Patient Population

Patients ≥18 years old with New York Heart Association (NYHA) class II-IV heart failure (HF) and left ventricular ejection fraction (LVEF) ≥40%, elevated N-terminal (NT)-pro hormone BNP (NT-proBNP) ≥300pg/m without atrial fibrillation (≥900pg/mL with atrial fibrillation), and chronic HF diagnosed ≥3 months before visit 1 and at least one of: hospitalization for heart failure or structural heart disease characterized by left atrial enlargement and/or left ventricular hypertrophy and body mass index (BMI) <45 kg/m2. Those with myocardial infarction, coronary artery bypass graft surgery (CABG) or other major cardiovascular surgery, stroke or transient ischemic attack (TIA) in prior 90 days, heart transplant recipient, any severe valvular heart disease, atrial fibrillation or atrial flutter with resting heart rate >110 at screening, systolic blood pressure (SBP) ≥180 or <100 mmHg or symptomatic hypotension, estimated glomerular filtration rate (eGFR) <20 mL/min/1.73 m2, history of ketoacidosis or acute or chronic liver disease were excluded.

Intervention (n=2997)

Empagliflozin 10mg PO daily

Comparison (n=2991)

Matching placebo PO daily


The primary outcome was a composite of the time to first event of cardiovascular death or hospitalization for heart failure with preserved ejection fraction (HFpEF). The main secondary outcome included a composite of total adjusted hospitalization for heart failure or slope of eGFR. Selected safety outcomes included: hypotension, acute renal failure, diabetic ketoacidosis (DKA) and genital infections. The median follow-up for the primary outcome was 26.2 months.

The primary composite outcome included hospitalization for HF and cardiovascular death. The individual components of the composite were reported separately. Empagliflozin significantly reduced HF hospitalization or cardiovascular death by 21% among patients with symptomatic stable heart failure with preserved EF (HR 0.79, p-value <0.001). For every 31 patients with HFpEF treated with empagliflozin 10mg daily instead of standard of care treatment alone, one patient will avoid HF hospitalization or cardiovascular death with 26.2 months of follow-up. However, this effect was primarily driven by a 27.1% relative risk reduction for HF hospitalization (HR 0.71, CI 0.60–0.83). There was no significant reduction in cardiovascular mortality (HR 0.91, Cl 0.76–1.09). Hypotension and genital infection events were significantly higher in the empagliflozin group than placebo.

Health Care Professional Summary

The EMPEROR-Preserved study was a randomized, concealed, double-blind trial with ITT analysis. Potential co-intervention and contamination and proportion of patients without final outcome data at the end of the trial (2.9%) being close to the absolute risk reduction (3.3%) introduces possible risk of bias. The primary outcome of HF hospitalization and cardiovascular death had an absolute risk reduction of 3.3% and a relative risk reduction of 19.3% for empagliflozin, with an NNT of 31. However, this benefit was mainly driven by a reduction in time to first HF hospitalization and subgroup analysis showed there was no significant difference on cardiovascular mortality, all-cause death or total HF hospitalization. Patients taking empagliflozin had more adverse events, including hypotension (absolute risk increase 1.8%, NNH 55) and genital infection (ARI 1.5%, NNH 66). The ideal patient population for empagliflozin use is adults with symptomatic, stable HFpEF already optimized on HF GDMT, without an acute cardiovascular event in the prior 90 days and with an eGFR at least 20mL/min/1.73m2.

Patient Summary

Empagliflozin is a prescription medication that is taken once daily by mouth. This medication was originally introduced as a drug to lower blood sugar for diabetes by helping your body eliminate sugar through the kidneys. The result of the EMPEROR-Preserved study showed a benefit in heart failure management. It found that patients with heart failure who received empagliflozin had a lower chance of being admitted to hospital for heart failure or death from heart disease compared with patients who received standard care of treatment for heart failure alone. This medication may cause low blood pressure and infections in the genital area, although these side effects can often be managed or prevented. Empagliflozin may be an additional treatment to improve heart failure management on top of standard care of treatment in those who have heart failure whether or not you have diabetes.

Coverage, Formulary Restrictions and Affordability of Sodium-Glucose Cotransporter 2 Inhibitors by U.S. Insurance Plan Types
JAMA Health Forum
PMCID: PMC8796944.
2. [Internet]
Los Angeles
[cited 2022Mar19]. Available from:

Author notes

Citation: S.D. Anker, J. Butler, G. Filippatos, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021; 385:1451-1461. doi: 10.1056/NEJMoa2107038.