Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial Infarction

Abstract

Background: Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because of their baseline risk, patients with previous myocardial infarction (MI) may derive even greater benefit from sodium glucose transporter-2 inhibitor therapy. Methods: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) randomized 17 160 patients with type 2 diabetes mellitus and either established atherosclerotic cardiovascular disease (n=6974) or multiple risk factors (n=10 186) to dapagliflozin versus placebo. The 2 primary end points were composite of MACE (cardiovascular death, MI, or ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure. Those with previous MI (n=3584) made up a prespecified subgroup of interest. Results: In patients with previous MI (n=3584), dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% (15.2% versus 17.8%; hazard ratio [HR], 0.84; 95% CI, 0.72–0.99; P =0.039), whereas there was no effect in patients without previous MI (7.1% versus 7.1%; HR, 1.00; 95% CI, 0.88–1.13; P =0.97; P for interaction for relative difference=0.11; P for interaction for absolute risk difference=0.048), including in patients with established atherosclerotic cardiovascular disease but no history of MI (12.6% versus 12.8%; HR, 0.98; 95% CI, 0.81–1.19). There seemed to be a greater benefit for MACE within 2 years after the last acute event ( P for interaction trend=0.007). The relative risk reductions in cardiovascular death/hospitalization for heart failure were more similar, but the absolute risk reductions tended to be greater: 1.9% (8.6% versus 10.5%; HR, 0.81; 95% CI, 0.65–1.00; P =0.046) and 0.6% (3.9% versus 4.5%; HR, 0.85; 95% CI, 0.72–1.00; P =0.055) in patients with and without previous MI, respectively ( P interaction for relative difference=0.69; P interaction for absolute risk difference=0.010). Conclusions: Patients with type 2 diabetes mellitus and previous MI are at high risk of MACE and cardiovascular death/hospitalization for heart failure. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. Future studies should aim to confirm the large clinical benefits with sodium glucose transporter-2 inhibitors we observed in patients with previous MI. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

European Society of Cardiology/Heart Failure Association position paper on the role and safety of new glucose‐lowering drugs in patients with heart failure

“…By contrast, in non‐HFrEF patients (either without known HF or without known reduced LVEF), HF risk reduction was lower compared with HFrEF patients and there was no effect on mortality. Yet another sub‐analysis of the same trial has demonstrated a reduction in hospitalisation irrespective of baseline CV risk profile (established CV disease or multiple risk factors), albeit individuals with prior MI derived the greatest benefit, including a reduction in the risk of 3‐point MACE with dapagliflozin …”

Effects of sodium‐glucose cotransporter‐2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

“…In the DECLARE–TIMI 58 study, dapagliflozin was associated with a significant reduction in the risk of CV death or hospitalization for HF (17%), but this risk reduction was the result of a reduced risk of hospitalization for HF (27%) as the risk of CV death was not significantly different (Table ) . In subgroup analyses of the DECLARE–TIMI 58 study, the risk of CV death or hospitalization for HF was reduced to a greater extent in patients with HFrEF at baseline (38%) than in those without HFrEF (12%) ( P for interaction, 0.046), while the risk of this composite outcome was consistently reduced with dapagliflozin compared with placebo in patients with or without prior MI at baseline . The greater treatment effect of dapagliflozin in patients with HFrEF may be driven by a reduction in the risk of CV death in this patient subgroup (45%) that was not observed in those without HFrEF (hazard ratio [HR] 1.08) ( P for interaction, 0.012) …”

Cardiorenal protection with SGLT2: Lessons from the cardiovascular outcome trials

“…This is noteworthy considering that no such effect was established in patients who did not suffer from previous MI (HR 1.00; 95% CI, 0.88‐1.13; P = .97). A statistically significant increase in RR reduction of 31.5% for CV death or hospitalization for HF in patients with MI (1.9%) compared to patients without MI (0.6%) was noted . This effect was attributed to the increased baseline risk of adverse CV events in MI patients.…”

“…A subanalysis of the DECLARE‐TIMI58 study by Furtado et al was conducted to expand upon the use of SGLT2 inhibitors in those patients who had suffered a previous MI (N = 3584) . This analysis defined two primary end points as a composite of MACE (defined by CV death, MI, or ischemic stroke) and CV death or hospitalization for HF.…”