Diabetes Mellitus 101 for Medical Professionals

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

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 Initial Trial Long Term Follow-up ↑- likely due to hypoglycemia and weight gain

4. Lancet Meta-analysis 0.9% Dec. HbA1c, 17% Dec. non-fatal MI, 15% Dec. CV events of CAD Probability of events of non-fatal MI with intensive glucose-lowering vs. standard treatment 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Intensive treatment better Standard treatment better Probability of events of CAD with intensive glucose-lowering vs. standard treatment 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Intensive treatment better Standard treatment better www.thelancet.com. Vol 373 May 23, 2009. *Included on-fatal MI and death from all-cardiac mortality

5. bromocriptine-QR A Brief Review of Glycemic Control and CV Events Based on Pivotal Trials With Peripheral and Central Acting Hypoglycemics *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). 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

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

7. 3.0 2.6 2.2 1.8 1.4 1.0 0.6 Overweight and Obesity Increase the Risk of CV Disease Mortality Men Women Relative Risk of Cardiovascular Disease Mortality Normal weight Overweight Obese >18 25 30 >40 BMI, kg/m2 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.

8. Weight Loss Reduces Cardiometabolic Risk Factors in Patients With Type 2 Diabetes Intensified Lifestyle Intervention, 8.6% Weight Loss Diabetes Support and Education, 0.7% Weight Loss 4 0 * 3 -0.2 Δ HDL Cholesterol (mg/dL) Δ A1C (%) -0.4 2 -0.6 1 * -0.8 0 Systolic Diastolic 0 0 -10 -2.5 Δ Triglycerides(mg/dL) Δ Blood Pressure(mm Hg) * -20 -5.0 -30 * -7.5 * -40 Randomized, controlled trial; n = 5145; Patients with type 2 diabetes, age >18 y; Mean ± SEIntensified 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

9. But Why was there an apparent increase in Mortality in ACCORD, lack of benefit in ADVANCE, VADT • Weight Gain-in ACCORD avg 6 lb, 20%>10kg • Hypoglycemia • ACCORD recorded PRIOR history mild/severe events- • NO DOCUMENTATION OF GLUCOSE AT TIME OF DEATH • 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 ( increases inflammation, ICU mortality Hirsch ADA2010)

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

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- • 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 • Modify goals for ‘elderly’ • Disagree- lowest possible without hypoglycemia, weight gain

16. RCT: Benefits of Tight Glycemic Control – Surgical Studies Van Ber Berge, 2006 MICU Mixed 47% Van Ber Berge, 2009 PICU Mixed Peds 54%  mortality RCT, randomized clinical trial. Kitabchi & Umpierrez. Metabolism. 2008;57:116-120.

17. RISK OF TOO TIGHT CONTROL OF HYPERGLYCEMIA IN HOSPITALS