1. SGLT-2 Inhibitors Surprising New Information

2. Logic for SGLT-2 Inhibition : My Own Comment on MOA- Logic for Benefit: 1.Kidney is an ‘active player’ in Hyperglycemia-- 2.EARLY (in pre-diabetes) Up-regulation of SGLT-2 protein is a Mal-adaptive response to body perceiving lose of glucose as a risk for insufficient glucose for brain function 3.Lowering blood sugar by reducing tubular re-absorption of glucose treats THE Core defect in Diabetes- abnormal b-cell function, by decreasing glucotoxicity, AND, by virtue of weight loss, improves Insulin Resistance

3. Therapeutic Logic of SGLT-2 Inhibitors to Fulfill Unmet Needs; I’ve seen:  Effective Glycemic Control – HGA1C FBS, PPG  No undue risk for hypoglycemia (unless combined with Insulin or Insulin Secretagogue Therapy)  Decreases variability, even, especially T1DM  Additive benefits with incretins, esp. GLP-1 RA’s  Delay, prevent need for insulin; delay, prevent need for fast-analog insulin in T2DM (thus decrease potential hypo-with insulin Rx (85% reduction if avoid fast-analogs)  Weight Loss, Modest BP reduction  Minimal GI side effects (with volume depletion)  No edema,, decreases modest existing edema;  decreases/obviates edema of pioglitazone  Durable long-term glycemic control  Acceptable side effect profile - minimize by quality pro-active care- volume depletion, UTI, yeast infections 1.Blonde L. Am J Manag Care. 2007;13(suppl 2):S36-S40. 2.Blonde L, et al. J Manag Care Pharm. 2006;12(7 suppl A):S2-S12. GI: gastrointestinal.

4. Weight Reduction Issues : GLP-1 RA- SGLT-2, best DPP-4 + SGLT-2 = GLP-1 RA ( by the way, incretins counteract increased hepatic glucose production seen with SGLT-2 inh.) Schwartz, Fabricatore, Diamond, Weight Reduction in Diabetes, Book Chapter “Diabetes: An Old Disease, a New Insight,” edited by Dr. Ahmad., Landes Bioscience, 2011 1. In Metabolic Syndrome- 2. GLP-1RA Before Pioglitazone- 3. GLP-1 RA’s preferred over DPP-4 in ‘right patient’ 4. GLP-1 RA’s always before go to Insulin, even a short trial 5. Unless ‘sick’, avoid insulin if not following NCS diet 6. Keep on Incretin when add insulin. 7. If on insulin, decrease 25% as start NCS diet decrease 25% if was having hypoglycemia add pioglitazone, metformin, if possible add incretin, GLP-1 preferred May be able to stop insulin, lose weight

5. Likely Benefit, Not Harm, to Kidneys Over Time: if Wanted to Protect Kidney in DM, one would want  Decrease glucose; Decrease BP; Decrease weight  Decrease Hyperfiltration; Decrease microalbuminuria Canagliflozin (SGLT-2 Inhibitors do it All) david.cherneyCurr Opin Nephrol Hypertens 2015, 24:96–103 DOI:10.1097/MNH.0000000000000084

6. Therapeutic Logic of SGLT-2 Inhibitors to Fulfill Unmet Needs; Can Tell Patient :  Effective Glycemic Control with No undue risk for hypoglycemia (unless combined with Insulin or Insulin Secretagogue Therapy) Durable- (2 yr data)  Reduces HgA1c, Fasting and Postprandial Hyperglycemia, variability  Additive benefits with incretins, esp. GLP-RA’s  Weight Loss, Modest BP reduction  Minimal GI side effects (with volume depletion)  No edema,, decreases modest existing edema; decreases/obviates edema of pioglitazone  Durable long-term glycemic control  Acceptable side effect profile - minimize by quality pro-active care- volume depletion, UTI, yeast infections  Delay, prevent need for basal insulin; and fast-analog insulin  Works with FIRST DOSE- patients love to see QUICK benefit

7. Use least number agents treating maximal # of modes of hyperglycemia SGLT-2 Inhibition addresses 5 of these Mechanisms of Hyperglycemia Up-regulation of SGLT-2 SGLT-2 EFFECTS: 11- acts at Kidney 4,5,6 by wt. loss 1 by decreased glucotoxicity