Consistent benefit with SGLT2i in ischemic and nonischemic HFrEF

Impact of Empagliflozin in Heart Failure With Reduced Ejection Fraction in Patients With Ischemic Versus Nonischemic Cause

Literature - Shahzeb Khan M, Butler J, Anker SD, et al. - J Am Heart Assoc. 2023 Jan 3;12(1):e027652. doi: 10.1161/JAHA.122.027652.

Introduction and methods

Background and aim of the study

The EMPEROR-Reduced trial previously showed that empagliflozin reduced the combined risk of CV death or hospitalization for HF in patients with HFrEF, compared with placebo [1]. The current post-hoc analysis examined whether the treatment effects of empagliflozin on cardiovascular and renal outcomes varied between patients with ischemic HFrEF and patients with nonischemic HFrEF.


The EMPEROR-Reduced trial enrolled HFrEF patients with NYHA class II to IV and LVEF ≤ 40%, who were either hospitalized for HF within 12 months or had elevated NT-proBNP levels (≥600 pg/mL, ≥1000 pg/mL or ≥2500 pg/mL in those with LVEF ≤ 30%, 31% to 35%, or 36% to 40%, respectively). A total of 3730 patients were randomized (1:1) to receive either empagliflozin or placebo. Information on the cause of HF was investigator reported and was retrieved from the case report form. Among the randomized patients, 1929 (51.7%) had ischemic HFrEF and 1801 (48.3%) had nonischemic HFrEF. Among those who had nonischemic HFrEF, the cause of HFrEF was most often related to idiopathic dilated cardiomyopathy (n=637, 35.4%), followed by a hypertensive cause (n=506, 28.1%), valvular heart disease (n=105, 5.8%), a diabetic cause (n=47, 2.6%), and alcoholism (n=41, 2.3%). A total of 506 patients (28.1%) were classified as having other nonischemic causes of HFrEF.


The primary end point was the time-to-first-event of CV death or hospitalization for HF. Key secondary end points were total HF hospitalizations, and rate of decline in eGFR. The composite renal end point was the need for chronic dialysis or renal transplant, or a ≥40% decrease in eGFR , or a sustained eGFR<15 ml/min/1,73 m² or <10 mL/min/1.73m² if the eGFR was ≥30 ml/min/1,73 m² or <30 mL/min/1.73m² at baseline, respectively. Health status was investigated using the Kansas City Cardiomyopathy Questionnaire- Clinical Summary Score (KCCQ-CSS). Safety endpoints were hypotension, volume depletion, bone fracture, hypoglycemia, and adverse events leading to drug discontinuation.

Main results

  • Among patients receiving placebo, patients with ischemic HFrEF did not have a significantly higher risk of the primary outcome compared with patients with nonischemic HFrEF.
  • The treatment effect of empagliflozin on the primary endpoint was similar in patients with an ischemic and with a nonischemic cause of HFrEF. Empagliflozin reduced the primary endpoint compared with placebo in patients with an ischemic cause (HR: 0.82, 95%CI: 0.68-0.99) and those with a nonischemic cause (HR: 0.67, 95%CI: 0.55-0.82; P for interaction=0.149).
  • The effects of empagliflozin on the key secondary endpoints of total HF hospitalizations, and rate of the decline in eGFR were also consistent across patients with and without an ischemic cause. Empagliflozin reduced the risk of total HF hospitalizations compared with placebo in patients with ischemic HFrEF (HR: 0.73, 95%CI: 0.56-0.95) and in those with nonischemic HFrEF (HR: 0.66, 95%CI: 0.60-0.88, P for interaction=0.620). The placebo-corrected eGFR slope change was 1.57 (95%CI: 0.70-2.44) in patients with an ischemic cause and 1.93 (95%CI: 1.01-2.86) in patients with a nonischemic cause (P for interaction=0.572).
  • Similarly, the cause of HFrEF did not modify the effect of empagliflozin on the renal composite endpoint (HR: 0.42, 95%CI: 0.24-0.74 in ischemic HFrEF and HR: 0.62, 95%CI: 0.31-1.23 in nonischemic HFrEF; P for interaction=0.399).
  • Empagliflozin improved the KCCQ-CSS in ischemic HFrEF (+1.70, +0.79, and +1.07 at 12, 32, and 52 weeks) and nonischemic HFrEF (+2.21, +1.96, and +2.22 at 12, 32, and 52 weeks; P for interaction=0.61).
  • There were no significant differences in adverse events in the empagliflozin arm across patients with ischemic HFrEF and patients with nonischemic HFrEF.


This post-hoc analysis of the EMPEROR-Reduced trial demonstrated that the cause of HFrEF (ischemic vs. nonischemic) did not modify the treatment benefits of empagliflozin on cardiovascular and renal outcomes.


1. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–1424. doi: 10.1056/NEJMoa2022190

Find this article online at J Am Heart Assoc.

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