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

Trial design and population

The design of the EMPA-REG OUTCOME® trial has been described and the study protocol has been published [8]. Briefly, eligible participants had type 2 diabetes (with HbA_1c 53–75 mmol/mol [7.0–9.0%] for drug-naive participants and 53–86 mmol/mol [7.0–10.0%] for those on stable glucose-lowering therapy), established cardiovascular disease and estimated (e)GFR, according to modification of diet in renal disease (MDRD) ≥30 ml min⁻¹ 1.73 m⁻². Participants were identified as having a history of CABG at baseline based on case report forms in which the investigator noted a history of CABG (based on the participant’s self-report) using a yes/no checkbox. Participants were randomised to receive empagliflozin 10 mg, empagliflozin 25 mg or placebo, once daily. Background glucose-lowering therapy was to remain unchanged for 12 weeks. After week 12, investigators were encouraged to adjust glucose-lowering therapy to achieve glycaemic control according to local guidelines. Investigators were encouraged to treat cardiovascular risk factors to achieve the best standard of care according to local guidelines throughout the trial. Serum creatinine and urinary albumin were measured from spot urine samples obtained during study visits at screening (creatinine only), during the placebo run-in period, at baseline, at weeks 12, 28 and 52 and then every 14 weeks until the final visit. Events that were consistent with changes in the albuminuria category were captured if any laboratory assessment during the trial fulfilled the given criteria on at least one occasion. The trial was to continue until ≥691 participants experienced an adjudicated event included in the primary outcome (three-point MACE: composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke). Participants who prematurely discontinued study medication continued to be followed for ascertainment of cardiovascular outcomes, adverse events and vital status.

The EMPA-REG OUTCOME® trial was registered with ClinicalTrials.gov (NCT01131676) and carried out in compliance with the protocol and the principles of the Declaration of Helsinki, and in accordance with the International Conference on Harmonization Harmonized Tripartite Guideline for Good Clinical Practice. All participants provided signed and dated informed consent. The trial was conducted at 590 sites in 42 countries.

Outcomes

All cardiovascular outcome events and deaths were prospectively adjudicated by Clinical Events Committees who were blinded to treatment allocation. The following outcomes were analysed in subgroups by history of CABG (yes/no) at baseline: three-point MACE (composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke); fatal or non-fatal myocardial infarction; fatal or non-fatal stroke; cardiovascular death; four-point MACE (composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for unstable angina); hospitalisation for heart failure; composite of heart failure hospitalisation or cardiovascular death; all-cause mortality; incident or worsening nephropathy (defined as progression to macroalbuminuria [urine albumin-to-creatinine ratio >300 mg/g], doubling of serum creatinine accompanied by eGFR [MDRD] ≤45 ml min⁻¹ 1.73 m⁻², initiation of renal replacement therapy or death due to renal disease). Safety was assessed based on adverse events that occurred during treatment or within 7 days after the last dose of study drug.

Analyses

Analyses in subgroups by CABG at baseline were post hoc and based on participants who received ≥1 dose of study drug, except for incident or worsening nephropathy. This outcome was analysed in participants who received ≥1 dose of study drug who did not have macroalbuminuria at baseline, who had serum creatinine measurements at baseline and after baseline, and who had post-baseline urine albumin-to-creatinine ratio measurements (unless participants who did not fulfil these criteria had at least one of the other components of the composite renal outcome).

Differences between empagliflozin (pooled) and placebo in the risk of an outcome were assessed using a Cox proportional hazards model, with factors for age, sex, baseline BMI, baseline HbA_1c, baseline eGFR, region, treatment, CABG and treatment by CABG interaction, using events observed from randomisation to the end of the trial. Adjustment for these factors is consistent with the pre-specified analyses in subgroups by other baseline characteristics [8].

The p values for treatment by subgroup interaction were obtained from tests of homogeneity of treatment group differences among subgroups, with no adjustment for multiple testing. Data from participants who did not have an event were censored on the last day they were known to be free of the outcome. Kaplan–Meier estimates are presented for three-point MACE, cardiovascular death, hospitalisation for heart failure, all-cause mortality and incident or worsening nephropathy.

In participants with a history of CABG, we assessed cardiovascular death, hospitalisation for heart failure and all-cause mortality in subgroups by time from CABG to randomisation (≤5, >5 to ≤10, >10 years) and the proportion of participants with different numbers of coronary revascularisation (redo CABG; redo and/or new PCI) procedures during the trial. Outcomes in subgroups by time from CABG to randomisation and the proportion of participants with different numbers of coronary revascularisation procedures during the trial were assessed descriptively. Adverse events in subgroups by history of CABG were assessed descriptively, consistent with how adverse events in other subgroups were to be analysed according to the statistical analysis plan [8].

