Part 10

FPG (mg/dL) BaselineDay 8Day 15 Vehicle (n=6) 0.01 mg/kg (n=6) 0.1 mg/kg (n=6) 1 mg/kg (n=6) 10 mg/kg (n=6) *P<0.05; † P< vs vehicle. ZDF=Zucker diabetic fatty. Han S, et al. Diabetes. 2008;57: ; Whaley J, et al. Diabetes. 2007;56(suppl 2). Abstract 0559-P. Effects of Dapagliflozin on Fasting Plasma Glucose in ZDF Rats * * * † † * †

Hepatic Glucose Production (mg/kg min) Glucose Infusion Rate (mg/kg min) CONDAPACONDAPA P<0.01 CON=controls; DAPA=dapagliflozin. Han S, et al. Diabetes. 2008;57: Effect of Dapagliflozin on Insulin-Stimulated Glucose Disposal and Hepatic Glucose Production in ZDF Rats

Dapagliflozin-Induced Glucosuria Reduces HbA 1c : A Dose-Ranging Trial Study design 12 week, double-blind, placebo-controlled12 week, double-blind, placebo-controlled –Dapagliflozin: 2.5, 5, 10, 50 mg/day –Metformin XR: 1500 mg/day –Placebo Patients 389 drug-naive T2DM patients HbA 1c >7.0% MeasurementsFPG, PPG, HbA 1c List JF, et al. Diabetes Care. 2009;32:

Baseline HbA 1c (%) All comparisons vs placebo; no statistical comparisons with metformin were made. List JF, et al. Diabetes Care. 2008;2009;32: P<0.01 Effect of Dapagliflozin on HbA 1c Δ HbA 1c (%) P< DAPA 2.5 DAPA 5 DAPA 10 DAPA 50 PBO MET XR 1500

Dapagliflozin: Glucosuric and Metabolic Effects Glucosuria g/day ↑ g/dayFPG ↓ mg/dL PPG ↓ mg/dL Body weight ↓ kg (↓ 2.5%-3.4%) Urine volume ↑ mL/day List JF, et al. Diabetes Care. 2009;32:

Adverse Events With Dapagliflozin PBO (n=54) Met 1500 mg QD (n=56) Dapa 2.5 mg QD (n=59) Dapa 5 mg QD (n=58) Dapa 10 mg QD (n=47) Dapa 20 mg QD (n=59) Dapa 50 mg QD (n=56) Hypoglycemia, n (%) 2 (4)5 (9)4 (7)6 (10)3 (6)4 (7) UTIs, n (%)3 (6)5 (9)3 (5)5 (9)5 (11)7 (12)5 (9) Genital infection, n (%) 0 (0)1 (2)2 (3)1 (2) 4 (7) Hypotensive event, n (%) 1 (2)2 (4)0 (0) 1 (2) UTI=urinary tract infection. List JF, et al. Diabetes Care. 2009;32:

Investigational SGLT2 Inhibitors AgentManufacturer Phase III DapagliflozinAstraZeneca/Bristol-Myers Squibb Phase II AVE-2268 sanofi-aventis BI Boehringer Ingelheim JNJ Johnson & Johnson Remogliflozin Sergliflozin GSK/Kissei TS-033 Taisho YM-543 Astellas/Kotobuki Pharmaceuticals Phase I CSG-452A Chugai/Roche SAR-7226 sanofi-aventis TA-7284 Mitsubishi Tanabe/Johnson & Johnson

Highly specific for the kidney and SGLT2 transporter ~80% reduction in SGLT2 mRNA/protein in Sprague- Dawley rats, ZDF rats, and dogs without any effect on SGLT1 Marked reduction in FPG, PPG, and HbA 1c in all three species No changes in plasma or urine electrolytes Wancewicz EV, et al. Diabetes. 2008;57(suppl 2). Abstract 334-OR. ISIS – A Specific SGLT2 Antisense Oligonucleotide

Unanswered Questions About SGLT2 Inhibition Durability The efficacy of SGLT2 inhibition may wane once blood glucose falls into the normal range Safety and tolerability The long-term safety of this class remains to be proven Risk of nocturia and genitourinary infections may limit use in some patients Renal impairment SGLT2 inhibition may not be effective in patients with renal impairment

SGLT2 Inhibition: Meeting Unmet Needs in Diabetes Care Weight Management Type 2 Diabetes Multiple Defects in Type 2 Diabetes Adverse Effects of Therapy Hyperglycemia CVD Risk (Lipid and Hypertension Control) Improvements in Glucose and Weight Support Other CVD Interventions Complements Action of Other Antidiabetic Agents Promotes Weight Loss Corrects a Novel Pathophysiologic Defect No Hypoglycemia Improves Glycemic Control

Conclusions SGLT2 inhibition represents a novel approach to the treatment of type 2 diabetes Studies in experimental models of diabetes have demonstrated that induction of glucosuria reverses glucotoxicity –Restores normoglycemia –Improves  -cell function and insulin sensitivity

Conclusions Genetic mutations leading to renal glucosuria support the long-term safety of SGLT2 inhibition in humans Early results with dapagliflozin provide proof of concept of the efficacy of SGLT2 inhibition in reducing both fasting and postprandial plasma glucose concentrations in type 2 diabetes

Overall Conclusions Understanding of the pathophysiology of type 2 diabetes is an evolving process As new concepts emerge, there is potential for new treatment modalities Optimal management of type 2 diabetes requires a multifaceted approach that targets multiple defects in glucose homeostasis