Empagliflozin Efficacy and Mineralocorticoid Receptor Antagonists in Patients With HF

Researchers sought to compare the effect of empagliflozin in patients that do vs patients that do not take mineralocorticoid receptor antagonists for HFpEF.

An analysis found little evidence of an interaction between mineralocorticoid receptor antagonists (MRAs) and empagliflozin on outcomes among patients with heart failure (HF). These findings were published in Journal of the American College of Cardiology.

This study was a prespecified secondary analysis of data from the EMPEROR-Preserved trial, which was a phase 3, international, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial. Patients (N=5988) with chronic HF were randomly assigned in a 1:1 ratio to receive placebo or 10 mg/d empagliflozin. The composite primary endpoint was adjudicated cardiovascular death and HF hospitalization. This study evaluated whether baseline use of MRAs altered empagliflozin’s efficacy on the primary endpoint.

The patients who had no baseline MRA (n=3744) or MRA (n=2244) exposure were aged mean 72.5±9.1 and 70.9±9.8 years (P <.0001) and 44.4% and 45.1% were women, respectively. MRA use was associated with higher heart rate, lower systolic blood pressure, lower left ventricular ejection fraction, and poorer New York Heart Association functional class.

Among MRA users, the treatment effect for the primary composite outcome was 0.87 (95% CI, 0.71-1.06) compared with 0.73 (95% CI, 0.62-0.87) among nonusers (P =.22).

Significant interactions with MRA were observed for the outcomes of total HF hospitalization (treatment effect, 0.90 vs 0.60; P =.038) and first HF hospitalization (treatment effect, 0.86 vs 0.60; P =.032).

Compared with placebo, empagliflozin was favored for reducing the primary composite endpoint overall (hazard ratio [HR], 0.79; 95% CI, 0.69-0.90) and among the no MRA cohort (HR, 0.73; 95% CI, 0.62-0.87) and for reducing total HF hospitalizations overall (HR, 0.73; 95% CI, 0.61-0.88) and among the no MRA cohort (HR, 0.60; 95% CI, 0.47-0.77) with a significant MRA interaction (P =.0379).

For the extended endpoint of first instance of outpatient diuretic intensification, urgent care or emergency department visit requiring intravenous diuretic therapy, HF hospitalization, or cardiovascular death, empagliflozin was favored overall (HR, 0.77; 95% CI, 0.70-0.85) and among both the no MRA (HR, 0.73; 95% CI, 0.64-0.82) and MRA (HR, 0.85; 95% CI, 0.73-0.99) cohorts.

Compared with placebo, receiving empagliflozin did not significantly alter rates of MRA discontinuation (HR, 0.87; 95% CI, 0.73-1.04; P =.12) or initiation (HR, 0.88; 95% CI, 0.74-1.04; P =.14).

This analysis was limited as MRA was not prescribed by trial-associated clinicians and patients were not stratified by MRA prior to randomization.

“The benefit of empagliflozin to reduce the primary outcome was not significantly different between MRA nonusers and MRA users,” the study authors wrote. “Empagliflozin reduced hyperkalemia, with no significant treatment–by–MRA subgroup interaction.”

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Ferreira JP, Butler J, Zannad F, et al. Mineralocorticoid receptor antagonists and empagliflozin in patients with heart failure and preserved ejection fraction. J Am Coll Cardiol. Published online on March 21, 2022. doi:10.1016/j.jacc.2022.01.029