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 16

2. New ADA Guidelines- 4/20/12 Inzucchi, Diabetologia 4/20/12 SU Still Prominent But Incretins including DPP-4s on list Inzucchi, Diabetes Care 2012;35:1364

3. Figure 1 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] (Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554) Strongly disagree with less stringent Advice- ie: I would be as aggressive in care as other Patients, as long as don’t use agents that cause weight gain or hypoglycemia

4. AACE/ACE: Recommendations Based on A1C at Diagnosis/ or When you see in Office EMPHASIS on Using Combination Therapy to ADDRESS multiple etiologies of hyperglycemia in Octet Rodbard HW, et al. Endocr Pract. 2009;15:540-559. A1C 6.5%-7.5%A1C 7.6%-9.0% A1C > 9.0% If under treatment If drug naive Insulin plus other agent(s)* Insulin plus other agent(s)* Symptoms No symptoms Lifestyle Modifications Use Sulfonylureas/Glinides LAST, IF AT ALL Monotherapy Dual therapy Triple therapy Dual therapy Triple therapy Therapeutic Choice, based on Safety/ Efficacy, Should Match The Drug Characteristics With P atient Characteristics

5. Follow current AACE GUIDELINE PRINCIPLES  Treat as many of the Ominous Octet Targets as needed, with least # of agents, to get lowest sugars/HgA1c as possible without undue weight gain or hypoglycemia  Early Combination Therapy First Tier- Efficacy, ( my add- CV event reduction, Weight Loss)  Treat with agents that address FBS AND PPG  Ideally agents will stabilize, preserve beta-cells, the CORE DEFECT ( NO SU/GLINIDES)  Ideally agents will have potential to synergistically decrease in CV risk factors/ outcomes

6. Initial Triple Combination Therapy is Superior to ADA Guide 147 newly diagnosed T2DM (age = 45±1; BMI=36±0.5; A1c = 8.6±0.1%; diabetes duration = 5.6±0.5mo) were randomized to receive Results: Triple Therapy, A1c 8.6 to 6.1% at 6 mo and remained stable at 6.1% at 24 Conventional Therapy, 6.1% at 6 mo and then increased to 6.6% at 24 mo (p < 0.01). More subjects in Conventional Arm failed to achieve the treatment A1c goal <6.5% (46 vs 22%, p<0.0001)., Triple Therapy subjects had a 13.6-fold lower rate of hypoglycemia compared to subjects receiving Conventional Therapy. Triple Therapy subjects had mean weight loss of 1.2 kg versus 3.6 kg weight gain (p=0.02) in subjects on Conventional Therapy.

7. First Tier/ Second Tier AACE Meds  First Tier- drop HgA1c 1-2%  Metformin, pioglitazone, GLP-1 RA  Second Tier  SGLT-2 inh.  DPP-4 Inh, ranolazine,  bromocriptine-QR, colsevalam, alpha-glucosidase inh.

8. Uses Across Continuum of Care 1. Pre-Diabetes 2. Rest of Continuum of Care 3. AACE Guidelines, Triple RX before Insulin Pick Right Drug for Right Patient 4. Delay Need for Insulin No need for Early Insulin 5. If need Insulin, Continue Non-Insulin RX Avoids need for Meal-Time Insulin Decrease Risk Hypoglycemia 85% 6. Get Patients off insulin Had been given Early Insulin

9. Concurrent Therapy

10. Aggressive medical therapy in diabetes Adapted from Beckman JA et al. JAMA. 2002;287:2570-81. Atherosclerosis Metformin TZDs Sulfonylureas/Glinide RANOLAZINE colsevalam Incretins Insulin Statins Fibric acid derivatives Colsevalam ACE inhibitors ARBs β-blockers CCBs Diuretics ASA Clopidogrel Ticlopidine Hyperglycemia/ Insulin resistance Dyslipidemia Hypertension Platelet activation and aggregation

11. StrategyComplication Reduction of Complication Blood glucose control▪Heart attack  37% 1 Blood pressure control ▪Cardiovascular disease ▪Heart failure ▪Stroke ▪Diabetes-related deaths  51% 2  56% 3  44% 3  32% 3 Lipid control ▪Coronary heart disease mortality ▪Major coronary heart disease event ▪Any atherosclerotic event ▪Cerebrovascular disease event  35% 4  55% 5  37% 5  53% 4 Treating the ABCs Reduces Diabetic Complications 1 UKPDS Study Group (UKPDS 33). Lancet. 1998;352:837-853. 2 Hansson L, et al. Lancet. 1998;351:1755-1762. 3 UKPDS Study Group (UKPDS 38). BMJ. 1998;317:703-713. 4 Grover SA, et al. Circulation. 2000;102:722-727. 5 Pyŏrälä K, et al. Diabetes Care. 1997;20:614-620.

12. Synergies In Therapy for the Cardiometabolic Syndrome ?√

13. Summary  Treat aggressively-benefit on cost and complications  Treat elements of pathophysiology  Resistance-glycemia,endothelial dysfunction,lipids,BP,coag.  Secretion-first phase,incretin,importance of PPG  Multi-hormonal issues  Use SIDE-BENEFITS of the various agents  Treat to new goals using combinations that make pathophysiologic sense  Guidelines should help pick right drug(s) for right patients