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. Structure of Our Discussion: 1.Following Flow of Discussion with Patient 1.General principles 2.SGLT-2 Principles 2.First Visit Process of Care 3.Follow-up Visit Process of Care

3. Updated Natural History of Type 2 Diabetes Risk of Dev. Complications ETOH BP Smoking Eye Nerve Kidney Blindness Amputation CRF Disability MI CVA Amp Age 0-1515-40+15-50+25-70+ Macrovascular Complications IGT Type II DM Microvascular Complications DEATH pp>7.8 β-Cell secretion/mass Gene Environmental Inflam. Triggers eg: viral,endocrine disruptors, food AGE’s, biome endocrine disruptors, food AGE’s,biome Environmental Triggers Resistance inflammatory, adipokines Resistance-FFA Poor diet, inactivity EPIGENITICSEPIGENITICS EPIGENITICSEPIGENITICS Polygenic- other Monogenic (HLA) Polygenic Monogenic – MODY IR Phenotype

4. Treat Aggressively to Delay or Prevent Complications Pearl

5. Impact of Intensive Therapy in Type 2 Diabetes Summary of Major Clinical Trials: BUT Subset Evaluations Show Reduced CV Outcomes if shorter duration of DM, without significant pre-existing complications StudyMicrovascularMacrovascularMortality UGDP ↔↔↔ UKPDS ↓↓↔↓↔↓ DCCT/EDIC* ↓↓↔↓↔ ↔ ACCORD ↓↔ ↑ (unadj.), ↔ (adj.) ADVANCE ↓↔↔ VADT ↔↔↔ Initial Trial Long Term Follow-up ↑- likely due to hypoglycemia and weight gain

6. Early Treatment Decreases Micro and Macro Vascular RISK/ OUTCOMES As long as do without Undue Hypoglycemia or Weight Gain Pearl

7. Consequences of Hypoglycemia Prolonged QT- intervals - Diabetologia 52:42,2009 –Can be of pronged duration IJCP Sup 129, 7/02 –Greater with higher catecholamine levels Europace 10,860 Associated with Angina Diabetes Care 26, 1485, 2003 / Ischemic EKG changes Porcellati, ADA2010 Associated with Arrhythmias Associated with Sudden Death Endocrine Practice 16,¾ 2010 Increased Variabilty - explains highest mortality in intensive group had highest HgA1c in ACCORD ( i ncreases inflammation, ICU mortality Hirsch ADA2010) Sulfonylureas block Ischemic Preconditioning

8. There is No perfect Exogenous Insulin: All result in HyperInsulinemia and Potential Hypoglycemia Exogenous Insulin Perfect glucose sensor- Insulin secretion modulator Hypoglycemia/ Wt. Gain NORMAL: Insulin into portal system and B-cell= CONCLUSION: DELAY INSULIN THERAPY; AVOID BOLUS RX if possible

9. Pearl No more Sulfonylureas or Glinides Delay Insulin Most will not need Bolus Insulin

10. HYPERGLYCEMIA 7. Stomach/Sma ll intestine 10. Kidney 11. Immune System / Inflammation 4. Increased hepatic glucose production 8. Colon / Biome 6. Adipose 5. Decreased peripheral muscle uptake 9. Brain Incretin Dopa agonist SGLT2 Inhibitors Anti-Inflam- matories, Immune modulators Metformin, TZDs Incretins/Pro biotics GLP-1 RAs AGI Pramlintide 1. Decreased insulin secretion Incretins Ranolazine 2. Unsuppressed glucagon secretion Incretins Pramlintide 3. Decreased incretin effect Incretins BETA CELL-CENTRIC VIEW OF DIABETES: Matching Rx with Etiology use least number agents treating maximal # of modes of hyperglycemia FOCUS on SGLT-2 Inhibition- addresses 5/11 MOH CORE DEFECT Resistance Issues New Construct Older Construct Islet Cell Issues