Squibb Company, GlaxoSmithKline, Merck & Co., Inc., Pfizer Inc, sanofi-aventis, Schering-Plough Corporation, and Scios, Inc. W. Frank Peacock, MD, FACEP , of the Cleveland Clinic in Cleveland, Ohio reports no such relationships.

Gregg C. Fonarow, MD , has served as a consultant to and has received research support and honoraria from Bristol-Myers Squibb Company, GlaxoSmithKline, Merck & Co., Inc., Pfizer Inc, sanofi-aventis, Schering-Plough Corporation, and Scios, Inc.

W. Frank Peacock, MD, FACEP , of the Cleveland Clinic in Cleveland, Ohio reports no such relationships.

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

Polling Question #1 Yes, always Yes, most of the time No Do you screen for diabetes and metabolic syndrome in patients hospitalized with an acute event associated with cardiovascular disease?

Yes, always

Yes, most of the time

No

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.

Metabolic Syndrome: Prevalence of Components* Abdominal obesity 44% Hypertriglyceridemia 33% Low HDL cholesterol 40% High blood pressure or medication use 39% High fasting glucose † or medication use 31% *US adults aged 20 years and older (NHANES 1999-2000 data). † Fasting plasma glucose  100 mg/dL. Ford ES, et al. Diabetes Care. 2004;27:2444-2449. ~ 64 million US residents had the metabolic syndrome in 2000

Abdominal obesity 44%

Hypertriglyceridemia 33%

Low HDL cholesterol 40%

High blood pressure or medication use 39%

High fasting glucose † or medication use 31%

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).

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.

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

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

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.

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

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

Association of Insulin Resistance With Cardiovascular Risk Factors and Atherosclerosis Central Obesity Impaired thrombolysis  PAI-1  tPA Atherosclerosis Insulin resistance McFarlane SI, et al. J Clin Endocrinol Metab . 2001;86:713-718. Glucose intolerance AGEs Hypertension Endothelial dysfunction  VCAM, E-selectin  NO Inflammation  CRP  IL-6 Dyslipidemia Low HDL Small, dense LDL particles Hyper-triglyceridemia

Impaired thrombolysis

 PAI-1

 tPA

Glucose intolerance

AGEs

Endothelial dysfunction

 VCAM,

E-selectin

 NO

Inflammation

 CRP

 IL-6

Dyslipidemia

Low HDL

Small, dense LDL particles

Hyper-triglyceridemia

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

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

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

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

Inpatient Management of Hyperglycemia and Diabetes American College of Endocrinology Task Force on Inpatient Diabetes and Metabolic Control Values above 180 mg/dL are an indication to monitor glucose levels more frequently to determine need, if any, for more intensive intervention Targets for non-ICU patients are supported only by prospective observational studies Separate targets for pregnant patients (not shown) American College of Endocrinology. Endocr Pract. 2004;10:77-82. 180 mg/dL (10.0 mmol/L) 110 mg/dL (6.1 mmol/L) 110 mg/dL (6.1 mmol/L) Maximal Glucose Preprandial Intensive Care Unit Noncritical Care Units Upper Limits for Glycemic Targets

Values above 180 mg/dL are an indication to monitor glucose levels more frequently to determine need, if any, for more intensive intervention

Targets for non-ICU patients are supported only by prospective observational studies

Separate targets for pregnant patients (not shown)

Inpatient Management of Metabolic Syndrome Evaluate all patients with hyperglycemia for metabolic syndrome Patients with hyperglycemia but no diabetes diagnosis during hospitalization should receive a written plan for follow-up testing after discharge Treatment of the metabolic syndrome often requires more than one pharmacotherapeutic agent for each component Interventions aimed at reducing the burden of obesity in the US would reduce the risk for metabolic syndrome Selig PM. AACN Clin Issues. 2006;17:79-85.

