1. Diabetes Mellitus 101 for Medical Professionals An Aggressive Pathophysiologic Approach to Cardiometabolic Therapy for Type 2 Diabetes: Stan Schwartz MD,FACP Clinical Associate Professor of Medicine, U of Pa. Cardiometabolic Institute Penn-Presbyterian Hospital, UPHS Part 9

2. Therapy for Type II Diabetes

3. American Diabetes Association. Clinical Practice Recommendations. Diabetes Care. 2004,27:S15-S35 The American Association of Clinical Endocrinologists. Medical Guidelines for the Management of Diabetes Mellitus. Endocr Pract. 2002; 8(Suppl. 1): 40-82 A1C (%) Normal: 4-6% Fasting/Preprandial (mg/dL) (plasma equivalent) Postprandial (mg/dL) (2-hour) ACE <6.5 <110 <140 ADA <7.0 90-130 <180* * Peak Goals for individual patients may vary. Aim for the Lowest A1C Possible without Hypoglycemia. Targets for Glycemic Control

4. Relative Contribution of FBG and PPG Varies With A1C Range Adapted from Monnier L, et al. Diabetes Care. 2003;26:881-885. Thus, to get to glycemic goals, one must control PPG as well as FBS. (incretins, alpha-glucosidase inhibitors, TZDs, glinides, fast-insulin analogues) Inc PPG increases Micro- and macro- vascular disease

5. Non-Insulin Therapy for Type II Diabetes

6. Non-Insulin Therapy for Hyperglycemia in Type 2 Diabetes, Treating Defronzo’s Octet: Match Patient Characteristics to Drug Characteristics 5. Gut CHO Absorption: Incretin, Pramlintide, Glucosidase inh. Peripheral glucose uptake -- - 1.Pancreatic insulin Secretion: Incretin, ranolazine 2.Pancreatic glucagon Secretion- Incretin HYPERGLYCEMIA 6.Fat- TZD, metformin 7.Brain- TZD,INCRETIN, bromocryptine 8.Kidney- SGLT2 3. Muscle- TZD, Incretin 4.Liver Hepatic glucose production: Metformin, incretin De

7. The New ADA Guidelines for Type 2 Diabetes: AKA- David Nathan’s Regimen- DNR Revised Treatment Algorithm Intensive insulin At diagnosis: Lifestyle + metformin At diagnosis: Lifestyle + metformin STEP 1 STEP 2 Tier 1*Tier 2 † STEP 3 Add basal insulin Add sulfonylurea Add GLP-1 agonist Add pioglitazone ± SU HbA1C >7.0% NOT Glyburide, chlorpropamide NOT Rosiglitazone

8. Simplified- AACE/ACE: Recommendations Based on A1C at Diagnosis 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 *Pramlintide can be used with prandial insulin, but insulin secretagogues should be discontinued with multidose insulin Monotherapy Dual therapy Triple therapy Dual therapy Triple therapy Therapeutic Choice, based on Safety/ Efficacy, Should Match The Drug Characteristics With Patient Characteristics

9. Monotherapy Metformin Pioglitazone GLP-1 agonist Bromocriptine DPP-4 Inhibitor SGLT-2 Colsevelam AGI/Ranolazine Dual Combination Metformin Pioglitazone GLP-1 agonist Bromocriptine DPP-4 Inhibitor SGLT-2 Colesevelam AGI/Ranolazine Triple Combination M etformin Pioglitazone GLP-1 agonist Bromocriptine DPP-4 Inhibitor SGLT-2 Colesevelam AGI/Ranolazine Insulin* +/- Other agents *Insulin analogs  Not NPH/regular  If over 9.0% or above and symptomatic  If triple combo fails 5.7 HbA1c Continuum 6.5% – if not at goal, advance Rx 7.5% 9.0 12% Asymptomatic Symptomatic Principles of the AACE Guidelines / A1C Goal, lowest without hypoglycemia 1. Minimize risk/severity of Hypoglycemia5. Lifestyle Modification Essential and NO SMOKING 2. Minimize risk/severity of Weight gain 6. Combination frequently required; Complimentary mechanisms of action 3. Fast therapeutic changes (2-3 months, earlier even better) 7. When using insulin, add an insulin-sensitizing agent if possible 4. Address fasting and postprandial glucose8. Cost is important but, safety and efficacy trump cost Future AACE Guideline- Modest Proposal Therapeutic Choice Should Match The Drug Characteristics With Patient Characteristics Diet and Exercise Prevention Pioglitazone [Incretin] [Bromocriptine] Metformin Colsevelam

10. Concurrent Therapy

11. 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

12. 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.

13. Synergies In Therapy for the Cardiometabolic Syndrome ?√

14. 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