1. Diabetes Mellitus 101 for Medical Professionals An Aggressive Pathophysiologic Approach to Cardiometabolic Therapy for Type 2 Diabetes: Stanley Schwartz, MD, FACE, FACP Emeritus, Clinical Associate Professor of Medicine, University of Pennsylvania Affiliate, Main Line Health System, Wynnewood, Pennsylvania stschwar@gmail.com 6105472000 Part 1

2. Natural History of Type 2 Diabetes IR phenotype Atherosclerosis obesity hypertension  HDL,  TG, HYPERINSULINEMIA Endothelial dysfunction PCO,ED Envir.+ Other Disease Obesity (visceral) Poor Diet Inactivity Insulin Resistance Risk of Dev. Complications ETOH BP Smoking Eye Nerve Kidney  Beta Cell Secretion Genes Blindness Amputation CRF Disability MI CVA Amp Age 0-1515-40+15-50+25-70+ Macrovascular Complications IGT Type II DM Microvascular Complications DEATH pp>7.8

4. Natural History of Type 2 Diabetes IR phenotype Atherosclerosis obesity hypertension  HDL,  TG, HYPERINSULINEMIA Endothelial dysfunction PCO,ED Envir.+ Other Disease Obesity (visceral) Poor Diet Inactivity Insulin Resistance Risk of Dev. Complications ETOH BP Smoking Eye Nerve Kidney  Beta Cell Secretion Genes Blindness Amputation CRF Disability MI CVA Amp Age 0-1515-40+15-50+25-70+ Macrovascular Complications IGT Type II DM Microvascular Complications DEATH pp>7.8

5. Why Bother to Treat Agressively?

7. One third of adults with diabetes are undiagnosed  ~10% of US adults have diabetes/~20 million persons in 2005  Nearly one third don’t know they have diabetes  26% of US adults have impaired fasting glucose (IFG)* *100–125 mg/dL Cowie CC et al. Diabetes Care. 2006;29:1263-8. NIDDK. National Diabetes Statistics. www.diabetes.niddk.nih.gov. Total: 35% of US adults with diabetes or IFG ~73.3 million persons

8. Considering the Epidemic of Metabolic Syndrome, Prediabetes, Prevention Data, Undiagnosed Diabetes- ER Office and Pre-Admission IDENTIFICATION IS CRITICAL! Family history: whether parents or siblings have had diabetesFamily history: whether parents or siblings have had diabetes Obesity: especially with an increase in abdominal girthObesity: especially with an increase in abdominal girth High-risk ethnic group: African Americans, Hispanics, Native Americans, Asians, and Pacific IslandersHigh-risk ethnic group: African Americans, Hispanics, Native Americans, Asians, and Pacific Islanders Age: we’re looking at all ages, if patient seems at riskAge: we’re looking at all ages, if patient seems at risk Impaired fasting glucose or impaired glucose toleranceImpaired fasting glucose or impaired glucose tolerance Hypertension: blood pressure ≥ 140/90 mm Hg in adultsHypertension: blood pressure ≥ 140/90 mm Hg in adults High density lipoproteins < 35 mg/dL or triglyceride levels ≥ 250 mg/dLHigh density lipoproteins < 35 mg/dL or triglyceride levels ≥ 250 mg/dL Gestational diabetes or given birth to an infant weighing > 9 poundsGestational diabetes or given birth to an infant weighing > 9 pounds Pre-adm, pre-cath, pre-op, pre-CABGPre-adm, pre-cath, pre-op, pre-CABG FBS >100, ppg >140, POC HgA1c >6.0

9. 9 Hyperglycemia Spike PPG Continuous A1C Acute toxicity Chronic toxicity Tissue lesion Diabetic complications (Brownlee hypothesis) Microvascular Macrovascular RetinopathyNephropathyNeuropathyPVD MIStroke American Diabetes Association. At: http://www.diabetes.org/diabetes-statistics/complications.jsp. Brownlee M. Diabetes mellitus: theory and practice. Elsevier Science Publishing Co., Inc; 1990:279-291. Ceriello A. Diabetes. 2005;54:1-7. Hyperglycemia Leads to Complications: Risk Starts with Pre-Diabetes 21% 18% 12% % of pts. with complication at DX 60% ASVD

10. FBS>126 Ppg>200 New Hyperglycemia #223 (12%) Known Diabetes #495 (26%) Normo- Glycemia #1168 Mortality, total 16 3 1.7 Mortality, ICU 31 11 10 Mortality, non-ICU 10 1.7 0.8 LOS 9 5.5 4.5 ICU Admission 29 14 9 D/c Dispo. Home 56 74 84 Transition Care 20 15 10 Nursing Home 8 9 4 RISK OF UNRECOGNIZED HYPERGYCEMIA: Effect of Hyperglycemia on Mortality, LOS, ICU admission, D/C Disposition Umpierrez, JCEM 2002;87:978

