Dapagliflozin and CV outcomes in patients with type 2 diabetes and - - PowerPoint PPT Presentation

American College of Cardiology Scientific 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

NCT01730534

DECLARE 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

5 10 15 20 25 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, MI or stroke

To investigate the benefit of dapagliflozin in the particular subgroup

• f

patients with T2DM and prior MI

Objective

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DECLARE TIMI-58 trial randomized patients with T2DM and either established ASCVD or only MRF to dapagliflozin 10 mg QD versus placebo

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Prior MI was pre-specified as a subgroup of interest

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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)

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Efficacy of dapagliflozin regarding both MACE and CVD/HHF was evaluated stratified by history of MI

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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

Cumulative incidence

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

Cumulative incidence

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 %

Cumulative incidence

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 %

Cumulative incidence

Study Endpoints by History of MI

HR P-interaction for HR Dapagliflozin % 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 ARR P-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% 0.54 Ischemic 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 0.83 8.6% 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 2.0

0.25 0.50 1.0 2.0

HR P-interaction for HR Dapagliflozin % 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

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Patients with T2DM and prior MI are at heightened risk

• f both MACE and CV death/HF hospitalization

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Dapagliflozin appeared to robustly reduce the risk of MACE, and particularly MI, in patients with prior MI

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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

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Patients with T2DM and prior MI derived important CV events reductions with dapagliflozin.

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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.

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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