Effect of qualifying atherosclerotic cardiovascular disease diagnosis proximity on cardiovascular risk and benefit of empagliflozin in EMPA-REG OUTCOME

Background In patients with type 2 diabetes mellitus (T2DM), a history of an ischemic event is associated with increased risk for cardiovascular disease. Whether patients with T2DM and a recent atherothrombotic diagnosis benefit from early intervention with a sodium-glucose co-transporter 2 (SGLT2) inhibitor is unknown. Methods This is a secondary analysis of EMPA-REG OUTCOME, which compared empagliflozin to placebo in adults with T2DM and atherosclerotic cardiovascular disease (ASCVD). Participants were categorized based on the time since their last qualifying ASCVD diagnosis (≤1 year versus >1 year). Qualifying ASCVD diagnoses included ischemic or hemorrhagic stroke, myocardial infarction (MI), coronary artery disease, or peripheral artery disease. The primary outcome was a composite of cardiovascular death, non-fatal MI, or non-fatal stroke. Results 6,796 participants (n=4,547 empagliflozin, n=2,249 placebo) were included. Median time since the last qualifying ASCVD diagnosis was 3.8 years (Quartile1–Quartile3: 1.5–7.6), and most qualifying diagnoses occurred >1 year before randomization (≤1 year: n=1,214, >1 year n=5,582). Empagliflozin reduced the primary outcome irrespective of the time since the last qualifying ASCVD diagnosis (≤1 year: hazard ratio [HR] 0.82, 95% confidence interval [CI]: 0.57–1.16; versus >1 year : HR 0.85, 95%-CI: 0.72–1.00; p-interaction=0.84). Results were similar for the composite of cardiovascular death or hospitalization for heart failure. Conclusions Empagliflozin improved cardiovascular outcomes in participants with T2DM, irrespective of the time since the last qualifying ASCVD diagnosis at randomization. Prospective trials are necessary to investigate the use of SGLT2 inhibitors at the time of an acute ASCVD event.