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

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 Squibband AstraZeneca

2

Dapagliflozin Mechanism of Action

Proximal tubule

SGLT2 SGLT1

S1

S3

Glomerulus Distal tubule

Loop of Henle

Collecting duct

Glucosefiltration

Reduced glucosereabsorption

Increasedglucose

excretion

Dapagliflozin

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.

3

• 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.

Background and Aims

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)

4

MET + Dapagliflozin 2.5 mg (n=137)

MET + Dapagliflozin 5 mg (n=137)

MET + Dapagliflozin 10 mg (n=135)

MET + Placebo (n=137)Rand

omize

d (n

=546

)

Lead-in period Double-blind treatment period

Study Week

-2 -1 0 4 8 12 16 20 24

Study Designs

Dapagliflozin 2.5 mg (n=65)

Dapagliflozin 5 mg (n=64)

Dapagliflozin 10 mg (n=70)

Placebo (n=75)Rand

omize

d (n

=274

)Treatment-naïve patients with HbA1c 7%–10%1

Patients inadequatelycontrolled with metformin (≥1500 mg/d for ≥8 weeks)and HbA1c 7%–10%2

MB102013 (NCT00528372) monotherapy

MB102014 (NCT00528879) add-on to MET

1Ferrannini et al Diabetes Care 2010;33:2217-2224; 2Bailey et al Lancet 2010;375:2223-22335

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

6

MB102013 – monotherapy MB102014 – add-on to MET

Dapagliflozin Dapagliflozin

Placebo n=75

2.5 mg n=65

5 mg n=64

10 mg n=70

Placebo n=137

2.5 mg n=137

5 mg n=137

10 mg n=135

Age, y 52.7±10.3 53.0±11.7 52.6±10.9 50.6±10.0 53.7±10.3 55.0±9.3 54.3±9.4 52.7±9.9

Men, n, (%) 31 (41) 36 (55) 31 (48) 34 (49) 76 (55) 70 (51) 69 (50) 77 (57)

HbA1c, % 7.84±0.87 7.92±0.90 7.86±0.94 8.01±0.96 8.13±0.96 7.99±0.89 8.16±0.96 7.95±0.84

FPG, mg/dL 159.9±42.1 164.1±48.0 162.2±45.0 166.6±41.5 165.9±46.3 161.5±43.1 169.3±48.8 156.3±38.6

Duration of diabetes, y

2.1±3.1 2.1±3.2 1.0±1.6 2.3±3.7 5.8±5.1 6.0±6.2 6.4±5.8 6.1±5.4

HOMA–2%β, % 76.6±37.6 80.0±40.4 71.5±37.4 67.9±29.3 67.4±34.3 71.1±36.7 70.4±41.7 71.3±36.4

HOMA–2 IS, % 39.1±17.0 34.7±12.9 40.2±18.5 36.4±18.7 42.8±22.1 40.4±17.6 40.2±18.2 43.7±19.2

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.

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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.

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

P<0.0001

-0.23

-0.58

-0.77-0.89

Dapagliflozin

HbA

1c, %

Adj

uste

d M

ean

Cha

nge

Fro

m B

asel

ine

MB102014 add-on to MET

Placebo 2.5 mg 5 mg 10 mg-1.25

-1.00

-0.75

-0.50

-0.25

0.00

P<0.0001*

*P<0.0001

*P<0.0002

-0.30

-0.67-0.70

-0.84

Dapagliflozin

HbA

1c, %

Adj

uste

d M

ean

Cha

nge

Fro

m B

asel

ine

8

Adjusted Mean Change from Baseline in Fasting Plasma Glucose at 24 Weeks (LOCF)

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.


Placebo 2.5 mg 5 mg 10 mg-40

-30

-20

-10

0

**P<0.001

P<0.0001

-4.1

-15.2

-24.1-28.8

Dapagliflozin

Fast

ing

Plas

ma

Glu

cose

, mg/

dLA

djus

ted

Mea

n C

hang

e F

rom

Bas

elin

e



-30

-20

-10

0

** *

P=0.0019

P<0.0001 P<0.0001

-6.0

-17.8-21.5 -23.5

DapagliflozinFa

stin

g Pl

asm

a G

luco

se, m

g/dL

Adj

uste

d M

ean

Cha

nge

Fro

m B

asel

ine

9

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

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

<0.0001 <0.0001

<0.0001 *

* *



-3

-2

-1

0

-2.2

-3.3

-2.8-3.2

Dapagliflozin

Bod

y W

eigh

tA

djus

ted

Mea

n C

hang

eFr

om B

asel

ine,

kg



-3

-2

-1

0-0.9

-2.2

-3.0 -2.9

DapagliflozinB

ody

Wei

ght

Adj

uste

d M

ean

Cha

nge

From

Bas

elin

e, k

g

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.


