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Empagliflozin (Jardiance) improved outcomes in heart failure with preserved ejection fraction (HFpEF) regardless of mineralocorticoid receptor antagonist (MRA) background therapy in the EMPEROR-Preserved trial.

In a subanalysis, the SGLT2 inhibitor reduced combined cardiovascular death and hospitalization for heart failure in both MRA users (HR 0.73, 95% CI 0.62-0.87) and non-users (HR 0.87, 95% CI 0.71-1.06) without a significant interaction.

However, there was a signal for greater benefits in MRA non-users for heart failure hospitalization, reported João Pedro Ferreira, MD, PhD, of the Universidade do Porto in Portugal, and colleagues in the .

Combining first and recurrent admissions, participants not on an MRA had a relative 40% reduction with empagliflozin compared with the 10% reduction among MRA users, with a significant interaction term (P=0.038).

"This finding and trends observed with other endpoints indicate that we cannot rule out decreasing SGLT2 inhibitor benefit with MRA use," wrote Marvin A. Konstam, MD, of Tufts Medical Center in Boston, in an .

There is "mechanistic overlap among renin-angiotensin-aldosterone receptor inhibitors, beta-adrenergic blockers, and SGLT2 inhibitors," he noted.

That might influence clinicians' managment of select individuals, Konstam suggested. "However, in the absence of an SGLT2 inhibitor contraindication, such as type 1 diabetes or severe renal impairment, and given the relatively benign safety profile of these agents, the weight of evidence favors SGLT2 inhibitor use in both MRA users and non-users."

In fact, the subanalysis showed reduced risk for hyperkalemia or initiation of potassium binders particularly for MRA users, albeit without significant interaction (HR 0.74, 95% CI 0.56-0.96 vs HR 0.90, 95% CI 0.69-1.19, for non-users).

These trend data "raise a question of SGLT2 inhibitors' increasing clinical effectiveness of MRAs by reducing the frequency of drug discontinuation," Konstam wrote, additionally pointing to the "nonsignificant trend toward reduced MRA discontinuation with empagliflozin, a finding that might prove clinically relevant in a real-world population."

Empagliflozin gained expanded approval across the spectrum of left ventricular ejection fraction (LVEF) earlier this year based on the main findings from the EMPEROR-Preserved trial.

It showed a relative 21% reduction in the primary composite endpoint of mortality and heart failure hospitalization for HFpEF patients randomized to empagliflozin versus placebo. Of the study's 5,988 participants with class II-IV heart failure and an LVEF over 40%, 37.5% were using MRAs at baseline.

MRA users tended to have "a more congested clinical picture," according to Ferreira and team, "which is supported by the higher placebo event rates seen in this subgroup." Also, they had higher prevalence of prior hospitalization within 12 months, worse heart failure functional class, more frequent use of loop diuretic agents, and higher baseline N-terminal pro-brain natriuretic peptide levels.

Further statistical adjustment for those differences, along with urinary albumin-to-creatinine ratio and hemoglobin and sodium levels, didn't significantly alter the results. "But it is worth recalling that one cannot adjust for variables that are not measured," Konstam noted.

Additional analyses by patient characteristics suggested that the difference between MRA users and non-users fell mainly to those with LVEF of 50% or greater, not in those with midrange ejection fraction, as well as to those with volume overload.

"Of note, secondary analysis from TOPCAT suggested that the effect of spironolactone was attenuated in patients with LVEFs >50%-55%," Ferreira's group wrote.

They cautioned that use of MRAs was not randomized in the trial, that the results were not corrected for multiplicity of comparisons and should thus be considered exploratory, and that the LVEF and volume overload findings were based on small numbers.

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