1. Therapy of Type 2 Diabetes Mellitus: UPDATE Glycemic Goals in the Care of Patients with Type 2 Diabetes- 2013 ADA and AACE Guidelines: Room For Improvement (Be HAPPY/ Avoid Burnout, While Caring for Patients with DM) Stan Schwartz MD, FACP, FACE Affiliate, Main Line Health System Clinical Associate Professor of Medicine, Emeritus, U of Pa. stschwar@gmail.com 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 Meinert CL. Diabetes. 1970;19(suppl):789-830. Goldner MG. JAMA. 1971;218(9):1400-1410. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865. Holman RR. N Engl J Med. 2008;359(15):1577-1589. DCCT Research Group. N Engl J Med. 1993;329;977-986. Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. Gerstein HC, et al. N Engl J Med. 2008;358:2545-2559. Patel A, et al. N Engl J Med. 2008;358:2560-2572. Duckworth W, et al. N Engl J Med. 2009;360. *T1DM study. ↑- likely due to hypoglycemia 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

10. Hypoglycemia Outcomes VADT, ACCORD, ADVANCE

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. RISK OF TOO TIGHT CONTROL OF HYPERGLYCEMIA IN HOSPITALS VALUE OF CONTROLLING HYPERGLYCEMIA IN HOSPITAL

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

14. Greater Survival in Elderly (>75yo) with lower HgA1c EASD, 9/2010 So… WHY NOT BE AGGRESSIVE IN GLYCEMIC CONTROL IF… NOT USING HYPOGLYCEMIC AGENTS