1. Diabetes Mellitus 101 for Cardiologists (and Alike): 2015 Stan Schwartz MD,FACP Affiliate, Main Line Health System Emeritus, Clinical Associate Professor of Medicine, U of Pa. 6105472000 An Aggressive Pathophysiologic Approach to Therapy of Type 2 Diabetes in Cardiometabolic Patients: Looking at Diabetes Medications with a Cardiologists Eye Part 12

2. Incretins in Natural History of DM Delay of 1st-phase Metabolic syndrome Pre-diabetes DM- non- insulin Rx Insulin need insulin release Late-pp hypo, Prevention / Delay of DM Weight reduction methods- GLP-1;Glp-1 before pio; GLP-1 before insulin Dpp-4/ GLP-1 RA Instead of SU/Glinide Type 2- reduce bolus need Type 1- decrease variability, dawn, pumps Even late in DM AACE Guideline based Stress/ Steroid DM Get off Insulin

3. SGLT-2- INH. 80 SGLT-2 Inh. Renal Threshold DM NML SGLT-2 Inhibitors DM nml

4. Thus the Logic for SGLT-2 Inhibition: we’ll discuss Benefit/ Risks My Own Comment on MOA- Logic for Benefit: 1.Kidney is an ‘active player’ in Hyperglycemia-- eg: 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

5. 40-50% efficient as hepatic glucose production increased, yielding up to 1% drops; Obviate with incretin Rx- Durable up to 1 year No hypoglycemia Reduce fluctuation Durable and effective across natural Hx DM

6. SGLT-2 Inhibitors Canagliflozin Dapagliflozin Empagliflozin Principles in our discussion: There are no head-to-head-trials: can’t compare numbers so emphasize commonality of efficacy/ safety/risk ; minor differences between these agents !

7. General Observations Across Clinical Trials No significant changes in plasma electrolytes Slight increase in Hct and decreases in serum uric acid CV –Improvement in triglycerides and HDL cholesterol –Slight increase in LDL cholesterol –Consistent decreases in SBP, DBP, and weight Consistent increase in “genital infections” Inconsistent increase in lower urinary tract infections Volume depletion risk

8. SGLT-2 Inhibitor Infection Risk: Principles Increased incidence of urinary tract more common if history of frequent UTI’s or colonized; if get one, low risk recurrence Rare pyelonephritis/ urosepsis Genital yeast infections : more common if history of frequent UTI’s or colonized 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.

9. cana Minimize by- push PO intake, fastidious bathroom habits; urinate after intercourse before sleep If baseline BP low- cut back or d/c diuretic or antihyperetensive Watch K+, if older, eGFR 45-60, on ACE / spironolactone Side Effects SGLT-2 Inhibition

10. Practical Clinical Approaches To Maximize Benefits and Minimize Risks Initial Script –Check eGFR, BUN/Cr, K+, BP, recent sugar eGFR appropriate dosing lower doses for lower eGFR, older, on loop-diuretic; Advise push PO fluids, hold med with a GI flu, etc; note increased urination expected –Female- careful bathroom habits, urinate after intercourse before sleep –Male- especially uncircumsized- get tip of penis dry before leave bathroom –K+ high nml- adjust K=sparing diuretic,ACE/ARB decrease high K+ foods –Low BP- cut back/stop something- HCTZ, or BP med –Very High sugar- start other meds and NCS diet first, start SGLT-2 3 days later 2 - 4 week visit- Re-inforce benefits they’ve seen; supports compliance – Check eGFR, BUN/Cr, K+, BP Treat yeast infections- clotrimazole topical/vaginal; diflucan 150 mg and repeat 2 days later

11. Lowers Renal Glucose Threshold to 80 – Very EFFECTIVE, but…Should drop HgA1c more: Liver Compensates for increased glycosuria with increased hepatic glucose production

12. Thus Logic for SGLT-2 Inhibitor with Incretins