Time to Cardiovascular Benefits of Empagliflozin: A <i>Post Hoc</i> Observation from the EMPA-REG OUTCOME Trial
Subodh Verma, Lawrence A. Leiter, Bernard Zinman, Abhinav Sharma, Michaela Mattheus, David Fitchett, Jyothis T. George, Anne Pernille Ofstad, Mikhail Kosiborod, Christoph Wanner, Silvio E. Inzucchi
Abstract
AIMS: In the EMPA-REG OUTCOME trial, in patients with type 2 diabetes and established atherosclerotic cardiovascular (CV) disease, empagliflozin vs. placebo reduced the risk of hospitalization for heart failure (HHF) by 35%, CV death/HHF by 34%, and CV death by 38%, with an early separation of the cumulative incidence curves. We explored at what time point after randomization these benefits became apparent. METHODS AND RESULTS: We expressed time trajectories for the effect of pooled empagliflozin doses vs. placebo on HHF, CV death/HHF, and CV death based on hazard ratios (95% confidence interval) and calculated the hazard ratio on the day the effect reached significance using Cox proportional hazards models. Overall, 7020 patients aged ≥18 years were treated with empagliflozin 10 mg (N = 2345), empagliflozin 25 mg (N = 2342), or placebo (N = 2333) once daily in addition to standard of care. Mean age (years ± SD) was 63.1 ± 8.6, and 72% were male. The benefit of empagliflozin on CV death first reached statistical significance on Day 59 (HR [95% confidence interval]) (0.28 [0.08, 0.96], P = 0.0424) and was generally sustained throughout the trial (overall 0.62 [0.49, 0.77], P < 0.0001). Risk reduction with empagliflozin on HHF reached statistical significance on Day 17 (0.10 [0.01, 0.87], P = 0.0372) and was sustained throughout the study (overall 0.65 [0.50, 0.85], P = 0.0017). For the composite outcome of CV death or HHF, risk reduction with empagliflozin reached statistical significance on Day 27 (0.28 [0.08, 0.97], P = 0.0445) and was sustained throughout follow-up (overall 0.66 [0.55, 0.79], P < 0.0001). CONCLUSIONS: In EMPA-REG OUTCOME, the benefit of empagliflozin in reducing the risk of HHF, CV death/HHF, and CV death emerged within weeks after treatment initiation. The earliest benefit appears to be on HHF.