EMPEROR’s New Groove? Empagliflozin Provides Long-Awaited Treatment for HFpEF

Empagliflozin, a sodium glucose co-transporter 2 inhibitor (SGLT2i), significantly reduced the composite endpoint of heart failure (HF) hospitalization and cardiovascular death in patients with HF with preserved ejection fraction (HFpEF).

Presented at a Hot Line session at the European Society of Cardiology Congress 2021, empagliflozin has delivered a long-anticipated therapy for patients with HFpEF. Despite the armamentarium of beneficial medications for HF patients with reduced ejection fraction, HFpEF notoriously has limited treatment options. SGLT2i therapy was hypothesized to be the breakthrough for this population following reductions in HF hospitalization and cardiovascular death in patients with diabetes and HF across the full spectrum of ejection fraction (EF).1

The EMPEROR-Preserved trial, simultaneously published in the New England Journal of Medicine, randomized patients with symptomatic HFpEF (EF >40%) to empagliflozin 10 mg daily or placebo.2 Both patients with and without diabetes were included, but all had to have an elevated N-terminal pro-B-type natriuretic peptide (>300 pg/mL or >900 pg/mL if concurrent atrial fibrillation) and evidence of either structural heart disease or prior hospitalization for heart failure. The primary outcome was combined cardiovascular death or HF hospitalization.

A total of 5,988 participants (mean age 72 years, 45% women, mean EF 54%) were included in the trial. Over 26 months of median follow-up 415 of 2,997 participants (13.8%) had the primary outcome occur in the empagliflozin group, compared to 511 of 2,991 (17.1%) in the placebo group (HR=0.79; 95% CI 0.69 to 0.90, P=0.0003). The effect was carried by significantly reduced first, and recurrent, HF hospitalizations (HR=0.73; 95% CI 0.61 to 0,88, P<0.001).

Similar effects in the primary outcome were seen across pre-specified sub-groups of EF, up to 60%, and regardless of underlying diabetes status. The attenuation of benefit in the sub-group with EF >60% or lack of significant reduction in cardiovascular death stopped this trial from fully addressing the treatment gap in HFpEF.

Dr. Milton Packer, a principal investigator of the study, noted “we are pleased to have the first trial in patients with HFpEF that shows an unequivocally positive and clinically important result. We are looking forward to many secondary papers that will provide detailed information about what we have found, and what it means for patients.”

To date, HFpEF treatment has revolved around biologic plausibility, sub-analyses of neutral trials, and management of co-morbidities. Therefore, despite the lack of mortality benefit, a positive randomized-controlled trial indicating significant improvement in morbidity for this population is welcome. Following the results of EMPEROR-Preserved, the medical community seems to have found a new groove for HFpEF therapy.

References

  1. Bhatt DL, Szarek M, Steg PG et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N Engl J Med. 2021;384:117-128.
  2. Anker SD, Butler J, Filippatos G et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021.