Greater benefit of SGLT2 inhibitor in type 2 diabetes patients with history of MI

Dapagliflozin and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Prior Myocardial Infarction: A Sub-analysis From DECLARE TIMI-58 Trial

Literature - Furtado RHM, Bonaca MP, Raz I, et al. - Circulation 2019;

Introduction and methods

Residual CV risk is high in T2DM patient with prior myocardial infarction (MI) despite standard-of-care treatment [1] and robust benefit of major adverse cardiovascular events (MACE) can be achieved with more advanced secondary prevention therapies [2-4]. In addition, patients with history of MI have an increased risk of HF and lower long-term survival [5]. Therefore, there is an unmet need to prevent MACE and HF in T2DM patients with prior MI.

In the DECLARE TIMI-58 trial, T2DM patients with presence of ASCVD or multiple risk factors were randomized to dapagliflozin or placebo on top of standard-of-care medical therapy. Dapagliflozin reduced the composite of CV death and hospitalization for HF, in patients with T2DM (HR 0.83, 95%CI: 0.73 to 0.95, P=0.005). A potential signal of benefit for MACE with dapagliflozin was only observed in those with ASCVD (in total population MACE was not reduced, HR was 0.93, 95%CI: 0.84-1.03, P=0.17) [6]. To examine whether a subgroup of patients with T2DM and prior MI could derive greater benefit from dapagliflozin compared to those without prior MI, a prespecified analysis was performed.

In this prespecified analysis of patients with history of MI (n=3584) vs those without prior MI (n=13576) consisting of those with ASCVD (n=3390) or with multiple risk factors (n=10186), the two primary endpoints were MACE, a composite of CV death, MI or ischemic stroke) and composite of CV death and HF hospitalizations.

Main results

  • In patients with prior MI, 15.2% of patients with dapagliflozin vs. 17% in placebo group suffered from MACE (HR 0.84, 95%CI: 0.72-0.99, P=0.039, and absolute risk reduction 2.6%, 95%CI: 0.1-5.0%, NTT over 4 years was 39). In patients without prior MI, there was no reduction in MACE with dapagliflozin compared to placebo group (HR 1.00, 95%CI: 0.88-1.13, P=0.97) (relative P-interaction=0.1, absolute risk reduction P-interaction=0.048). Also, in patients with no prior MI but with established ASCVD, MACE was not reduced in those with dapagliflozin compared to placebo (HR 0.98, 0.81-1.19, P=0.85; absolute risk reduction 0.2%, 95% CI: -2.0 % to 2.4%).
  • Relative risk reductions in composite of CV death or HF hospitalizations in patients with and without prior MI were similar (HR 0.81, 95%CI: 0.65-1.00 and HR 0.85, 95%CI: 0.72-1.00, respectively, Pinteraction=0.69). Because patients with prior MI had higher baseline risk, absolute risk reductions were greater with dapagliflozin vs. placebo in these patients (absolute risk reduction of 1.9%, 95%CI: 0.0-3.8%) compared with patients without MI (ARR 0.6%, 95%CI: 0.0-1.3%; absolute risk reduction Pinteraction=0.010). NNT over 4 years was 53.
  • Recurrent MI was reduced in patients with prior MI with dapagliflozin use vs. placebo (HR 0.78, 95% CI 0.63-0.95), both type 1 MI (HR 0.80, 95% CI 0.63-1.02) and type 2 MI (HR 0.64, 95% CI 0.42-0.97).
  • In those with prior MI, lower rates of the composite of CHD death, non-fatal MI or sudden cardiac death were observed with dapagliflozin vs. placebo (HR 0.81; 95 % CI 0.67-0.97).
  • In those with prior MI, reduction of MACE with dapagliflozin was greater the closer patients were to their qualifying MI (Pinteraction trend=0.007).


In this prespecified subanalysis of the DECLARE TIMI-58 trial, use of dapagliflozin resulted in a greater benefit in terms of reduction in MACE in T2DM patients with prior MI compared to those without prior MI or in those without prior MI but with ASCVD. Absolute risk reduction in CV death or HF hospitalization was greater with dapagliflozin in those with prior MI compared to those without. Interestingly, in those with prior MI, there was a reduction in type 2 MI with use of dapagliflozin, suggesting that dapagliflozin reduces MI’s caused by mismatch between myocardial oxygen supply and demand, rather than plaque rupture and atherothrombosis.


1. Bhatt DL, Eagle KA, Ohman EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA. 2010; 304:1350–1357.

2. Bhatt DL, Bonaca MP, Bansilal S, et al. Reduction in Ischemic Events With Ticagrelor in Diabetic Patients With Prior Myocardial Infarction in PEGASUS-TIMI 54. J Am Coll Cardiol. 2016; 67:2732-2740.

3. Giugliano RP, Cannon CP, Blazing MA, et al. Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes Mellitus: Results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation. 2018; 137: 1571-1582.

4. Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomized controlled trial. Lancet Diabetes Endocrinol. 2017; 5: 941-950.

5. Torabi A, Cleland JG, Khan NK, et al. The timing of development and subsequent clinical course of heart failure after a myocardial infarction. Eur Heart J. 2008; 29: 859–870.

6. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019; 380: 347-357.

Find this article online at Circulation

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