Afshin Salsali MD, Arnaud Bastien MD, Traci Mansfield PhD,

1. 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

2. 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

3. 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.

4. 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)

5. 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) Double-blind treatment period Lead-in period -2 -1 0 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

6. 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

7. 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.

8. MB102013 monotherapy MB102014 add-on to MET 0.00 0.00 -0.23 -0.30 -0.25 -0.25 -0.58 -0.67 -0.50 -0.50 -0.77 Adjusted Mean Change Adjusted Mean Change -0.70 From Baseline From Baseline HbA1c, % HbA1c, % -0.89 -0.84 -0.75 -0.75 * * <0.0002 P * <0.0001 P * -1.00 -1.00 <0.0005 P * <0.0001 P <0.0001 P -1.25 -1.25 Placebo 2.5 mg 5 mg 10 mg Placebo 2.5 mg 5 mg 10 mg Dapagliflozin Dapagliflozin Adjusted Mean Change from Baseline in HbA1c at 24 Weeks (LOCF) 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.

9. Adjusted Mean Change from Baseline in Fasting Plasma Glucose at 24 Weeks (LOCF) MB102014 add-on to MET MB102013 monotherapy 0 0 -4.1 -6.0 -15.2 -10 -10 -17.8 -21.5 -24.1 -23.5 Adjusted Mean Change Adjusted Mean Change Fasting Plasma Glucose, mg/dL Fasting Plasma Glucose, mg/dL From Baseline From Baseline -20 -20 -28.8 * * 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.

10. MB102013 monotherapy MB102014 add-on to MET 0 0 -0.9 -1 -1 -2.2 -2.2 Adjusted Mean Change From Baseline, kg Body Weight Adjusted Mean Change From Baseline, kg Body Weight -2.8 -2 -2 -3.2 -2.9 -3.3 -3.0 -3 -3 -4 -4 Placebo 2.5 mg 5 mg 10 mg Placebo 2.5 mg 5 mg 10 mg Dapagliflozin Dapagliflozin Adjusted Mean Change from Baseline in Body Weight at 24 Weeks (LOCF) * <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.

11. MB102014 add-on to MET MB102013 monotherapy 25 25 20 20 b b 15 15 Adjusted Mean Change Adjusted Mean Change From Baseline, % From Baseline, % HOMA-2% HOMA-2% 18.4 10 10 13.4 14.7 14.4 1.2 5 5 0.02 9.9 8.4 0 0 Placebo 2.5 mg 5 mg 10 mg Placebo 2.5 mg 5 mg 10 mg Dapagliflozin Dapagliflozin Adjusted Mean Change from Baseline in β-cell Function, HOMA-2%β at 24 Weeks (LOCF) Data are mean ± SE. Adjusted for baseline values. LOCF=last observation carried forward.

12. MB102013 monotherapy MB102014 add-on to MET 12 12 10 10 8 8 9.5 Adjusted Mean Change Adjusted Mean Change HOMA-2 IS HOMA-2 IS 8.9 6 6 From Baseline, % From Baseline, % 7.9 4 4 6.4 6.0 6.8 6.4 2 2 2.8 0 0 Placebo 2.5 mg 5 mg 10 mg Placebo 2.5 mg 5 mg 10 mg Dapagliflozin Dapagliflozin Adjusted Mean Change from Baseline in Insulin Sensitivity, HOMA-2 IS at 24 Weeks (LOCF) Data are mean ± SE. Adjusted for baseline values. LOCF=last observation carried forward.

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

14. Adverse Events Data are number of patients (%).

15. 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

16. Conclusions • 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.