Evaluate all patients with hyperglycemia for metabolic syndrome

Patients with hyperglycemia but no diabetes diagnosis during hospitalization should receive a written plan for follow-up testing after discharge

Treatment of the metabolic syndrome often requires more than one pharmacotherapeutic agent for each component

Interventions aimed at reducing the burden of obesity in the US would reduce the risk for metabolic syndrome

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

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

Current Approaches to Treating Obesity Diet, exercise, and behavioral therapy continue to be the mainstays of obesity treatment Short-term efficacy of pharmacotherapy has been noted in clinical trials Side effects of pharmacologic therapy vary and may impact administration Surgery is reserved for morbidly obese patients with comorbidities

Diet, exercise, and behavioral therapy continue to be the mainstays of obesity treatment

Short-term efficacy of pharmacotherapy has been noted in clinical trials

Side effects of pharmacologic therapy vary and may impact administration

Surgery is reserved for morbidly obese patients with comorbidities

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*

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

Rimonabant, the First CB 1 Blocker: May Affect Multiple Targets Brain  Food intake Rimonabant Adipocyte Central Peripheral CB 1 CB 1 Adiponectin:  Insulin resistance  Triglycerides  Glucose tolerance  HDL cholesterol Weight loss

Adiponectin:

 Insulin resistance

 Triglycerides

 Glucose tolerance

 HDL cholesterol

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

Placebo-subtracted Change in Metabolic Syndrome Parameters in 4 Rimonabant Trials Mean (+ SEM) * * * * * * * * * * * * Pi-Sunyer FX, et al. JAMA. 2006;295:761-775. Van Gaal LF, et al. Lancet. 2005;365:1389-1397. Despr és JP, et al. N Engl J Med . 2005;353:2121-2134. Scheen AF. Presented at: 65th Annual Scientific Sessions of the ADA; June 12, 2005; San Diego, Calif. HDL Cholesterol, % 7.2 8.9 8.1 8.4 -20 -15 -10 -5 0 5 10 % Waist Circumference, cm -3.6 -4.2 -4.7 -3.3 -6 -5 -4 -3 -2 -1 0 cm Triglycerides, % -13.2 -15.1 -12.4 -16.4 -20 -15 -10 -5 0 5 10 % Systolic Blood Pressure, mm Hg -1.2 -1.7 -2.3 -0.2 -3 -2.5 -2 -1.5 -1 -0.5 0 0.5 mm Hg *P <.001 *P <.001 *P <.001 NS NS *P <.05 *P <.05 N = >6600; ITT, LOCF RIO - North America 1 RIO - Europe 2 RIO - Lipids 3 RIO - Diabetes 4

Pi-Sunyer FX, et al. JAMA. 2006;295:761-775.

Van Gaal LF, et al. Lancet. 2005;365:1389-1397.

Despr és JP, et al. N Engl J Med . 2005;353:2121-2134.

Scheen AF. Presented at: 65th Annual Scientific Sessions of the ADA; June 12, 2005; San Diego, Calif.

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

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.

Summary The prevalence of obesity and diabetes is increasing dramatically Metabolic syndrome, a precursor to CVD and diabetes, also is increasing dramatically Obesity is a major risk factor for diabetes and CVD, and the driving force behind the metabolic syndrome Weight reduction and exercise are the cornerstone of cardiometabolic risk reduction Pharmacotherapy can be used along with lifestyle intervention to reduce cardiometabolic risk factors

The prevalence of obesity and diabetes is increasing dramatically

Metabolic syndrome, a precursor to CVD and diabetes, also is increasing dramatically

Obesity is a major risk factor for diabetes and CVD, and the driving force behind the metabolic syndrome

Weight reduction and exercise are the cornerstone of cardiometabolic risk reduction

Pharmacotherapy can be used along with lifestyle intervention to reduce cardiometabolic risk factors

Featured Institution Cleveland Clinic Foundation Cleveland, Ohio

Polling Question #2 We are currently on the same item We have since moved to the next checkbox on the checklist We have progressed by more than one item on the checklist ACS pathways are up-to-date and regularly followed If you participated in a previous teleconference, how much progress have you made since then? (Please refer to the checklists on the next 3 slides.)

We are currently on the same item

We have since moved to the next checkbox on the checklist

We have progressed by more than one item on the checklist

ACS pathways are up-to-date and regularly followed

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 

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 

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? 

Question-and-Answer Session

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)