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Program Editors Ralph Anthony DeFronzo, MD Professor of Medicine and Chief of the Diabetes Division University of Texas Health Science Center Audie L. Murphy Memorial Veterans Hospital San Antonio, Texas, USA Jaime A. Davidson, MD President, Worldwide Initiative for Diabetes Education Clinical Professor of Internal Medicine Division of Endocrinology University of Texas Southwestern Medical School Dallas, Texas, USA

Faculty Professor Rury Holman Professor of Diabetic Medicine Honorary Consultant Physician Diabetes Trials Unit University of Oxford Oxford, United Kingdom Professor Stefano Del Prato Professor of Endocrinology and Metabolism School of Medicine University of Pisa Pisa, Italy Professor Allan Vaag Chief Physician Steno Diabetes Center Gentofte, Denmark

SGLT2 Inhibition A Novel Treatment Strategy for Type 2 Diabetes

The Ominous Octet Islet  -cell Impaired Insulin Secretion NeurotransmitterDysfunction Decreased Glucose Uptake Islet  -cellIncreased Glucagon Secretion IncreasedLipolysis Increased Glucose Reabsorption IncreasedHGP Decreased Incretin Effect

Renal Glucose Reabsorption in Type 2 Diabetes Sodium-glucose cotransporter 2 (SGLT2) plays a role in renal glucose reabsorption in proximal tubule Renal glucose reabsorption is increased in type 2 diabetes Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose Wright EM, et al. J Intern Med. 2007;261:32-43.

SGLT1 (180 L/day) (900 mg/L)=162 g/day 10% Glucose No Glucose S1 S3 Renal Handling of Glucose SGLT2 90%

GLUT2 AMG Uptake NGTT2DMNGTT2DM AMG=methyl-  -D-[U 14 C]-glucopyranoside; CPM=counts per minute. Rahmoune H, et al. Diabetes. 2005;54: SGLT2 NGTT2DM Normalized Glucose Transporter Levels CPM Increased Glucose Transporter Proteins and Activity in Type 2 Diabetes P<0.05 4

5 mmol/L Fasting Plasma Glucose Muscle  Normal Glucose Homeostasis Fat Liver Pancreas

Fasting Plasma Glucose Pathophysiology of Type 2 Diabetes 10 mmol/L Islet  -cell Impaired Insulin Secretion Insulin Resistance Increased HGP 5 mmol/L

Rationale for SGLT2 Inhibitors Inhibit glucose reabsorption in the renal proximal tubule Resultant glucosuria leads to a decline in plasma glucose and reversal of glucotoxicity This therapy is simple and nonspecific Even patients with refractory type 2 diabetes are likely to respond