Practical Implementation as a Discussion with the Patient

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 Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224. 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

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 Hyperglycemia1, 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 • 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: • 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.) • SGLT-2 Before Pioglitazone- minimize edema and achieve weight loss • 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 Schwartz, Fabricatore, Diamond, Weight Reduction in Diabetes, Book Chapter “Diabetes: An Old Disease, a New Insight,” edited by Dr. Ahmad., Landes Bioscience, 2011

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 DiabetesSGLT-2 Inhibitors Newest and Key Class:Logical, Effective, SafePRACTICAL APPROACHES CAN MAXIMIZE EFFICACY and SAFETY Patients are Likely To Live Longer with Less Suffering Pearl Summary

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

10. Pathogenesis of Diabetes Environmentaltriggers andregulators Immunedysregulation Loss of first-phase insulin response Interactions betweengenes impartingsusceptibility and resistance May be relapsing/remitting β-cell Mass Variable insulitisβ-cell sensitivity to injury Glucose intolerance Overt diabetes Pre-diabetes Time Adapted with permission from Atkinson MA, Eisenbarth GS. Lancet. 2001;358:221

11. Phenotypic Presentation, defined by: • 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 100% − − − − − − − − − − 0%− Slope: Rate of Loss % β−Cell Function Pre-Diabetes = FBS ≥100, PPG ≥140 T2D = FBS ≥126, PPG ≥200 Critical β−Cell Mass Severity: Extent of beta cell loss Age at Presentation of Hyperglycemia 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