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 Pa. Affiliate, Main Line Health System Wynnewood, Pa. Part 2

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

4. Intensive treatment/ standard treatment Weight of study size Odds ratio (95% CI) ParticipantsEvents UKPDS3071/1549426/2598.6%0.75 (0.54–1.04) PROactive*2605/2633164/20220.2%0.81 (0.65–1.00) ADVANCE5571/5569310/33736.5%0.92 (0.78–1.07) VADT892/89977/909.0%0.85 (0.62–1.17) ACCORD5128/5123205/24825.7%0.82 (0.68–0.99) Overall17267/157731182/1136100%0.85 (0.77–0.93) 0.40.60.81.01.21.41.61.8 Intensive treatment betterStandard treatment better *Included on-fatal MI and death from all-cardiac mortality Probability of events of CAD with intensive glucose-lowering vs. standard treatment 2.0 Intensive treatment/ standard treatment Weight of study size Odds ratio (95% CI) ParticipantsEvents UKPDS3071/1549221/14121.8%0.78 (0.62–0.98) PROactive*2605/2633119/14418.0%0.83 (0.64–1.06) ADVANCE5571/5569153/15621.9%0.98 (0.78–1. 23) VADT892/89964/789.4%0.81 (0.58–1.15) ACCORD5128/5123186/23528.9%0.78 (0.64–0.95) Overall17267/15773743/754100%0.83 (0.75–0.93) Intensive treatment betterStandard treatment better Probability of events of non-fatal MI with intensive glucose-lowering vs. standard treatment www.thelancet.com. Vol 373 May 23, 2009. Lancet Meta-analysis 0.40.60.81.01.21.41.61.82.0 0.9% Dec. HbA 1c, 17% Dec. non-fatal MI, 15% Dec. CV events of CAD

5. A Brief Review of Glycemic Control and CV Events Based on Pivotal Trials With Peripheral and Central Acting Hypoglycemics Peripheral ActingCentral Acting ACCORDADVANCEVDATCycloset N10,25111,1401,7913070 Resulting A1c (Duration) -1.1% (1 yr) -0.8% (5 yrs) -1.5% (5.6 yrs) -0.6 to 0.9% (1yr)* CV EndpointsNonfatal MI, nonfatal stroke, or death from CVD MI, stroke, death from CVD, CHF, surgery for vascular disease, inoperable CAD, or amputation for ischemic gangrene MI, stroke, coronary revascularization, hospitalization for congestive heart failure or angina HR of primary outcome (95% CI) 0.90 (0.78–1.04)0.94 (0.84–1.06)0.88 (0.74–1.05)0.58 (0.35-0.96)** HR of mortality (95% CI) 1.22 (1.01–1.46)0.93 (0.83–1.06)1.07 (0.81–1.42)Check with Veroscience Brown A. Nature Review Cardio 2010;7:369-375 Skyler JS. ADA/AHA Statements. Diabetes Care 2009;32:187–192 Gaziano M. Diabetes Care 2010;33:1503-1508 *Efficacy analysis was evaluated at 24 weeks in Met, SU, Met+/-SU and TZD failure patients, 52 weeks in TZD failure patients, 52 weeks for SAE and CV endpoints. **MACE CVD Endpoint – MI, Stroke, CVD Death: HR 0.45 (95% CI 0.2-0.99). bromocriptine-QR

6. But Why was there an apparent increase in Mortality in ACCORD, lack of benefit in ADVANCE, VADT 1.Weight Gain-in ACCORD avg 6 lb, 20%>10kg 2.Hypoglycemia 1.ACCORD recorded PRIOR history mild/severe events- 2. NO DOCUMENTATION OF GLUCOSE AT TIME OF DEATH 3.Highestst risk in those who tried to get good control but did not succeed- eg: variability/ hypoglycemia/ weight gain

7. 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

8. 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

9. But Why was there an apparent increase in Mortality in ACCORD, lack of benefit in ADVANCE, VADT 1.Weight Gain-in ACCORD avg 6 lb, 20%>10kg 2.Hypoglycemia 1.ACCORD recorded PRIOR history mild/severe events- 2. NO DOCUMENTATION OF GLUCOSE AT TIME OF DEATH 3.Highestst risk in those who tried to get good control but did not succeed- eg: variability/ hypoglycemia/ weight gain

11. 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)

12. “Real World” CV Risk of SU and Insulin Pharmacoepidemiology and Drug Safety. 2008;(17):753-759. So benefit of both SU/Insulin in research studies –UKPDS, DCCT/EDIC But adverse risk in ‘real world’ use

13. So given epidemiologic data, CV risk/glucose data and now ADVANCE, VADT, ACCORD, implications of weight gain and hypogycemia, what are/ should be goals (SSS) 1. ADA- stayed at <7.0 AACE – stayed at < 6.5 Lowest possible as long as no undue risk of hypoglycemia and visceral weight gain 2. ADA and AACE- a.Start early in DM - implications for prevention- lifestyle and drug therapy of metabolic syndrome and IGT b. do not aim for aggressive control in those with significant pre-existing CV disease Disagree- lowest possible without hypoglycemia, weight gain 3.Modify goals for ‘elderly’ Disagree- lowest possible without hypoglycemia, weight gain

16. StudySettingPopulationClinical Outcome Furnary, 1999ICU DM undergoing open heart surgery 65%  infection Furnary, 2003ICUDM undergoing CABG 57%  mortality Krinsley, 2004 Medical/surgical ICU Mixed, no Cardiac 29%  mortality Malmberg, 1995CCUMixed 28%  mortality After 1 year Van den Berghe, 2001Surgical ICUMixed, with CABG 42%  mortality Lazar, 2004OR and ICUCABG and DM 60%  A Fib post op survival 2 yr RCT, randomized clinical trial. Kitabchi & Umpierrez. Metabolism. 2008;57:116-120. RCT: Benefits of Tight Glycemic Control – Surgical Studies Van Ber Berge, 2006 MICU Mixed 47% Van Ber Berge, 2009 PICU Mixed Peds 54%  mortality Van Ber Berge, 2006 MICU Mixed 47% Van Ber Berge, 2009 PICU Mixed Peds 54%  mortality

17. RISK OF TOO TIGHT CONTROL OF HYPERGLYCEMIA IN HOSPITALS