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

American College of Cardiology Scientific Meeting 2019 Dapagliflozin and CV outcomes in patients with type 2 diabetes and prior myocardial infarction: a sub-analysis from DECLARE TIMI-58 Remo H. M. Furtado, et al. On behalf of the DECLARE TIMI-58 Executive & Steering Committees and Investigators NCT01730534 DECLARE TIMI- 58 was funded by a grant from AstraZeneca to Brigham and Women’s Hospital

Background (CVD/MI/Ischemic Stroke) ~ 60 % with no prior athero CV disease > 90 % eGFR > 60 ml/min/1.73 m 2 Wiviott et al. N Eng J Med 2019; 380: 347

Background Atherosclerotic Cardiovascular Disease (ASCVD): Multiple Risk Factors (MRF): Zelniker et al. Lancet 2019; 393: 31

Background – ACC guidelines Das et al. J Am Coll Cardiol 2018;72: 3200

Background MACE in REACH registry (n = 19,699) across the spectrum of atherothrombotic risk Adj K-M 25 (%) 20 Diabetes + ASCVD with prior ischemic CV death, MI or stroke event 15 Diabetes + ASCVD without prior ischemic event 10 Diabetes + only risk factors 5 0 0 5 10 15 20 25 30 35 40 Months Cavender et al. Circulation 2015;132:923

Objective To investigate the benefit of dapagliflozin in the particular subgroup of patients with T2DM and prior MI

Methods ▪ 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.

Results - Baseline Prior MI No prior MI P (n = 3,584) (n = 13,576) 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 m 2 , 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

Event rates in placebo arm MACE – CV death, MI or ischemic stroke % with events: 17.8 % (prior MI) vs. 7.1 % (no prior MI) 20% Adj HR * (95 % CI) = 2.28 (1.96 to 2.65); p < 0.001 Cumulative incidence 15% 10% 5% Prior MI No prior MI 0% 12 36 48 24 Months * 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 CV death or hospitalization for HF % with events: 10.5 % (prior MI) vs. 4.5 % (no prior MI) 12.5% Adj HR * (95 % CI) = 1.77 (1.46 to 2.14); p < 0.001 Cumulative incidence 10% 7.5% 5% 2.5% Prior MI No prior MI 0% 12 24 48 36 Months * Adjusted for: age, sex, race, weight, diabetes duration, region, baseline insulin, HF, dyslipidemia, hypertension, smoking, ischemic stroke and peripheral artery disease.

CV outcomes with dapagliflozin MACE – CV death, MI or ischemic stroke 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 20% % with events: 17.8 % vs. 15.2 % HR (95% CI) = HR 0.84 (0.72 to 0.99) ARR = 2.6 % Patients without prior MI 15% Cumulative incidence % with events: 7.1 % vs. 7.1 % HR (95% CI) = HR 1.00 (0.88 to 1.13) P-int ARR = 0.048 10% P-int HR = 0.11 ARR = 0.0 % 5% 0% 360 24 36 48 12 Months

CV outcomes with dapagliflozin CVD or HF hospitalization Prior MI – Placebo (N = 1,807) Prior MI – Dapagliflozin (N = 1,777) No Prior MI – Placebo (N = 6,771) Patients with prior MI 12.5% No Prior MI – Dapagliflozin (N = 6,805) % with events: 10.5 % vs. 8.6 % HR (95% CI) = HR 0.81 (0.65 to 1.00) Patients without prior MI 10% ARR = 1.9 % % with events: 4.5 % vs. 3.9 % Cumulative incidence HR (95% CI) = HR 0.85 (0.72 to 1.00) 7.5% P-int ARR = 0.01 5% P-int HR = 0.69 ARR = 0.6 % 2.5% 0% 12 24 36 48 Months

CV outcomes with dapagliflozin Study Endpoints by History of MI Prior MI (N = 3,584) No Prior MI (N = 13,576) P-interaction P-interaction ARR HR Dapagliflozin Placebo for HR for ARR % % 2.5% 9.2% 11.7% 0.78 0.019 0.082 MI 3.4% 3.4% 0.99 0.0% 1.6% 6.7% 8.3% 0.80 Type 1 MI 2.5% 2.3% 1.08 - 0.2 % 0.64 1.1% 3.2 % 2.0 % Type 2 MI 0.9% 0.9% 1.01 0.0 % -5.0 -4.0 -3.0 -2.0 -1.0 0.0 1.0 Placebo better Dapagliflozin better Dapagliflozin better Placebo better

CV outcomes with dapagliflozin Study Endpoints by History of MI Prior MI (N = 3,584) No Prior MI (N = 13,576) P-interaction Dapagliflozin HR P-interaction ARR Placebo for ARR % for HR % 0.4 % 4.9% 5.3 % 0.92 0.50 CV death 0.56 - 0.1 % 2.3 % 2.3% 1.03 0.3 % 3.7% 3.9% 0.93 0.56 Ischemic 0.54 - 0.1 % 2.5% 2.4% 1.05 stroke 1.8 % 0.71 4.6% 6.3% HHF 0.77 0.001 0.6 % 1.9% 2.5% 0.75 All cause 0.83 1.7 % 8.6% 10.3% 0.22 death 0.084 5.5% 0.97 5.7% 0.1 % 0.25 0.50 1.0 2.0 -5.0 -4.0 -3.0 -2.0 -1.0 0.0 1.0 2.0 Dapagliflozin better Placebo better Dapagliflozin better Placebo better

MACE by time from last MI Dapagliflozin P-interaction Placebo HR (trend) % % 17.8% Overall ( N = 3,584 ) 15.2% 0.84 0.66 ≤ 12 months ( N = 488 ) 13.8% 20.3% 0.42 12-24 months (N = 356) 11.8% 25.7% 0.007 0.83 15.8% 24-36 months (N = 339) 18.8% 1.01 > 36 months (N = 2,400) 15.8% 15.8% Dapagliflozin better Placebo better

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 DAPT 1 and intensive lipid lowering 2 1- Bonaca et al. N Engl J Med. 2015; 372: 1791 2- Sabatine et al. Circulation. 2018; 138: 756

Conclusions ▪ 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.

Additional Information Article available at www.ahajournals.org Slides available at www.TIMI.org