Dapagliflozin Improves Hyperglycemia and Beta-Cell Function Without Increasing Hypoglycemic Episodes in Patients With Type 2 Diabetes Mellitus Afshin Salsali MD, Arnaud Bastien MD, Traci Mansfield PhD, Lisa Ying PhD, Shoba Ravichandran MD,* James List, MD, PhD Bristol-Myers Squibb, Princeton, NJ *Presenter

Disclosures Shoba Ravichandran, MD Employee of Bristol-Myers Squibb Other Contributors Employees of Bristol-Myers Squibb, Princeton, NJ Supported by: Bristol-Myers Squibb and AstraZeneca

Dapagliflozin Mechanism of Action Dapagliflozin (DAPA) is a selective inhibitor of the renal sodium-glucose co-transporter 2 (SGLT2) that lowers plasma glucose levels in patients with T2DM by inhibiting renal glucose reabsorption.

Background and Aims Impaired insulin secretion and insulin resistance are the main defects in type 2 diabetes mellitus (T2DM).1 Normalization of plasma glucose by phlorizin (SGLT2 inhibition) in diabetic rats led to correction of insulin secretion.2 DAPA has also been shown to preserve β-cell function and pancreatic islet morphology in animal models.3 The aim of this presentation is to present select efficacy and safety data from two Phase 3, randomized, double-blind, placebo-controlled, multicenter trials. The data suggest that DAPA produces improvement in glycemic parameters and improves beta-cell function without causing hypoglycemia. 1Defronzo RA. Diabetes. 2009;58(4):773-795); 2Rossetti et al J Clin Invest 1987:79;1510-1515); 3Macdonald FR et al. Diabetes Obes Metab. 2010 Nov;12(11):1004-12)

Double-blind treatment period Study Designs MB102013 (NCT00528372) monotherapy Randomized (n=274) Treatment-naïve patients with HbA1c 7%–10%1 Dapagliflozin 2.5 mg (n=65) Dapagliflozin 5 mg (n=64) Dapagliflozin 10 mg (n=70) Placebo (n=75) MB102014 (NCT00528879) add-on to MET Patients inadequately controlled with metformin (≥1500 mg/d for ≥8 weeks) and HbA1c 7%–10%2 Randomized (n=546) MET + Dapagliflozin 2.5 mg (n=137) MET + Dapagliflozin 5 mg (n=137) MET + Dapagliflozin 10 mg (n=135) MET + Placebo (n=137) Lead-in period Double-blind treatment period -2 -1 4 8 12 16 20 24 Study Week 1Ferrannini et al Diabetes Care 2010;33:2217-2224; 2Bailey et al Lancet 2010;375:2223-2233

Trial End Points and Outcomes Efficacy Primary efficacy end point Change from baseline in HbA1c at week 24 Select secondary end points Change from baseline in fasting plasma glucose Change from baseline in body weight Exploratory end point Change from baseline in β-cell function as assessed by HOMA–2%β and HOMA–2 IS Select Safety Parameters Overall AEs AEs of special interest Hypoglycemia Urinary tract and genital infections

Demographics and Baseline Characteristics Data are mean ± SD unless otherwise specified. FPG=fasting plasma glucose; HOMA-2%β=β-cell function; HOMA-2 IS=insulin sensitivity.

Adjusted Mean Change from Baseline in HbA1c at 24 Weeks (LOCF) MB102013 monotherapy Placebo 2.5 mg 5 mg 10 mg -1.25 -1.00 -0.75 -0.50 -0.25 0.00 * P <0.0005 <0.0001 -0.23 -0.58 -0.77 -0.89 Dapagliflozin HbA1c, % Adjusted Mean Change From Baseline MB102014 add-on to MET <0.0002 -0.30 -0.67 -0.70 -0.84 Data are mean ± SE. Adjusted for baseline values. *Primary end point was tested at α=0.019 applying Dunnett’s adjustment. LOCF=last observation carried forward.

Adjusted Mean Change from Baseline in Fasting Plasma Glucose at 24 Weeks (LOCF) MB102013 monotherapy MB102014 add-on to MET -4.1 -6.0 -15.2 -10 -10 -17.8 -21.5 -24.1 -23.5 Fasting Plasma Glucose, mg/dL Adjusted Mean Change From Baseline Adjusted Mean Change -20 Fasting Plasma Glucose, mg/dL From Baseline -28.8 -20 * P =0.0019 * * -30 * -30 P <0.0001 P <0.0001 P <0.001 * P <0.0001 -40 -40 Placebo 2.5 mg 5 mg 10 mg Placebo 2.5 mg 5 mg 10 mg Dapagliflozin Dapagliflozin Data are mean ± SE. Adjusted for baseline values. *Secondary end points were tested at α=0.05 based on a sequential testing procedure. LOCF=last observation carried forward.

Adjusted Mean Change from Baseline in Body Weight at 24 Weeks (LOCF) MB102013 monotherapy Placebo 2.5 mg 5 mg 10 mg -4 -3 -2 -1 -2.2 -3.3 -2.8 -3.2 Dapagliflozin Body Weight Adjusted Mean Change From Baseline, kg MB102014 add-on to MET -0.9 -3.0 -2.9 * <0.0001 * * <0.0001 <0.0001 Data are mean ± SE. Adjusted for baseline values. *Secondary end points were tested at α=0.05 based on a sequential testing procedure. LOCF=last observation carried forward.

Adjusted Mean Change from Baseline in β-cell Function, HOMA-2%β at 24 Weeks (LOCF) MB102013 monotherapy Placebo 2.5 mg 5 mg 10 mg 5 10 15 20 25 1.2 14.7 14.4 18.4 Dapagliflozin HOMA-2% b Adjusted Mean Change From Baseline, % MB102014 add-on to MET 0.02 9.9 8.4 13.4 Data are mean ± SE. Adjusted for baseline values. LOCF=last observation carried forward.

Adjusted Mean Change from Baseline in Insulin Sensitivity, HOMA-2 IS at 24 Weeks (LOCF) MB102013 monotherapy Placebo 2.5 mg 5 mg 10 mg 2 4 6 8 10 12 2.8 6.4 7.9 6.8 Dapagliflozin HOMA-2 IS Adjusted Mean Change From Baseline, % MB102014 add-on to MET 6.0 9.5 8.9 Data are mean ± SE. Adjusted for baseline values. LOCF=last observation carried forward.

Overall Adverse Event Summary Data are number of patients (%). AE=adverse event; SAE=serious adverse event.

Adverse Events Data are number of patients (%).

Summary of Hypoglycemic Events *Patient experienced a minor and other episode during the trial. Major: symptomatic with plasma glucose <54 mg/dL and requires assistance due to severe impairment in consciousness or behavior Minor: symptomatic with plasma glucose <63 mg/dL regardless of need for external assistance Other: episodes suggestive of hypoglycemia but not meeting above criteria

Conclusions control in patients with T2DM. DAPA as monotherapy or add-on to metformin improved glycemic control in patients with T2DM. Improvements in glycemic control were accompanied by improvements in β-cell function as assessed by HOMA–2%β and HOMA–2 IS. Events of hypoglycemia were infrequent and occurred in similar proportions in the DAPA and placebo groups. There were no episodes of major hypoglycemia reported.