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Evevident
Original paper
2021NEJMCardiology

EMPEROR-Preserved

Empagliflozin in Heart Failure with a Preserved Ejection Fraction

RCTHFpEF

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Overview

Empagliflozin reduced CV death or HF hospitalization in HFpEF, mainly through fewer HF hospitalizations.

Clinical takeaway

EMPEROR-Preserved provided one of the first clear outcome-improving drug signals in HFpEF and broadened SGLT2 inhibitor use across EF ranges.

Key result

Primary composite outcome was lower with empagliflozin (HR 0.79; 95% CI 0.69-0.90).

Practice impact

SGLT2 inhibitors became a core option for HFpEF/HFmrEF management.

Evidence

Study design

Randomized, double-blind, placebo-controlled trial.

Enrollment

5,988

Follow-up

Median 26.2 months.

Geography

Multinational

Clinical question

Does empagliflozin improve outcomes in HFpEF?

Population

  • Patients with NYHA class II-IV heart failure and an ejection fraction >40%, with or without diabetes.

Intervention

Empagliflozin 10 mg daily, added to usual therapy.

Comparator

Placebo, added to usual therapy.

Primary outcome

Composite of CV death or hospitalization for heart failure.

Empagliflozin reduced cardiovascular death or heart-failure hospitalization in HFpEF, driven mainly by fewer HF hospitalizations.

Hazard ratio / 0.79 / CI 95% CI 0.69-0.90 / p=<0.001

Key results

  • Primary composite outcome: 13.8% with empagliflozin vs 17.1% with placebo; HR 0.79; 95% CI 0.69-0.90; p<0.001.
  • The benefit was driven mainly by fewer hospitalizations for heart failure (HR 0.73; 95% CI 0.61-0.88).
  • Effects were consistent in patients with and without diabetes.
  • Cardiovascular death alone was not significantly reduced.

Harms

  • Uncomplicated genital and urinary tract infections were reported more often with empagliflozin.
  • Hypotension was reported more frequently with empagliflozin.

Clinical Use

When to cite

  • When discussing SGLT2 inhibitors for HFpEF, where the main demonstrated benefit is reducing heart-failure hospitalization.

Practice impact

  • SGLT2 inhibitors became a core option for HFpEF/HFmrEF management.

Applicability

  • Most applicable to patients with symptomatic heart failure and an ejection fraction above 40%, including HFmrEF and HFpEF.

Limitations

  • Cardiovascular death alone was not significantly reduced; the benefit was driven by fewer HF hospitalizations.
  • HFpEF remains heterogeneous; absolute benefit varies with baseline risk.
  • Subgroup data suggested attenuated benefit at the highest ejection fractions.

Common misinterpretations

  • Do not expect a mortality benefit in HFpEF; EMPEROR-Preserved reduced hospitalizations, not cardiovascular death.
  • The result was later reinforced by DELIVER (dapagliflozin), supporting a class effect across the HFpEF/HFmrEF spectrum.

Related evidence

DAPA-HF - Same Drug ClassEMPEROR-Reduced - Earlier Trial

Citation

Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385(16):1451-1461. doi:10.1056/NEJMoa2107038

Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes.