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): ); 2Rossetti et al J Clin Invest 1987:79; );
3Macdonald FR et al. Diabetes Obes Metab Nov;12(11): )

5. Double-blind treatment period
Study Designs
MB (NCT ) 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)
MB (NCT ) 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: ; 2Bailey et al Lancet 2010;375:

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. Adjusted Mean Change from Baseline in HbA1c
at 24 Weeks (LOCF)
MB 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
MB 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.

9. Adjusted Mean Change from Baseline in
Fasting Plasma Glucose at 24 Weeks (LOCF)
MB monotherapy
MB 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.

10. Adjusted Mean Change from Baseline in Body Weight at 24 Weeks (LOCF)
MB 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
MB 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.

11. Adjusted Mean Change from Baseline in
β-cell Function, HOMA-2%β at 24 Weeks (LOCF)
MB 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, %
MB 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.

12. Adjusted Mean Change from Baseline in
Insulin Sensitivity, HOMA-2 IS at 24 Weeks (LOCF)
MB 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, %
MB add-on to MET
6.0
9.5
8.9
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 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.