Empagliflozin in Heart Failure with Preserved Ejection Fraction: A Worthy Opponent Against a Formidable Foe

Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with significant morbidity, mortality and risk for hospitalization – without drug therapies, to date, demonstrating a clear, clinical benefit. EMPEROR-Preserved1 is the first trial in HFpEF patients to demonstrate significantly improved clinical outcomes. The trial was conducted in class II-IV patients with an ejection fraction (EF) of >40%, median follow up was 26 months. The primary outcome was a composite of cardiovascular death or hospitalization for HF.

In this randomized, double-blind, placebo-controlled study of 5,988 patients, the primary endpoint occurred in 13.8% of patients on empagliflozin and 17.1% patients receiving placebo (P < .0003; NNT= 31). The benefit was predominantly driven by reduced HF hospitalization (HR= 0.71; 95% CI: 0.6-0.83) and evident across pre-specified subgroups, independent of diabetes status. The primary outcome was significant in those with EF 40-59% but not at an EF ≥60% (32.5% of total enrollment). Other pre-specified groups that did not reach statistical significance included younger (<70yrs), obese (body mass index [BMI] ≥30) participants with estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73m2 or NYHA III-IV.

EMPEROR-Preserved is a ground-breaking trial that addressed a crucial, clinically relevant endpoint and demonstrated the benefits of empagliflozin across a broad range of patients with HF, specifically those with EF <60%. Interestingly, the trial included patients with EF's lower than 50%, traditionally used to define HFpEF, and observed less benefit at higher EF's. This attenuation of effect has also been noted in other trials such as PARAGON-HF, and it will be interesting to see if similar results occur in the ongoing DELIVER trial of dapagliflozin. These observations highlight the need for continued research for improved understanding of HFpEF phenotypes and development of new therapeutics. Based on EMPEROR-Preserved, the Food and Drug Administration recently granted breakthrough designation to empagliflozin for the treatment of HFpEF – a milestone in the long journey against this formidable foe.


  1. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021;Aug 27:[Epub ahead of print].

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Diabetes and Cardiometabolic Disease

Keywords: ESC Congress, ESC21, Body Mass Index, Heart Failure, Stroke Volume, Glomerular Filtration Rate, Double-Blind Method, United States Food and Drug Administration, Follow-Up Studies, Benzhydryl Compounds, Glucosides, Hospitalization, Cardiovascular System, Morbidity, Obesity, Phenotype, Diabetes Mellitus

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