Empagliflozin in Heart Failure with Preserved Ejection Fraction

Empagliflozin in Heart Failure with Preserved Ejection Fraction
Abigail Sirek, PharmD, CentraCare Health - Paynesville

Background: Previous studies have shown sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce development and progression of heart failure in patients with type 2 diabetes and heart failure with reduced ejection fraction (HFrEF). The effects of this class of medications in patients with heart failure with preserved ejection fraction (HFpEF) have not been well studied.

Purpose: The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) aimed to evaluate the effects of empagliflozin on major heart failure outcomes in patients with HFpEF.

Study Design: This was a randomized, double-blind, parallel-group, placebo-controlled, event-driven trial conducted at 622 centers in 23 countries. To be eligible, participants had to be over the age of 18, have New York Heart Association (NYHA) functional class II-IV chronic heart failure with left ventricular ejection fraction (LVEF) of more than 40%, and have an N-terminal pro-B type natriuretic peptide (NT-proBNP) level of greater than 300 pg/dL (participants with atrial fibrillation at baseline required greater than 900 pg/mL). Participants were excluded if they had a condition, independent of heart failure, that could change their clinical course or jeopardize patient safety, including but not limited to: current/prior use of an SGLT2i, history of ketoacidosis, acute/chronic liver disease, or chronic pulmonary disease requiring home oxygen, oral corticosteroid therapy or hospitalization for exacerbation in the last 12 months. Participants were not required to have type 2 diabetes to be included in the study. Randomization was performed with permuted block design and was stratified by geographic region, diabetes status, estimated glomerular filtration rate (eGFR), and LVEF. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. The secondary outcomes were the occurrence of all hospitalizations due to heart failure, including first and recurrent events, and rate of decline in eGFR during treatment.

Results: Of the 11,583 patients screened for eligibility, 5,988 patients were assigned to empagliflozin 10 mg daily (n=2997) or placebo (n=2991), in addition to usual heart failure therapy including renin-angiotensin inhibitors with or without neprilysin inhibitor, mineralocorticoid receptor antagonists, and beta-blockers. Characteristics between the two treatment groups were similar at baseline, including diabetes status (48.9% in empagliflozin group vs. 49.2% in placebo group) and eGFR. The primary composite outcome event occurred in 415 patients (13.8%) in the empagliflozin group and 541 patients (17.1%) in the placebo group (p<0.001). These results were also significant among subgroups, including those with or without diabetes, LVEF between 40-60%, and eGFR less than 60 mL/min/1.73 m2. At the median trial period of 26 months, the NNT with empagliflozin to prevent one primary outcome event was 31. The total number of hospitalizations for heart failure was lower with the empagliflozin group compared to placebo (n=259 vs. 352; p<0.001). Additionally, rate of decline in eGFR was slower in the empagliflozin group than placebo (-1.25 vs. -2.62 mL/min per 1.73 m2 per year; p<0.001). Adverse events and discontinuation rates were similar between the two groups, with genital and urinary tract infections and hypotension being the most common concerns in patients treated with empagliflozin. Rates of hypoglycemic events were similar between empagliflozin and placebo, both in patients with and without diabetes (2.4% vs. 2.6%).

Conclusion/Key Point: Empagliflozin was shown to reduce the risk of composite cardiovascular death and hospitalization for heart failure in patients with HFpEF. This was seen regardless of diabetes status and in patients with an eGFR less than 60 mL/min/1.73 m2. Additionally, the use of empagliflozin was shown to slow the rate of eGFR decline. The use of empagliflozin may be considered in patients with HFpEF with or without diabetes to reduce the risk of composite cardiovascular death and hospitalization. 

Reference: 

  1. 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