1. Diabetes Mellitus 101 for Cardiologists (and Alike): 2015 Stan Schwartz MD,FACP Affiliate, Main Line Health System Emeritus, Clinical Associate Professor of Medicine, U of Pa. 6105472000 An Aggressive Pathophysiologic Approach to Therapy of Type 2 Diabetes in Cardiometabolic Patients: Looking at Diabetes Medications with a Cardiologists Eye Part 3

2. Early Treatment Decreases Micro and Macro Vascular RISK

3. Impact of Intensive Therapy in Type 2 Diabetes Summary of Major Clinical Trials: BUT Subset Evaluations Show Reduced CV Outcomes if shorter duration of DM, without significant pre-existing complications StudyMicrovascularMacrovascularMortality UGDP ↔↔↔ UKPDS ↓↓↔↓↔↓ DCCT/EDIC* ↓↓↔↓↔ ↔ ACCORD ↓↔ ↑ (unadj.), ↔ (adj.) ADVANCE ↓↔↔ VADT ↔↔↔ Initial Trial Long Term Follow-up ↑- likely due to hypoglycemia and weight gain

5. WEIGHT GAIN IN ACCORD TRIAL Avg ~6 lb, 10% >20 lbs

6. Overweight Overweight and Obesity Increase the Risk of CV Disease Mortality 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 weightObese 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

7. Weight Loss Reduces Cardiometabolic Risk Factors in Patients With Type 2 Diabetes -0.8 -0.6 -0.4 -0.2 0 Δ A1C (%) * Δ HDL Cholesterol (mg/dL) * Intensified Lifestyle Intervention, 8.6% Weight Loss Diabetes Support and Education, 0.7% Weight Loss Randomized, controlled trial; n = 5145; Patients with type 2 diabetes, age >18 y; Mean ± SE Intensified lifestyle intervention (n = 2496) vs diabetes support and education (n = 2463) therapy; *P<0.001 between groups Look AHEAD Research Group. Diabetes Care. 2007;30:1374-1383 -40 -30 -20 -10 0 Δ Triglycerides (mg/dL) * -7.5 -5.0 -2.5 0 Δ Blood Pressure (mm Hg) * * 0 1 2 3 4 SystolicDiastolic

10. Consequences of Hypoglycemia Prolonged QT- intervals- Diabetologia 52:42,2009 –Can be of pronged duration IJCP Sup 129, 7/02 –Greater with higher catecholamine levels Europace 10,860 Associated with Angina Diabetes Care 26, 1485, 2003 / Ischemic EKG changes Porcellati, ADA2010 Associated with Arrhythmias Associated with Sudden Death Endocrine Practice 16,¾ 2010 Increased Variabilty- explains highest mortality in intensive group had highest HgA1c in ACCORD ( i ncreases inflammation, ICU mortality Hirsch ADA2010)

13. Cardiovascular effects of Hypoglycemia Clin. Cardiol. (in press) 3 V. Sanon et al: Cardiovascular effects of hypoglycemia Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:10.1002/clc.22288 © 2014 Wiley Periodicals, Inc.