Empagliflozin reduces cardiovascular events, mortality and renal events in participants with type 2 diabetes after coronary artery bypass graft surgery: subanalysis of the EMPA-REG OUTCOME® randomised trial

Abstract

Aims/hypothesis: After coronary artery bypass graft (CABG) surgery in individuals with type 2 diabetes, there remains a considerable residual cardiovascular risk. In the EMPA-REG OUTCOME® trial in participants with type 2 diabetes and established cardiovascular disease, empagliflozin reduced the risk of cardiovascular death by 38%, all-cause mortality by 32%, hospitalisation for heart failure by 35% and incident or worsening nephropathy by 39% vs placebo when given in addition to standard of care. The aim of this post hoc analysis of the EMPA-REG OUTCOME® trial was to determine the effects of the sodium glucose cotransporter 2 inhibitor empagliflozin on cardiovascular events and mortality in participants with type 2 diabetes and a self-reported history of CABG surgery.

Methods: The EMPA-REG OUTCOME® trial was a randomised, double-blind, placebo-controlled trial. Participants with type 2 diabetes and established cardiovascular disease were randomised 1:1:1 to receive placebo, empagliflozin 10 mg or empagliflozin 25 mg, once daily, in addition to standard of care. In subgroups by self-reported history of CABG (yes/no) at baseline, we assessed: cardiovascular death; all-cause mortality; hospitalisation for heart failure; and incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine, initiation of renal replacement therapy or death due to renal disease). Differences in risk between empagliflozin and placebo were assessed using a Cox proportional hazards model.

Results: At baseline, 25% (1175/4687) of participants who received empagliflozin and 24% (563/2333) of participants who received placebo had a history of CABG surgery. In participants with a history of CABG surgery, HRs (95% CI) with empagliflozin vs placebo were 0.52 (0.32, 0.84) for cardiovascular mortality, 0.57 (0.39, 0.83) for all-cause mortality, 0.50 (0.32, 0.77) for hospitalisation for heart failure and 0.65 (0.50, 0.84) for incident or worsening nephropathy. Results were consistent between participants with and without a history of CABG surgery (p > 0.05 for treatment by subgroup interactions).

Conclusions/interpretation: In participants with type 2 diabetes and a self-reported history of CABG surgery, treatment with empagliflozin was associated with profound reductions in cardiovascular and all-cause mortality, hospitalisation for heart failure, and incident or worsening nephropathy. These data have important implications for the secondary prevention of cardiovascular events after CABG in individuals with type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT01131676.

Keywords: Cardiovascular disease; Coronary artery bypass graft; Coronary revascularisation; Diabetes mellitus; Empagliflozin; Sodium glucose cotransporter 2 inhibition; Type 2 diabetes.

Conflict of interest statement

SV has received research grants and/or speaking honoraria from Boehringer Ingelheim, Eli Lilly, AstraZeneca, Janssen, Merck, Amgen, Sanofi, Valeant, Bayer, Pfizer and Valeant, holds a tier 1 Canada Research Chair, is national lead investigator for the DAPA-HF trial (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients with Chronic Heart Failure), the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt failure with Reduced ejection fraction (EMPEROR-Reduced) and the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt failure with Preserved ejection fraction (EMPEROR-Preserved), and is a member of the steering committees of the Cardiovascular Inflammation Reduction Trial (CIRT) and the Behavior of Valve Leaflets (BELIEVE) trial. CDM has received consulting fees from Amgen, Boehringer Ingelheim and OctaPharma. DF reports honoraria from Sanofi, Merck & Co., Amgen, AstraZeneca, Eli Lilly and Company and Boehringer Ingelheim. SEI has consulted for Janssen, vTv Therapeutics and Alere, served on Clinical Trial Steering/Executive Committees for Boehringer Ingelheim, AstraZeneca, Novo Nordisk, Sanofi/Lexicon Pharmaceuticals, Daiichi-Sankyo and Eisai (Thrombolysis in Myocardial Infarction [TIMI]) and served on Data Monitoring Committees for Intarcia Therapeutics, Inc. BZ has received research grants awarded to his institution from Boehringer Ingelheim, AstraZeneca and Novo Nordisk, and honoraria from Janssen, Sanofi, Eli Lilly and Company, Boehringer Ingelheim, Novo Nordisk and Merck. EP and JTG are employees of Boehringer Ingelheim.

Figures

Fig. 1

Cardiovascular outcomes, all-cause mortality and incident or worsening nephropathy by history of CABG surgery. Cox regression analysis in participants treated with ≥1 dose of study drug, except for incident or worsening nephropathy, which was analysed in participants who received ≥1 dose of study drug who did not have macroalbuminuria at baseline, had serum creatinine measurements at baseline and after baseline, and had post-baseline urine albumin-to-creatinine ratio measurements. Interaction p value is for test of homogeneity of treatment group difference among subgroups (test for treatment by subgroup interaction) with no adjustment for multiple tests. CV; cardiovascular

Fig. 2

Time to cardiovascular death, all-cause mortality and three-point MACE by history of CABG. (a) Cardiovascular death in participants with a history of CABG (HR 0.52 [95% CI 0.32, 0.84]). (b) Cardiovascular death in participants without a history of CABG (HR 0.65 [95% CI 0.51, 0.84]). (c) All-cause mortality in participants with a history of CABG (HR 0.57 [95% CI 0.39, 0.83]). (d) All-cause mortality in participants without a history of CABG (HR 0.73 [95% CI 0.59, 0.90]). (e) Three-point MACE in participants with a history of CABG (HR 0.80 [95% CI 0.60, 1.06]). (f) Three-point MACE in participants without a history of CABG (HR 0.88 [95% CI 0.74, 1.04]). Kaplan–Meier estimates in participants treated with ≥1 dose of study drug. HR and 95% CI are based on Cox regression analyses. Solid line, empagliflozin; dashed line, placebo. No., number

Fig. 3

Time to hospitalisation for heart failure and incident or worsening nephropathy by history of CABG. (a) Time to hospitalisation for heart failure in participants with a history of CABG (HR 0.50 [95% CI 0.32, 0.77]). (b) Time to hospitalisation for heart failure in participants without a history of CABG (HR 0.76 [95% CI 0.54, 1.06]). (c) Incident or worsening nephropathy in participants with a history of CABG (HR 0.65 [95% CI 0.50, 0.84]). (d) Incident or worsening nephropathy in participants without a history of CABG (HR 0.60 [95% CI 0.51 0.69]). Kaplan–Meier estimates in participants treated with ≥1 dose of study drug, except for incident or worsening nephropathy, which was analysed in participants who received ≥1 dose of study drug who did not have macroalbuminuria at baseline, had serum creatinine measurements at baseline and after baseline and had post-baseline urine albumin-to-creatinine ratio measurements. HR and 95% CI are based on Cox regression analyses. Solid line, empagliflozin; dashed line, placebo. No., number