Placebo 2.5 mg 5 mg 10 mg0

5

10

15

20

25

1.214.7 14.4

18.4

Dapagliflozin

HO

MA

-2%

A

djus

ted

Mea

n C

hang

eFr

om B

asel

ine,

%



5

10

15

20

25

0.02 9.9 8.4

13.4

DapagliflozinH

OM

A-2

%

Adj

uste

d M

ean

Cha

nge

From

Bas

elin

e, %

11

12



2

4

6

8

10

12

2.86.4

7.96.8

Dapagliflozin

HO

MA

-2 IS

Adj

uste

d M

ean

Cha

nge

From

Bas

elin

e, %



2

4

6

8

10

12

6.0 6.4

9.58.9

DapagliflozinH

OM

A-2

ISA

djus

ted

Mea

n C

hang

eFr

om B

asel

ine,

%

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)



Placebo

n=75 2.5 mg n=65

5 mg n=64

10 mg n=70

Placebo n=137

2.5 mg n=137

5 mg n=137

10 mg n=135

At least one AE 45 (60) 41 (63) 37 (58) 48 (69) 88 (64) 89 (65) 95 (69) 98 (73)

At least one related AE 9 (12) 10 (15) 9 (14) 13 (19) 22 (16) 22 (16) 25 (18) 31 (23)

Deaths 0 0 0 1 (1) 0 0 0 0

At least one SAE 3 (4) 0 1 (2) 1 (1) 5 (4) 4 (3) 4 (3) 4 (3)

At least one related SAE 0 0 0 0 2 (2) 0 0 1 (1)

SAE leading to discontinuation

0 0 1 (2) 0 3 (2) 0 0 0

AE leading to discontinuation

1 (1) 2 (3) 3 (5) 5 (7) 5 (4) 3 (2) 3 (2) 4 (3)

Hypoglycemia leading to discontinuation

0 0 0 0 0 0 0 0

Overall Adverse Event Summary

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

13

14

Study MB102013 – monotherapy Study MB102014 – add-on to MET


Adverse event (≥5% in any group)

Placebo n=75

2.5 mg n=65

5 mg n=64

10 mg n=70

Placebo n=137

2.5 mg n=137

5 mg n=137

10 mg n=135

Headache 5 (7) 5 (8) 3 (5) 4 (6) 6 (4) 4 (3) 10 (7) 11 (8)

Back pain 7 (5) 5 (4) 3 (2) 10 (7)

Diarrhea 1 (1) 4 (6) 1 (2) 1 (1) 7 (5) 3 (2) 5 (4) 10 (7)

Urinary tract infection 1 (1) 1 (2) 0 4 (6) 7 (5) 4 (3) 7 (5) 9 (7)

Influenza 3 (4) 2 (3) 4 (6) 1 (1) 10 (7) 13 (9) 13 (9) 8 (6) Nasopharyngitis 4 (5) 7 (11) 3 (5) 2 (3) 11 (8) 12 (9) 4 (3) 8 (6)

Hypertension 2 (3) 2 (3) 3 (5) 2 (3) 6 (4) 9 (7) 4 (3) 5 (4)

Upper respiratory tract infection 1 (1) 1 (2) 0 4 (6) 10 (7) 5 (4) 4 (3) 3 (2)

Cough 7 (5) 4 (3) 4(3) 1(<1)

Arthralgia 1 (1) 2 (3) 4 (6) 4 (6)

Pharyngitis 5 (7) 1 (2) 2 (3) 4 (6)

Events by special interest category

Events suggestive of urinary tract infections 3 (4) 3 (5) 8 (12) 4 (6) 11 (8) 6 (4) 10 (7) 11 (8)

Events suggestive of genital infections 1 (1) 5 (8) 5 (8) 9 (13) 7 (5) 11 (8) 18 (13) 12 (9)

Hypotensive events 1 (1) 0 0 1 (1) 1 (<1) 0 2 (1) 0

Adverse Events

Data are number of patients (%).



Placebo n=75

2.5 mg n=65

5 mg n=64

10 mg n=70

Placebo n=137

2.5 mg n=137

5 mg n=137

10 mg n=135

Episodes Number of patients (%) Number of patients (%)

Total 2 (3) 1 (2) 0 2 (3) 4 (3) 3 (2) 5 (4) 5 (4)

Major 0 0 0 0 0 0 0 0

Minor 0 1 (2)* 0 0 0 1 (1)* 2 (2) 1 (1)

Other 2 (3) 1 (2)* 0 2 (3) 4 (3) 3 (2)* 3 (2) 4 (3)

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 behaviorMinor: symptomatic with plasma glucose <63 mg/dL regardless of need for external assistanceOther: episodes suggestive of hypoglycemia but not meeting above criteria 15

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.

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Documents

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