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
Introduction and methods
Residual CV risk is high in T2DM patient with prior myocardial infarction (MI) despite standard-of-care treatment  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 . 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) . 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.
- 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.