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 6

2. Central mechanisms S atiety- appetite suppression Biologic clock

3. Implications for Therapy  Understand and Treat Central Mechanisms IR  Understand and Treat Peripheral IR- fat, liver, muscle  Understand and Treat Inflammation  Understand and Treat Biome

4. Then Learned we have same solution Diurnally- Increased IR at Night Daytime Nightime

5. ADAPTIVE IR MAL-ADAPTIVE IR AM in diurnal Variation of IR PM in diurnal Variation of IR

6. hyperinsulinemia

7. Bromocryptine QR: Proposed mechanism of action Morning administration (within 2 hours of waking) of AGENT Corrects Restoration of morning peak in dopaminergic activity (via D2 receptor-mediated activity) Decreased postprandial glucose levels Reduction in insulin resistance Day-long reduction in plasma glucose, TGs and FFAs  Sympathetic tone  HPA axis tone  Hepatic gluconeogenesis  FFA and TG  Insulin resistance  Inflammation/hypercoagulation Low dopaminergic tone in hypothalamus in early morning in diabetes  Sympathetic tone  HPA axis tone  Hepatic gluconeogenesis  FFA and TG  Insulin resistance  Inflammation/hypercoagulation Impaired glucose metabolism, hyperglycemia and insulin resistance Adverse cardiovascular pathology 7 Fonseca. Use of Dopamine agonists in Type-2-Diabetes. Oxford American Pocket Cards. OUP, 2010 Cincotta. Hypothalamic role in Insulin Resistance and insulin Resistance Syndrome. Frontiers in Animal Diabetes Research Series. Taylor and Francis, Eds Hansen, B Shafrir, E London, pp 271-312, 2002

8. Bromocriptine-QR (Cycloset) Holt RIG, et al. Diabetes, Obesity and Metabolism 12: 1048–57, 2010 Dosing: Start with 0.8 mg (one tablet) within two hours of awakening in the AM. Increase weekly as tolerated to target dose of 1.6 to 4.8 mg upon awakening

9. *MI, Stroke, hospitalization unstable angina, hospitalization CHF, or coronary revasc. KM Curve: the separation in favor of Cycloset begins 3 months and persists through the end of the study HR 0.58; 95% CI, 0.35-0.96 RRR=42% KM Curve – Fast-Acting Bromocryptine Safety Trial Cumulative Percent Composite CVD Endpoint Gaziano M. Diabetes Care 2010, March 23 online

10. Bromocriptine-QR (N=2054), n (%) * Placebo (N=1016), n(%) * * Hazard Ratio (95% CI) CV death-inclusive composite cardiovascular end point 39 (1.9)33 (3.2)0.61 (0.38 to 0.97) Myocardial infarction7 (0.3)9 (0.9)0.41 (0.15 to 1.11) Stroke5 (0.2)6 (0.6)0.44 (0.13 to 1.43) Hospitalization for angina9 (0.4)9 (0.9)0.52 (0.21 to 1.30) Hospitalization for heart failure9 (0.4)6 (0.6)0.77 (0.27 to 2.16) Coronary revascularization11 (0.5)8 (0.8)0.72 (0.29 to 1.80) CV death4 (0.2)2 (0.2)0.48 (0.07 to 3.43) Coronary revascularization following a primary end point (ie, CABG after MI) 9 (0.4)11 (1.1)0.43 (0.18 to 1.03) MACE composite—myocardial infarction, stroke, CV death 14 (0.7)15 (1.5)0.48 (0.23 to 1.00) Impact of Bromocriptine-QR on CV Events CI, confidence interval; CV, cadiovascular; CABG, coronary artery bypass graft; MACE, major cardiovascular adverse event; MI, myocardial infarction. *Percentage of events per total number per group: 2054 bromocriptine-QR, 1016 placebo. Gaziano J M, Cincotta AH, Vinik A, Blonde L, Bohannon N, Scranton R. J Am Heart Assoc 2012;1:e002279

11. Cardiac Autonomic Imbalance and Inflammation in the Progression of Diabetes Adipose Tissue Adipose Tissue Lieb DC, Vinik, Parson et al. Exp Diab Res 2012

12. Stress Sympathetic Overactivity Activation of Central SNS Enhanced SN responsiveness Renal Angiotensin Cardiac SNS Hypertension Nephropathy Myocyte apoptosis LV Dysfunction/Sudden Death Oxidative/Nitrosative Stress Autonomic Dysfunction and Sudden Death in Diabetes Vinik et al Endocrine Today2008

13. Causes of Death in Diabetic Autonomic Neuropathy Sudden unexplained Cardiac arrhythmia Silent myocardial infarction  More likely to die of heart attack  Greater incidence of cardiac failure Aspiration pneumonia Ulcers, amputations, gangrene Chronic renal failure