1. Practical Implementation as a Discussion with the Patient Practical Use of SGLT-2 Inhibitors in T2DM: Clinical Pearls- Perlas de Sabiduria Stan Schwartz MD, FACP Affiliate, Main Line Health System Emeritus, Clinical Associate Professor of Medicine, U of Pa. stschwar@gmail.com

2. SGLT-2 Inhibitor Infection Risk: Principles Increased incidence of urinary tract- 1% more common if history of frequent UTI’s or colonized; if get one, low risk recurrence Rare pyelonephritis/ urosepsis Genital yeast infections : ~3X more common if history of frequent yeast infections If get 1, low risk of recurrence In men, rare if circumcised; vast majority occurred in uncircumcised Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224.

3. Practical Clinical Approaches To Maximize Benefits and Minimize Risks 2 - 4 week visit- Reinforce benefits they’ve seen; sugar, weight, well-being; supports future compliance – Check eGFR, BUN/Cr, K+, BP If get’s a yeast infection/ UTI – not a reason to stop agent as repeat infection rate low Treat yeast infections- clotrimazole topical/vaginal; diflucan 150 mg and repeat 2 days later

4. Therapeutic Logic of SGLT-2 Inhibitors to Fulfill Unmet Needs; Can Remind 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 1, Decreases variability, (related to increased risk of DM complications Additive benefits with incretins, esp. GLP-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) Works with FIRST DOSE- patients love to see QUICK benefit 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.

5. Weight Reduction Issues : Schwartz, Fabricatore, Diamond, Weight Reduction in Diabetes, Book Chapter “Diabetes: An Old Disease, a New Insight,” edited by Dr. Ahmad., Landes Bioscience, 2011 1.GLP-1 RA- SGLT-2, best 2.DPP-4 + SGLT-2 = GLP-1 RA ( by the way, incretins counteract increased hepatic glucose production seen with SGLT-2 inh.) 1.SGLT-2 Before Pioglitazone- minimize edema and achieve weight loss 4.Keep on SGLT-2 Inhibitor (and other non-insulin Rx) when add Basal Insulin) 5.. If on insulin, decrease 25% as start NCS diet decrease 25% if was having hypoglycemia add incretin, GLP-1 preferred; decrease adjusted dose 25% add SGLT-2 inh. ; decrease adjusted dose 20% can add pioglitazone, metformin, if necessary May be able to stop bolus and even basal insulin, lose additional weight, avoid hypoglycemia

6. Thus Logic for SGLT-2 Inhibitor with Incretins

7. Conclusions Treat elements of pathophysiology-especially –Improve Beta Cell Function-reduce glucotoxity, (SGLT-2), –Use SIDE-BENEFITS of the various agents, (SGLT-2)- Weight loss, BP control, potentially decrease CV risk SGLT-2 inhibitors act by a novel mechanism and are useful in patients who have not achieved goal HbA1c levels Research show that SGLT-2 inhibitors lower HbA1c levels and also have the benefit of weight reduction and modest BP improvements in patients with T2DM SGLT-2 inhibitors have been generally well tolerated, maybe surprisingly so, with most AEs being mild to moderate They should be used in a patient-centric approach to the pharmaco- therapy of our patients with Diabetes

8. We and Our Patients Have Been Blessed with Multiple New, Safer Therapies for Type II Diabetes SGLT-2 Inhibitors Newest and Key Class: Logical, Effective, Safe PRACTICAL APPROACHES CAN MAXIMIZE EFFICACY and SAFETY Patients are Likely To Live Longer with Less Suffering Pearl Summary

9. The Age at presentation. The ‘Severity’ at presentation: The Slope Argues for early discovery/Therapy Phenotypic Presentation, defined by: 100% − − 0% − Pre-Diabetes = FBS ≥100, PPG≥140 T2D = FBS ≥126, PPG ≥200 I I I I I / ≈ / I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I Increasing Age % β−Cell Function Critical β−Cell Mass Severity: Extent of beta cell loss Slope: Rate of Loss Age at Presentation: Where gene/env triggers Hyperglycemia All mechanisms of hyperglycemia start in pre-DM

10. Pathogenesis of Diabetes Variable insulitis  -cell sensitivity to injury Interactions between genes imparting susceptibility and resistance Environmental triggers and regulators Immune dysregulation Pre-diabetes Overt diabetes  -cell Mass Time Loss of first-phase insulin response Glucose intolerance Adapted with permission from Atkinson MA, Eisenbarth GS. Lancet. 2001;358:221 May be relapsing/remitting

11. The Age at presentation = tipping point when the combined Gene Effect Environmental trigger is exposed as phenotypic hyperglycemia. The ‘Severity’ at presentation: Reflects the β-cell loss-function/mass- at presentation The Slope = Progressive ‘Natural History’ over time ie: = Rate of β-cell loss Phenotypic Presentation, defined by: 100% − − 0% − Pre-Diabetes = FBS ≥100, PPG ≥140 T2D = FBS ≥126, PPG ≥200 I I I I I / ≈ / I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I I Increasing Age % β−Cell Function Critical β−Cell Mass Severity: Extent of beta cell loss Slope: Rate of Loss Age at Presentation of Hyperglycemia