American College of CardiologyScientific Meeting 2019
Remo H. M. Furtado, et al. On behalf of the DECLARE TIMI-58
Executive & Steering Committees and Investigators
Dapagliflozin and CV outcomes in
patients with type 2 diabetes and prior
myocardial infarction: a sub-analysis
from DECLARE TIMI-58
NCT01730534DECLARE TIMI-58 was funded by a grant from AstraZeneca to Brigham and Women’s Hospital
Background
Wiviott et al. N Eng J Med 2019; 380: 347
~ 60 % with no prior athero CV disease> 90 % eGFR > 60 ml/min/1.73 m2
(CVD/MI/Ischemic Stroke)
Background
Zelniker et al. Lancet 2019; 393: 31
Atherosclerotic Cardiovascular Disease (ASCVD):
Multiple Risk Factors (MRF):
Das et al. J Am Coll Cardiol 2018;72: 3200
Background – ACC guidelines
0
5
10
15
20
25
0 5 10 15 20 25 30 35 40
Background
Cavender et al. Circulation 2015;132:923
MACE in REACH registry (n = 19,699) across the spectrum of atherothrombotic risk Adj K-M
(%)
Months
Diabetes + only risk
factors
Diabetes + ASCVD
without prior ischemic
event
Diabetes + ASCVD
with prior ischemic
event
CV
death
, M
I or
str
oke
To investigate the benefit of
dapagliflozin in the particular
subgroup of patients with
T2DM and prior MI
Objective
▪ DECLARE TIMI-58 trial randomized patients with T2DM and
either established ASCVD or only MRF to dapagliflozin 10 mg
QD versus placebo
▪ Prior MI was pre-specified as a subgroup of interest
▪ The risks of MACE and CVD/HHF (dual primary EPs) in patients
with and without prior MI were compared in the placebo arm,
with adjustment for baseline differences (Cox model)
▪ Efficacy of dapagliflozin regarding both MACE and CVD/HHF
was evaluated stratified by history of MI
▪ Treatment-by-subgroup interactions for the absolute risk
reductions (ARR) were analyzed using Gail−Simon test.
Methods
Results - Baseline
Prior MI
(n = 3,584)
No prior MI
(n = 13,576)
P
value
Age, yrs, median (IQR) 62 (57 , 68) 64 (60 , 68) < 0.001
Female sex (%) 24 41 < 0.001
Duration of DM, yrs, median (IQR) 10 (5 , 16) 11 (6 , 16) < 0.001
Insulin (%) 46 40 < 0.001
GFR, ml/min/1.73 m2, median (IQR) 88 (73 , 97) 89 (75 , 96) 0.10
Hypertension (%) 87 91 < 0.001
Dyslipidemia (%) 93 77 < 0.001
Current smoker (%) 16 14 0.086
Heart failure (%) 22 7 < 0.001
Prior Ischemic Stroke (%) 6 7 0.27
Prior PAD (%) 8 6 < 0.001
% with events: 17.8 % (prior MI) vs. 7.1 % (no prior MI)
Adj HR* (95 % CI) = 2.28 (1.96 to 2.65); p < 0.001
* Adjusted for: age, sex, race, weight, diabetes duration, region, baseline insulin, HF, dyslipidemia, hypertension, smoking, ischemic
stroke and peripheral artery disease.
Event rates in placebo arm
MACE – CV death, MI or ischemic stroke
20%
10%
0%
15%
5%
12 24 36 48
No prior MI
Prior MI
Months
Cu
mu
lati
ve in
cid
en
ce
10%
5%
0%
7.5%
2.5%
12 24 36
No prior MI
Prior MI
48
12.5%
Months
Event rates in placebo arm
CV death or hospitalization for HF
* Adjusted for: age, sex, race, weight, diabetes duration, region, baseline insulin, HF, dyslipidemia, hypertension, smoking, ischemic
stroke and peripheral artery disease.
