In a post-hoc analysis of EMPEROR-Reduced, consistent treatment effect of empagliflozin versus placebo on HF hospitalization or CV death and a comparable safety profile were observed in HFrEF patients, irrespective of background diuretic therapy.

This summary is based on the publication of Dhingra NK, Verma S, Butler J, et al. - Efficacy and Safety of Empagliflozin According to Background Diuretic Use in HFrEF: Post-Hoc Analysis of EMPEROR-Reduced. JACC Heart Fail. 2024 Jan;12(1):35-46. doi: 10.1016/j.jchf.2023.06.036

Introduction and methods

Background

Patients with HFrEF are often prescribed diuretic agents, but it is not clear whether the clinical efficacy of SGLT2 inhibitors varies by baseline use and intensity of diuretic agents.

Aim of the study

In a post-hoc analysis of the EMPEROR-Reduced trial, the authors investigated potential modification of empagliflozin’s efficacy and safety by background diuretic therapy.

Methods

The EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial was a double-blind, placebo-controlled, parallel-group, event-driven, phase 3 RCT in which 3730 patients with HFrEF (LVEF ≤40%; NYHA class ≥II HF symptoms; NT-proBNP ≥600 pg/mL, depending on LVEF) were randomized to empagliflozin 10 mg daily or placebo, in addition to guideline-directed therapy. In this post-hoc analysis, 3656 study participants were included, who were stratified into 4 groups based on their baseline diuretic use: no diuretic therapy (n=482; 13.2%), and oral furosemide-equivalent daily doses of <40 mg (n=731; 20.0%), 40 mg (n=1411; 38.6%), or >40 mg (n=1032; 28.2%).

Outcomes

The primary endpoint was a composite outcome of time-to-first hospitalization for HF or CV death. Key secondary endpoints were total (first and recurrent) HF hospitalizations, components of the primary endpoint, and time to all-cause mortality. Patient-reported health status was assessed using the KCCQ. Other outcomes of interest included changes in body weight, blood pressure, NT-proBNP and hematocrit levels, and the incidence of adverse events.

Main results

Primary and secondary endpoints

• For the primary composite endpoint, consistent benefit of empagliflozin over placebo was observed in all patients, regardless of their background diuretic therapy. The HR was 0.88 (95%CI: 0.71–1.10) for patients receiving an oral furosemide-equivalent daily dose >40 mg, 0.65 (95%CI: 0.51–0.82) for those taking the 40-mg dose, 0.65 (95%CI: 0.46–0.92) for those on the <40-mg dose, and 0.78 (95%CI: 0.47–1.29) for those not receiving diuretic agents (P for trend across diuretic-dose groups=0.192).
• For total HF hospitalizations, there was a trend toward diminished efficacy of empagliflozin versus placebo in patients receiving the highest diuretic doses at baseline (P for trend across diuretic-dose groups=0.082). This trend reached significance for time to first HF hospitalization (HR for >40 mg: 0.84; 95%CI: 0.65–1.08; HR for 40 mg: 0.63; 95%CI: 0.47–0.83; HR for <40 mg: 0.56; 95%CI: 0.36–0.87; HR for no diuretic therapy: 0.48; 95%CI: 0.24–0.97; P for trend across diuretic-dose groups=0.036).
• The other key secondary endpoints did not show significant interaction by diuretic dose.

Other clinical outcomes

• The treatment effect of empagliflozin versus placebo on improving the KCCQ - Clinical Summary Score and Overall Summary Score at 12 and 52 weeks was similar, irrespective of baseline diuretic dose (all P for trend across diuretic-dose groups>0.05).
• In addition, baseline diuretic dose did not influence empagliflozin’s effect on body weight, systolic blood pressure, NT-proBNP, or hematocrit at 52 weeks.
• The total rate of adverse events was higher in patients receiving higher baseline diuretic doses, regardless of randomization to empagliflozin or placebo (>40 mg: 82.9% vs. 85.8%; 40 mg: 72.9% vs. 77.0%; <40 mg: 76.6% vs. 75.2%; no diuretic therapy: 71.5% vs. 73.7%).
• Incidence rates of acute kidney injury, volume depletion, hypotension, hyperkalemia, genital infections, and confirmed hypoglycemia were similar across diuretic subgroups in the empagliflozin and placebo groups.

Changes in diuretic dose

• Empagliflozin lengthened the time to the first diuretic dose increase in all patients taking diuretic agents at baseline (HR: 0.68; 95%CI: 0.58–0.80; P<0.001), although there was a trend toward reduced efficacy in patients receiving the highest diuretic doses (HR for >40 mg: 0.85; 95%CI: 0.66–1.08; HR for 40 mg: 0.58; 95%CI: 0.44–0.76; HR for <40 mg: 0.59; 95%CI: 0.43–0.83; P for trend across diuretic-dose groups=0.054).
• Among patients not taking diuretic agents at baseline, time to diuretic initiation was lengthened with empagliflozin compared with placebo (HR: 0.62; 95%CI: 0.44–0.88; P=0.008).

Conclusion

In this post-hoc analysis of the EMPEROR-Reduced trial, consistent benefit of empagliflozin over placebo for the primary composite endpoint of HF hospitalization or CV death was observed in HFrEF patients, irrespective of their background diuretic therapy. In addition, empagliflozin exhibited a diuretic-sparing effect, by delaying the time to the first diuretic dose increase (in patients receiving oral furosemide-equivalent daily dose ≤40 mg) and the time to diuretic initiation (in those not taking diuretic agents at baseline). The safety profile of empagliflozin versus placebo was not affected by baseline diuretic dose.

A potentially attenuated effect of empagliflozin on time to first HF hospitalization was seen among patients taking the highest diuretic dose (>40 mg). The authors offer several explanations for this observation and conclude that, “in concert with the consistency of effect of empagliflozin regardless of diabetes or CKD, the available evidence suggests that diuresis is not a significant component of the mechanism of action of empagliflozin.”

Find this article online at JACC Heart Fail.