1. Practical Implementation as a Discussion with the Patient, Part 2 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. PEARL: Match Patient characteristics to Drug Characteristics and Vice Versa AACE/ACE: Recommendations Based on A1C Rodbard HW, et al. Endocr Pract. 2009;15:540-559. A1C 6.5%-7.5%A1C 7.6%-9.0% A1C > 9.0% If under treatment If drug naive Insulin plus other agent(s)* Insulin plus other agent(s)* Symptoms No symptoms Lifestyle Modifications * Monotherapy Dual therapy Triple therapy Dual therapy Triple therapy PEARL Not first,second, third line; not competition between classes; It’s early combination therapy

3. 350 300 250 200 150 100 50 250 200 150 100 50 0 Insulin-Resistance Relative  -cell Function (%) Insulin Level Fasting Glucose (mg/dl) Onset of Diabetes Postmeal Glucose Incretins* ( GLP-1 RA, DPP-4 Inh.) Insulin TZD (Pioglitazone), metformin, bromocriptine QR Insulin  -10 -5-051015202530 Insulin  Modified from Bergenstal RM, International Diabetes Center. Rx PRINCIPLES- Rx PRINCIPLES- Uses Across Continuum of Care Consider therapy for prevention (future) Early treatment, even with IGT FAST THERAPEUTIC CHANGES Not 1st,2nd,3rd line; not competition betw. classes; early combo therapy -Delay Need for Insulin -No need for Early Insulin -If need Insulin, Continue Non- Insulin RX (Avoids need for Meal-Time Insulin- Decrease Risk Hypoglycemia 85%- Get Patients off insulin Who had been given early Insulin Combo therapy-in AACE >7.5 PICK RIGHT DRUG FOR RIGHT PT. Nutrition Exercise, NO SMOKING. SGLT-2 Inhibitors * with caution re:Immune Sup. Levels 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

4. 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

5. But Won’t Sugar Hurt My Kidneys?

6. Likely No Undue Risk to Kidney Familial Renal Glucosuria Presentation Glucosuria: 1-170 g/dayGlucosuria: 1-170 g/day AsymptomaticAsymptomatic Blood Normal glucose concentration No hypoglycemia or hypovolemiaNo hypoglycemia or hypovolemia Kidney / bladder No tubular dysfunction Normal histology and function Complications No increased incidence of –Chronic kidney disease –Diabetes –Urinary tract infection Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882; Wright EM, et al. J Intern Med. 2007;261:32-43.

7. 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

8. 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 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.

9. Therapeutic Logic of SGLT-2 Inhibitors to Fulfill Unmet Needs; I’ve seen: Minimal GI side effects (only with volume depletion) No edema, in fact, decreases modest existing edema; decreases/obviates edema of pioglitazone Acceptable side effect profile that can be minimized 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.

10. CV Risk Factor Changes with SGLT-2 Inhibitors- Can Reassure Patient Changes in fasting lipids –Increases in LDL-C –Increases in HDL-C –Minimal change in LDL-C/HDL-C ratio –Decreases in TG  Smaller increases in non-HDL-C, Apo B, LDL particle number Decreases in systolic and diastolic blood pressure Improved glycemic control Decrease in body weight

11. Practical Clinical Approaches To Maximize Benefits and Minimize Risks As Write Initial Script –Check eGFR, BUN/Cr,  eGFR appropriate dosing lower doses for lower eGFR, older, on loop-diuretic; Advise push PO fluids, hold med with a GI flu, sweaty exercise etc; Note to patient increased urination expected= 12-14oz/d early, later ~6 oz/d –Check K- if K+ high nml- adjust K=sparing diuretic,ACE/ARB decrease high K+ foods –Check BP- if Low BP- cut back/stop something- HCTZ, spironolactone, or BP med- ACE inh. –Check Recent Sugars- Very High sugar- start other meds and NCS diet first, start SGLT-2 3 days later

12. Practical Clinical Approaches To Maximize Benefits and Minimize Risks As Write Initial Script –Teach Volume Issues  Keep Urine Dilute (let kidney tell patient if they’re drinking ‘enough’) –UTI/ Yeast Infection Issues  Make sure ho history frequent issues in past- if so, don’t use  Female- careful bathroom habits, urinate after intercourse before sleep  Male- especially uncircumsized- get tip of penis dry before leave bathroom