Lifestyle Modifications 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 Lifestyle Modifications A1C 6.5%-7.5% A1C 7.6%-9.0% A1C > 9.0% If under treatment If drug naive Symptoms No symptoms Monotherapy Dual therapy Triple therapy Dual therapy Insulin plus other agent(s)* Insulin plus other agent(s)* Triple therapy Triple therapy Use Sulfonylureas/Glinides LAST, IF AT ALL Therapeutic Choice, based on Safety/ Efficacy, Should Match The Drug Characteristics With Patient Characteristics Rodbard HW, et al. Endocr Pract. 2009;15:540-559. 1

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

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

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%)

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