Empagliflozin Provides Consistent Benefit in HFrEF, Regardless of Diuretic Use

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Data from the EMPEROR-Reduced trial provide insight into the effects of empagliflozin in patients with heart failure with reduced ejection fraction based on baseline diuretic use from the phase 3 trial.

A posthoc analysis of the EMPEROR-Reduced trial is offering clinicians with additional insight into the effects of empagliflozin use across subgroups of patients with heart failure with reduced ejection fraction (HFrEF).

An analysis examining effects according to background diuretic use, results of the study suggest the effects of empagliflozin on time to cardiovascular death or heart failure hospitalization regardless of baseline diuretic therapy status, with no difference in safety profile across patient subgroups.1

“The present findings of a consistency of effect of empagliflozin on the primary outcome of [cardiovascular] death or [heart failure] hospitalization in HFrEF irrespective of baseline diuretic doses mirrors previous findings from DAPA-HF (Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction),” wrote investigators.1 “However,unlike the analysis from DAPA-HF, in which total [heart failure] hospitalization rates and time to first [heart failure] hospitalization were not assessed, this analysis also demonstrates a potential attenuated efficacy of empagliflozin on [heart failure] hospitalizations among patient staking the highest doses of diuretic agents.”

Empagliflozin has been played an integral role in the ascent of the SGLT2 inhibitor into the spotlight of cardiometabolic care. With approvals for heart failure across the spectrum of ejection fraction in patients with or without diabetes, and with a potential indication in chronic kidney disease on the horizon, the patient population for the agent has grown by leaps and bounds in recent years.2

Led by Nitish K. Dhingra, MD, a cardiac surgery resident within the Division of Cardiac Surgery for St. Michael’s Hospital at the University of Toronto, and conducted on behalf of the EMPEROR-Reduced trial committees and investigators, the current study was launched with the intent of further exploring the clinical efficacy of SGLT2 inhibitors according to baseline diuretic use. With this in mind, investigators designed the analysis to assess the trial’s primary outcome as well as the effect on body weight, systolic blood pressure, NT-proBNP, and hematocrit across 4 groups defined as having no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline.1

Of the 3730 patients included in EMPEROR-Reduced, 3656 were included in the current analysis. Among this cohort, 13.2% were receiving no diuretic therapy, and 20.0%, 38.6%, and 28.2% were receiving <40 mg, 40 mg, and >40 mg, respectively.1

Upon analysis, results indicated the effect of empagliflozin for the primary outcome was consistent regardless of background diuretic use (P =.192):1

  • >40 mg: HR, 0.88; 95% CI, 0.71-1.10
  • 40 mg: HR, 0.65; 95% CI, 0.51-0.82
  • <40 mg: HR, 0.65; 95% CI,0.46-0.92
  • No diuretic agents: HR, 0.78; 95% CI, 0.47-1.29

Further analysis suggested baseline diuretic status did not impact the effect of empagliflozin on body weight, systolic blood pressure, NT-proBNP, or hematocrit at 52 weeks. Analysis of safety outcomes revealed a similar trend, with the safety profile relative to placebo unaffected by baseline diuretic use. However, investigators pointed out total rates of adverse events were greater among those with elevated baseline doses of diuretic agents, with this trend independent of treatment allocation.1

“In summary, empagliflozin in EMPEROR-Reduced demonstrated a consistent effect on the primary composite outcome of hospitalization for [heart failure] or [cardiovascular] death, along with a comparable safety profile, regardless of baseline diuretic doses,” investigators wrote.1


  1. Dhingra NK, Verma S, Butler J, et al. Efficacy and safety of Empagliflozin according to background diuretic use in heart failure with reduced ejection fraction. JACC: Heart Failure. Published online September 2023. doi:10.1016/j.jchf.2023.06.036
  2. Campbell P, Iapoce C. 10 years of SGLT2 inhibitors: A Decade of Redefining Cardiometabolic Care. HCP Live. March 29, 2023. Accessed September 15, 2023.