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Hot Line - Does empagliflozin improve outcomes in HFpEF as well as HFrEF?

27 Aug 2021
Hot Line presented at ESC Congress

The EMPEROR-Reduced trial previously showed that the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin reduced the risk of cardiovascular (CV) death or hospitalisation for heart failure (HF) in patients with HF and a reduced ejection fraction (HFrEF; left ventricular ejection fraction [LVEF] ≤40%), regardless of the presence or absence of type 2 diabetes mellitus (T2DM).1 But until now, it was uncertain whether empagliflozin would provide such benefits in patients with HF and a preserved ejection fraction (HFpEF).

Results from the EMPEROR-­Preserved trial were presented by Professor Stefan Anker (Charité University Hospital Berlin, Germany) in a Hot Line session today and are now published in the New England Journal of Medicine. This international double-blind trial enrolled 5,988 symptomatic HFpEF patients (LVEF >40%) with and without T2DM who had elevated N-terminal pro-B-type natriuretic peptide concentrations (>300 pg/mL in patients without and >900 pg/mL in patients with atrial fibrillation) along with evidence of structural changes in the heart or documented history of HF hospitalisation. Participants were randomised 1:1 to receive empagliflozin 10 mg daily or placebo, added to all appropriate treatments for HFpEF and co-morbidities. The primary outcome and the first two secondary outcomes were included in a hierarchical testing procedure. The primary endpoint was a composite of CV death or hospitalisation for HF. The first secondary outcome was HF hospitalisations, including first and recurrent events, while the second secondary outcome assessed the rate of decline in the estimated glomerular filtration rate (eGFR) during study treatment.

Average age of participants was 72 years, 45% were women and average LVEF was 54%. During a median follow-up of 26 months, a primary outcome event occurred in 415 of 2,997 patients (13.8%) in the empagliflozin group and in 511 of 2,991 patients (17.1%) in the placebo group (6.9 vs. 8.7 events per 100 patient-years; hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.69 to 0.90; p=0.0003), which was mainly related to a lower risk of HF hospitalisation in the empagliflozin group. The number of patients who needed to be treated with empagliflozin to prevent one primary outcome event was 31 (95% CI 20 to 69). The effects on the primary outcome were observed across all prespecified subgroups, including patients with or without T2DM and those with LVEF <50%, 50 to <60% or >=60%.

Regarding secondary outcomes, the total number of HF hospitalisations was lower with empagliflozin than with placebo (HR 0.73; 95% CI 0.61 to 0.88; p<0.001). Furthermore, the rate of eGFR decline was slower with empagliflozin than placebo (–1.25 vs. –2.62 mL/min/1.73 m2/year; p<0.0001).

Regarding safety, serious adverse events occurred in 47.9% of patients in the empagliflozin group and 51.6% in the placebo group. Adverse events leading to discontinuation of treatment occurred in 19.1% of patients in the empagliflozin group and 18.4% in the placebo group. Uncomplicated genital and urinary tract infections and hypotension were more common in patients treated with empagliflozin.

Prof. Anker summarised the findings by saying, “Empagliflozin convincingly reduced the combined risk of CV death or hospitalisation for HF in patients with HFpEF with and without T2DM. This drug has the potential to become a new standard treatment for these patients, who currently have few therapeutic options.”

Also presented in the same Hot Line Session was the EMPEROR-Pooled analysis, which pooled individual patient data from EMPEROR-Reduced and EMPEROR-­Preserved. This analysis was possible due to the very similar study designs. Dr. Milton Packer (Baylor University Medical Center, Dallas, USA) explained: “This analysis was prospectively designed and we developed a statistical plan before any patient was recruited in either trial. The evaluation was alpha-protected, meaning that the endpoints were statistically powerful and unbiased because by specifying the pooled analysis in the individual trials it was protected from an inflated false positive error rate.”

Across the 9,718 patients included in the analysis, empagliflozin reduced the risk of HF hospitalisation to a similar degree (about 30% risk reduction) in EMPEROR-Preserved and in EMPEROR-Reduced. The magnitude of the effect on HF hospitalisations was similar across a broad range of ejection fractions lower than 65%, with attenuation of the drug effect at higher ejection fractions (≥65%).

The analysis also found that empagliflozin reduced the risk of major renal outcomes in EMPEROR-Reduced, but not in EMPEROR-Preserved. However, when renal outcomes were defined using more stringent criteria in EMPEROR-Preserved, pretreatment ejection fraction influenced the effect of empagliflozin on renal outcomes in a manner that paralleled the drug’s effect on HF hospitalisations.

Dr. Packer said: “Taken together, these findings demonstrate the benefits of empagliflozin across a broad range of patients with HF with a reduced and preserved ejection fraction, including many not effectively treated with currently available agents.”


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1. Packer M, et al. N Engl J Med. 2020;383:1413–1424.