% with events: 10.5 % (prior MI) vs. 4.5 % (no prior MI)
Adj HR* (95 % CI) = 1.77 (1.46 to 2.14); p < 0.001
Cu
mu
lati
ve in
cid
en
ce
10%
5%
0%360 24 36 48
15%
Prior MI – Placebo (N = 1,807)
Prior MI – Dapagliflozin (N = 1,777)
No Prior MI – Placebo (N = 6,771)
No Prior MI – Dapagliflozin (N = 6,805) Patients with prior MI
% with events: 17.8 % vs. 15.2 %
HR (95% CI) = HR 0.84 (0.72 to 0.99)
Patients without prior MI
% with events: 7.1 % vs. 7.1 %
HR (95% CI) = HR 1.00 (0.88 to 1.13)
20%
Months
ARR = 2.6 %
P-int HR = 0.11
P-int ARR = 0.048
CV outcomes with dapagliflozin
MACE – CV death, MI or ischemic stroke
12
ARR = 0.0 %Cu
mu
lati
ve
in
cid
en
ce
10%
5%
0%
7.5%
2.5%
12 24 36 48
12.5%Patients with prior MI
% with events: 10.5 % vs. 8.6 %
HR (95% CI) = HR 0.81 (0.65 to 1.00)
Patients without prior MI
% with events: 4.5 % vs. 3.9 %
HR (95% CI) = HR 0.85 (0.72 to 1.00)
Months
P-int ARR = 0.01
P-int HR = 0.69
CVD or HF hospitalization
CV outcomes with dapagliflozin
ARR = 1.9 %
Prior MI – Placebo (N = 1,807)
Prior MI – Dapagliflozin (N = 1,777)
No Prior MI – Placebo (N = 6,771)
No Prior MI – Dapagliflozin (N = 6,805)
ARR = 0.6 %Cu
mu
lati
ve
in
cid
en
ce
Study Endpoints by History of MI
HRP-interaction
for HRDapagliflozin
%
Placebo
%
0.78
0.99
0.80
1.08
0.64
1.01
9.2% 11.7%
6.7%
2.0 % 3.2 %
MI
Type 1 MI
Type 2 MI
3.4% 3.4%
8.3%
2.5% 2.3%
0.9% 0.9%
0.082
ARRP-interaction
for ARR
2.5%
0.0%
1.6%
- 0.2 %
1.1%
0.0 %
0.019
-5.0 -4.0 -3.0 -2.0 -1.0 0.0 1.0
Prior MI (N = 3,584) No Prior MI (N = 13,576)
Placebo better Dapagliflozin better Placebo better Dapagliflozin better
CV outcomes with dapagliflozin
Study Endpoints by History of MI
Placebo better Dapagliflozin better
0.92
1.03
4.9% 5.3 %CV death
2.3% 2.3 %
0.93
1.05
0.71
0.75
0.97
3.7% 3.9%
4.6%
0.54Ischemic
stroke
HHF
2.5% 2.4%
6.3%
1.9% 2.5%
0.56
0.77
- 0.1 %
- 0.1 %
0.3 %
1.8 %
0.6 %
0.50
0.001
0.56
Placebo better Dapagliflozin better
All cause
death
0.838.6% 10.3%
5.5% 5.7%0.22
0.4 %
1.7 %
0.1 % 0.084
-5.0 -4.0 -3.0 -2.0 -1.0 0.0 1.0 2.00.25 0.50 1.0 2.0
HR P-interaction
for HRDapagliflozin
%Placebo
%
ARR P-interaction
for ARR
CV outcomes with dapagliflozin
Prior MI (N = 3,584) No Prior MI (N = 13,576)
MACE by time from last MI
Placebo better Dapagliflozin better
HR P-interaction
(trend)
0.84
0.007
Dapagliflozin
%Placebo
%
Overall (N = 3,584) 15.2% 17.8%
13.8% 20.3%≤ 12 months (N = 488)
12-24 months (N = 356)
24-36 months (N = 339)
> 36 months (N = 2,400)
11.8% 25.7%
15.8% 18.8%
15.8% 15.8%
0.66
0.42
0.83
1.01
Summary
▪ Patients with T2DM and prior MI are at heightened risk
of both MACE and CV death/HF hospitalization
▪ Dapagliflozin appeared to robustly reduce the risk of
MACE, and particularly MI, in patients with prior MI
▪ This 22 % RRR in MI with dapagliflozin is comparable
to other established therapies used in secondary
prevention, like DAPT1 and intensive lipid lowering2
1- Bonaca et al. N Engl J Med. 2015; 372: 1791
2- Sabatine et al. Circulation. 2018; 138: 756
▪ Patients with T2DM and prior MI derived important CV
events reductions with dapagliflozin.
▪ Those findings add new relevant information to recent
guidelines, reinforcing that these patients should be
strongly considered for SGLT2 inhibitors when
selecting glucose-lowering agents.
▪ The mechanisms which could explain the reduction in
recurrent MI with SGLT2 inhibitors should be clarified
in future studies.
Conclusions
Additional Information
Article available at www.ahajournals.org
Slides available at www.TIMI.org