1. Current Therapy for Type II Diabetes

3. New ADA Guidelines- 4/20/12 Inzucchi, Diabetologia 4/20/12 SU most prominent- First, reading L to R Added back glyburide

4. 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

5. 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

6. Issues 1. Tells you CONSIDER stopping SU- MUST 2. Doesn’t tell you what to do with other non-insulin therapies-CONTINUE 3. Doesn’t tell you use other non insulin agents before use prandial insulin since >80 % (conservative) of type 2 pts won’t require bolus insulin if on GLP-1 RA with SGLT-2 inhibitor +/- other

7. 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

8. Philosophy for Reduced Insulin Need in T2DM 1. No Perfect Insulin Exogenous insulin not put in portal system; no fine-tuning a la Beta Cell 2. Leads to Hyperinsulinism- leads to Insulin Resistance (suppresses dopamine in ‘biologic clock’ of hypothalamus)– leads to Increased Weight, Hypoglycemia Risk 3. So Goal of all Insulin Therapy- Least Hypoglycemia, Least Weight Gain 4. Old Logic- use Early Insulin to reduce Glucotoxicity, Lipotoxicity but GLP-1 RAs and SGLT-2 Inh. do that first day!!, with no weight gain, no hypoglycemia 5. Therefore no need for Early Insulin- use 3-4 Non-Insulin therapy before go to Basal Insulin; keep Non-Insulin Therapies and 95% of T2DM won’t need Bolus Insulin (by avoiding bolus insulin reduce hypoglycemic risk 85%)

9. 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 Colsevalam, ranolazine, AGI