Baseline characteristics

Background medication use was balanced between the empagliflozin and placebo groups in participants with and without CABG (Table 1). In individuals with a history of CABG, 96% were using any anti-hypertensive therapy (96% in the empagliflozin group and 98% in the placebo group), 81% were using angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy (82% in the empagliflozin group and 80% in the placebo group) and 8% were using mineralocorticoid receptor antagonists (8% in the empagliflozin group and 6% in the placebo group). In addition, 84% of individuals were using statins (83% in the empagliflozin group and 85% in the placebo group), 94% were using antiplatelet/anticoagulant therapy (93% in the empagliflozin group and 95% in the placebo group) and 57% were taking insulin (57% in the empagliflozin group and 56% in the placebo group) (Table 1).

Cardiovascular outcomes, mortality and renal outcomes

In participants with a history of CABG at baseline, empagliflozin was associated with a 48% reduction in the risk of cardiovascular death (HR 0.52 [95% CI 0.32, 0.84]) (Figs 1 and 2a). This was consistent with the overall trial population (HR 0.62 [95% CI 0.49, 0.77]), and there was no significant difference between participants with and without a history of CABG at baseline (p = 0.3976 for treatment by subgroup interaction) (Fig. 1). Results appeared to be consistent across subgroups by time from CABG to randomisation (ESM Table 1). In participants with a history of CABG at baseline, empagliflozin reduced the risk of all-cause mortality by 43% (HR 0.57 [95% CI 0.39, 0.83]) (p = 0.2695 for interaction between subgroups of participants with and without CABG at baseline) (Figs 1 and 2b).

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Consistent with the overall trial population, the HR for three-point MACE with empagliflozin vs placebo was 0.80 (95% CI 0.60, 1.06) in participants with a history of CABG at baseline (Figs 1 and 2c). This was consistent with participants without a history of CABG (HR 0.88 [95% CI 0.74, 1.04]) (p = 0.5586 for treatment by subgroup interaction). There was no difference between empagliflozin and placebo in the risk of myocardial infarction or stroke in participants with or without a history of CABG (Fig. 1). The HR for four-point MACE with empagliflozin vs placebo was 0.89 (95% CI 0.68, 1.15) in participants with a history of CABG at baseline, and this was consistent with participants without a history of CABG (HR 0.89 [95% CI 0.76, 1.04]) (p = 0.9933 for treatment by subgroup interaction). Of participants with a history of CABG at baseline, a smaller proportion treated with empagliflozin (7.7%) than placebo (9.8%) underwent ≥1 coronary revascularisation procedure during the trial. Of participants who underwent coronary revascularisation, most had only one such procedure (ESM Table 2).

Consistent with the overall trial population, empagliflozin reduced the risk of hospitalisation for heart failure by 50% in participants with a history of CABG at baseline (HR 0.50 [95% CI 0.32, 0.77]). Risk reductions were consistent between participants with and without a history of CABG (p = 0.1359 for treatment by subgroup interaction) (Figs 1 and 3a). Consistent with the overall trial population, the HR for the composite of heart failure hospitalisation or cardiovascular death in participants with a history of CABG was 0.52 (95% CI 0.37, 0.74). Risk reductions were consistent between participants with and without a history of CABG (p = 0.1264 for treatment by subgroup interaction) (Fig. 1). Also consistent with the overall trial population, empagliflozin reduced the risk of incident or worsening nephropathy by 35% in participants with a history of CABG at baseline (HR 0.65 [95% CI 0.50, 0.84]). This was consistent between participants with and without a history of CABG (p = 0.5673 for interaction) (Figs 1 and 3b).

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Conclusions

In participants with type 2 diabetes and a history of CABG, empagliflozin given in addition to standard of care was associated with significant reductions in cardiovascular and all-cause mortality, hospitalisation for heart failure and incident or worsening nephropathy compared with placebo. The relative risk reductions with empagliflozin were consistent with those observed in the overall EMPA-REG OUTCOME® trial population. Absolute risk reductions, particularly for hospitalisation for heart failure, were numerically greater in participants with a history of CABG, reflecting the higher event rates in these participants (although no statistical tests were performed to compare absolute risk reductions). These data have important implications for secondary prevention pharmacotherapy after CABG in individuals with type 2 diabetes.