Clinical Question

Does empagliflozin (Jardiance), a sodium-glucose cotransporter-2 inhibitor, safely improve outcomes for patients who have heart failure with preserved ejection fraction?

Bottom Line

In patients who have heart failure with preserved ejection fraction, empagliflozin, 10 mg once daily, reduces the likelihood of hospitalization for heart failure (number needed to treat = 59 per year). There is no effect on cardiovascular or all-cause mortality. The drug costs $529 per month in the United States (www.goodrx.com; accessed October 30, 2021) and $82 per month in Canada (https://www.formulary.health.gov.on.ca/formulary; accessed October 30, 2021). In the United States, the drug is not cost-effective, and would require $375,000 to prevent one hospitalization; in Canada, that cost is $58,000. (Level of Evidence = 1b)

Synopsis

This industry-sponsored trial identified patients with New York Heart Association Class II through IV heart failure, an ejection fraction of at least 40%, and an N-terminal pro-brain natriuretic peptide (NT pro-BNP) level of more than 300 pg per mL (more than 900 pg per mL if the patient had atrial fibrillation). Of the 11,583 patients at 622 centers in 23 countries who were screened for the trial, 5,988 were randomized to receive empagliflozin, 10 mg once daily, or placebo. The primary reason for exclusion was failure to meet the NT pro-BNP target.

Groups were balanced at the beginning of the study, with a mean age of 72 years. Approximately one-third of patients in each group had ejection fractions of 40% to 50%, 50% to 60%, and 60% or higher, and 82% had Class II heart failure with preserved ejection fraction. Analysis was by intention to treat, with 77% of patients completing the trial and a median follow-up of 26 months. For the remainder of the patients, the trial medication was stopped for a reason other than death, presumably because of adverse events, although this was not specified by the authors.

The primary outcome was a composite of cardiovascular death or hospitalization due to heart failure. Hospitalization for heart failure occurred less often in patients randomized to receive empagliflozin (4.3 vs. 6.0 per 100 person-years; hazard ratio = 0.71; 95% CI, 0.60 to 0.83; number needed to treat = 59 per year). In an exploratory subgroup analysis, benefit was greater for those with lower ejection fractions. There was no significant difference in the likelihood of cardiovascular death (3.4 vs. 3.8 per 100 person-years) or all-cause mortality (6.6 vs. 6.7 per 100 person-years), and no significant differences in renal outcomes or hospitalization for any cause. There were 20 more noncardiovascular deaths in the empagliflozin group, most often due to infection or sepsis, compared with 25 fewer cardiovascular deaths in that group. Hypotension and genital infections were more common in the empagliflozin group.

Study design: Randomized controlled trial (double-blinded)

Funding source: Industry

Allocation: Uncertain

Setting: Outpatient (any)

Reference: Anker SD, Butler J, Filippatos G, et al. EMPEROR-Preserved Trial InvestigatorsEmpagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451–1461.

Editor’s Note: Dr. Ebell is deputy editor for evidence-based medicine for AFP and cofounder and editor-in-chief of Essential Evidence Plus, published by Wiley-Blackwell.