11. Metabolic Sydrome, IGT, Diabetes, CV Disease 1. Beginning at 83 mg/dL, rising 2-hr pp glucose levels correlated linearly with CHD mortality 2. Even mild glucose elevations (fbs >110) increase mortality in patients undergoing PCI 3. Almost 70% of patients with first MI have IGT or undiagnosed diabetes 4. In multiple studies stress hyperglycemia in AMI is associated with 3-10 x mortality risk in patients without known diabetes 5. In a group of >31,000 patients without known diabetes but with CV disease (CVD), patients, an 18 mg/dL-higher FPG was associated with a 23% increase in the risk of hospitalization for HF 6. Inc mortality in hosp if admitted wth CVA

12. Cardiovascular disease and diabetes Bell DSH. Diabetes Care. 2003;26:2433-41. Centers for Disease Control (CDC). www.cdc.gov. T2DM = type 2 diabetes mellitus Cardiovascular complications of T2DM ~65% of deaths are due to CV disease Coronary heart disease deaths  2- to 4-fold Stroke risk  2- to 4- fold Heart failure  2- to 5-fold No A1C threshold is apparent Finnish study by Kuusisto et al; UKPDS epidemiologic analysis; EPIC-Norfolk Study Impaired glucose tolerance (IGT) and postprandial hyperglycemia are CV risk factors Funagata Diabetes Study; Honolulu Heart Program; DECODE Study; Rancho Bernardo Study

13. A1C Predicts Coronary Heart Disease in Type 2 Diabetes Khaw KT et al. Ann Intern Med. 2004;141:413-420. 3.8 1.7 6.4 2.1 8.7 3 10.2 7.3 16.7 9.6 28.4 16.2 21.9 15.7 0 5 10 15 20 25 30 <5.0%5.0%- 5.4% 5.5%- 5.9% 6.0%- 6.4% 6.5%- 6.9%  7.0% Known diabetes Men Women CHD events (events/100 persons) A1C concentration* *P<0.001 for linear trend across A1C categories.

14. High Risk of Cardiovascular Events in Type 2 Diabetes Cardiovascular deaths 0 5 10 15 20 25 30 35 40 45 50 7-year incidence of cardiovascular events (%) Myocardial infarction Stroke - + No diabetes Type 2 diabetes Prior myocardial infarction - + Haffner, NEJM 1998, 229-234

15. THE PREVALENCE OF CHRONIC ANGINA POSES A SIGNIFICANT BURDEN TO THE US HEALTH CARE SYSTEM ~16 million Americans have CHD ~9.1 million Americans have angina pectoris 500,000 new cases are reported annually Mean angina frequency is ~2 episodes per week > 18 million episodes each week or ~30 episodes each second American Heart Association. Heart Disease and Stroke Statistics, 2008 Update. Pepine CJ, et al. Am J Cardiol. 1994;74:226-231. New Cases of Stable Angina Per Year (Among Americans ≥ 45 Years of Age) Men Total Incidence (# of New Cases) 320,000 180,000 500,000 Women

16. SEVERITY OF ANGINA SYMPTOMS PREDICTS POOR SURVIVAL MORTALITY IN VA PATIENTS (N=8900) WITH CAD Mozaffarian D, et al. Am Heart J. 2003;146:1015-1022. Years 0 0.74 1 01234 *p<0.001 for log-rank test for equality of survivor function 75-100 50-74 25-49 0-24 Survival According to Physical Limitation Due to Angina (Seattle Angina Questionnaire Score) Little to no limitation Greatest limitation: 2.5 fold higher risk of death Mild limitation: 27% higher risk of death Moderate limitation: 61% higher risk of death After adjustment for potential confounders, greater physical limitation due to angina was associated with increased risk of death compared with patients with little or no limitation

18. Pathophysiology of Diabetic Complications: Implications for Goals of Therapy I Metabolic Disorder Glucose, insulin hormones, enzymes, metabolites, etc. (i.e., control) II Individual Susceptibility Genetic/ethnic ?Acquired III Modulating Factors Hypertension, diet, smoking, etc. Delayed Complications Retinal, renal neural, CV, cutaneous, etc. IV Early V Late Point of metabolic “no return” Epidemiology 1.Hyperglycemia is a continuous Risk Factor 2.No A1C threshold is apparent 3.Worse >A1C, longer duration DM Mechanisms 1.Unified Theory of Brownlee 2.Oxidative stress 3.AGE, PKC, Hexosamine, Aldose Reductase Eg: Macro- albuminuria; Proliferative retinopathy