afshin salsali md, arnaud bastien md, traci mansfield phd,
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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
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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)
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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.
MB102013 monotherapy
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
MB102014 add-on to MET
Placebo 2.5 mg 5 mg 10 mg-40
-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 *
* *
MB102013 monotherapy
Placebo 2.5 mg 5 mg 10 mg-4
-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
MB102014 add-on to MET
Placebo 2.5 mg 5 mg 10 mg-4
-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.
MB102013 monotherapy
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,
%
MB102014 add-on to MET
Placebo 2.5 mg 5 mg 10 mg0
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
MB102013 monotherapy
Placebo 2.5 mg 5 mg 10 mg0
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, %
MB102014 add-on to MET
Placebo 2.5 mg 5 mg 10 mg0
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)
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
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.
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Study MB102013 – monotherapy Study MB102014 – add-on to MET
Dapagliflozin Dapagliflozin
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 (%).
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
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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