1. Therapy for Type II Diabetes

3. Non-Insulin Therapy for Hyperglycemia in Type 2 Diabetes, 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

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. 350 300 250 200 150 100 50 250 200 150 100 50 0 Insulin-Resistance Relative  -cell Function (%) Insulin Level Fasting Glucose (mg/dl) Onset of Diabetes Postmeal Glucose Incretins* ( GLP-1 RA, DPP-4 Inh.) Insulin TZD (Pioglitazone), metformin, bromocriptine QR Insulin  -10 -5-051015202530 Insulin  Modified from Bergenstal RM, International Diabetes Center. Rx PRINCIPLES- Rx PRINCIPLES-Uses Across Continuum of Care Consider therapy for prevention (future) Early treatment, even with IGT FAST THERAPEUTIC CHANGES Not 1st,2nd,3rd line; not competition betw. classes; early combo therapy Delay Need for Insulin No need for Early Insulin If need Insulin, Continue Non- Insulin RX (Avoids need for Meal-Time Insulin- Decrease Risk Hypoglycemia 85%- Get Patients off insulin Who had been given early Insulin Combo therapy-in AACE >7.5 PICK RIGHT DRUG FOR RIGHT PT. Nutrition Exercise, NO SMOKING. SGLT-2 Inhibitors * with caution re:Immune Sup. Levels

6. There is No perfect Exogenous Insulin: All result in HyperInsulinemia and Potential Hypoglycemia Exogenous Insulin Perfect glucose sensor- Insulin secretion modulator Hypoglycemia NORMAL: Insulin into portal system and B-cell= CONCLUSION: DELAY INSULIN THERAPY; AVOID BOLUS RX if possible

7. Concurrent Therapy

8. 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.

9. Aggressive medical therapy in diabetes-ADD Adapted from Beckman JA et al. JAMA. 2002;287:2570-81. Atherosclerosis, CV Outcomes, CV Risk Factors, Mortality Statins Fibric acid derivatives Colsevalam PCSK-9 Inh ACE inhibitors ARBs β-blockers CCBs Diuretics ASA Clopidogrel Ticlopidine Dyslipidemia Hypertension Platelet activation and aggregation SGLT-2 Inh. Bromocriptine QR Pioglitazone Incretins, Metformin Ranolazine Hyperglycemia/ Insulin resistance

10. 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