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