Benefit of Empagliflozin in HFpEF Consistent Regardless of Diuretic Status

A post hoc analysis of the phase 3 EMPEROR-Preserved trial suggests empagliflozin treatment in patients with heart failure with preserved ejection fraction (HFpEF) should be independent of diuretic therapy and could reduce the need for diuretics.¹

The analysis showed empagliflozin was associated with comparable improvements in time to cardiovascular death (CV death) or hospitalization for heart failure (HHF), first and total HHF, rate of decline in estimated glomerular filtration rate (eGFR), and health status, regardless of baseline diuretic status or dose.

“This is in line with findings from heart failure with reduced ejection fraction (HFrEF) patients in the DAPA-HF trial, where baseline diuretic therapy did not modify the benefit of dapagliflozin on these outcomes,” wrote the investigative team, led by Javed Butler, MD, MPH, MBA, at the Baylor Scott and White Research Institute.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors primarily act through a diuretic mechanism and their benefit may be attenuated in patients already taking other diuretics. It is possible that the combined use of SGLT2 inhibitors with conventional diuretics may increase the risk of volume depletion events, acute kidney injury, and other adverse effects.² Butler and colleagues indicated that the use of SGLT2 inhibitors could additionally impact the need for conventional diuretic therapy.

As a result, the post hoc analysis of the EMPEROR-Preserved trial aimed to assess the safety and efficacy of empagliflozin in relation to background diuretic therapy, as well as to study the association of empagliflozin with the use of conventional diuretics over time. The phase 3 trial was conducted from March 2017 - April 2021 and included individuals with New York Heart Association (NYHA) class II to IV heart failure and left ventricular ejection fraction ≥40%. A total of 5988 patients were enrolled and randomized to receive either empagliflozin (10 mg), or placebo.

Of the enrolled population, 5815 (97.1%) had data on baseline diuretic use and were included in the present analysis. Patients were categorized into the following subgroups according to baseline diuretic therapy: no diuretic use and furosemide-equivalent doses of ≤40 mg, 40 mg, and ≥40mg at baseline. The main clinical outcomes of interest were the composite endpoint of the first hospitalization for heart failure (HHF) or cardiovascular death (CV death), and its various components. Data were analyzed from November 2021 to August 2022.

Among the 5815 patients with known baseline diuretic use, 1179 (20.3%) were not taking diuretics, 1725 (29.7%) were taking ≤40mg, 1772 (30.5%) were taking 40 mg, and 1139 (19.6%) were taking ≥40 mg of furosemide-equivalent doses.

In the placebo arm, compared with the nondiuretic group, the analysis found the diuretic group had a higher risk of HHF or CV death (hazard ratio [HR], 1.81; 95% CI, 1.38 - 2.39; P <.001), total HHF (HR, 3.21; 95% CI, 2.15 - 4.80; P <.001), first HHF (HR, 2.75; 95% CI, 1.85 - 4.07; P <.001), and all-cause mortality (HR, 1.40; 95% CI, 1.06 - 1.85; P = .02). The results were similar after stratification by diuretic dose, with higher diuretic doses associated with a stepwise increase in these clinical outcomes.

Moreover, the analysis revealed empagliflozin treatment decreased the risk of HHF or CV death, regardless of background diuretic status (HR, 0.81; 95% CI, 0.70 - 0.93 for the diuretic group vs. HR, 0.72; 95% CI, 0.48 - 1.06 for the nondiuretic group; P for interaction = .58). There was no treatment by diuretic status interaction observed for CV death or all-cause death endpoints.

Compared with placebo, empagliflozin was associated with a slower rate of decline in the eGFR regardless of baseline diuretic use or dose. Additionally, the therapy was associated with improved Kansas City Cardiomyopathy Questionnaire 23 (KCCQ) clinical summary scores similarly in both the diuretic and nondiuretic groups at 12-week, 32-week, and 52-week follow-up. Results were consistent when patients were categorized by diuretic dose.

Among those taking diuretics at baseline, empagliflozin was associated with a significantly greater probability of de-escalation (HR, 1.15; 95% CI, 1.02 - 1.30), as well as a decreased likelihood of diuretic dose escalation (HR, 0.74; 95% CI, 0.65 - 0.84; P <.001). However, the analysis showed empagliflozin was associated with a higher incidence of volume depletion events in the diuretic group (7.5 vs. 5.6 events per 100 patient-years; HR, 1.34; 95% CI, 1.13 - 1.59).

The investigative team noted the important clinical implications of the analysis, suggesting SGLT2 inhibitors should not be withheld in patients not taking diuretics due to concerns of destabilizing the euvolemic status. Empagliflozin improved clinical outcomes without increasing volume depletion events in this population.

Butler and colleagues noted that at the time of SGLT2 initiation, most patients with HFpEF would not require a change in diuretic dose. However, they suggested that like every patient with heart failure, physicians should be ready to adjust the diuretic dose according to a patient’s individual needs.

“Doing so will minimize the small risk of volume depletion when SGLT2 inhibitors and loop diuretics are combined,” investigators wrote. “Patient education, daily weights, and monitoring for volume depletion is advisable. In the longer term, as HF status improves in patients taking empagliflozin, the need for diuretics may be reduced.”

References

1. Butler J, Usman MS, Filippatos G, et al. Safety and Efficacy of Empagliflozin and Diuretic Use in Patients with Heart Failure and Preserved Ejection Fraction: A Post Hoc Analysis of the EMPEROR-Preserved Trial. JAMA Cardiol. Published online May 24, 2023. doi:10.1001/jamacardio.2023.1090
2. Verma A, Patel AB, Waikar SS. SGLT2 inhibitor: not a traditional diuretic for heart failure. Cell Metab. 2020;32(1):13-14. doi:10.1016/j.cmet.2020.06.014