dapagliflozin and cv outcomes in patients with type 2 ... prior mi - oral presentation... ·...

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


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


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


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


Prior MI (N = 3,584) No Prior MI (N = 13,576)

MACE by time from last MI


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

dapagliflozin and cv outcomes in patients with type 2 ... prior mi - oral presentation... ·...

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