Empagliflozin does it again: Results from EMPEROR-PRESERVED

Key Points:

• • Patients with chronic heart failure with preserved ejection fraction (HFpEF, defined here as EF>40%) with or without diabetes were treated with empagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, in addition to standard of care therapy. The control arm was treated with standard of care alone.
  • Treatment with empagliflozin led to a significant reduction in the primary endpoint (time to first event of adjudicated cardiovascular death or heart failure hospitalization [HHF]) as well as both secondary endpoints (first and recurrent HHF and slope of change of eGFR). There was no effect on all-cause mortality.
  • The benefit of empagliflozin was seen across all pre-specified subgroups, including patients with or without diabetes.

While many medical therapies have been shown to reduce major adverse cardiovascular events in heart failure with reduced ejection fraction (HFrEF), there has been limited success in the context of heart failure with preserved ejection fraction (HFpEF). Recently, several trials of SGLT-2 inhibitors have demonstrated improved cardiovascular outcomes in patients with HFrEF. Empagliflozin specifically has been examined in the EMPEROR-Reduced trial, which demonstrated a reduction in cardiovascular death or HHF at a median follow-up time of 16 months for patients with HFrEF with or without concomitant diabetes. In a Hot Line presentation at the 2021 European Society of Cardiology Conference today, Dr. Stefan Anker (Charité University, Berlin) and his team presented the results of their EMPEROR-Preserved trial (NCT03057951), which was the first dedicated clinical trial to examine the utility of an SGLT-2 inhibitor in HFpEF.

The aim of this study was to determine the efficacy and safety of empagliflozin versus placebo in addition to standard of care in patients with HFrEF, with or without diabetes. Patients aged 18 years or older with an EF <40% and stage NHYA II-IV HF were included. Patients with eGFR <20 were excluded. A total of 5,988 patients were randomized, of which 2,997 underwent empagliflozin therapy at a dose of 10mg per day. Patients were recruited from 622 sites in 23 countries and were followed for a median of 26 months. 23% of patients discontinued the study drug in both the empagliflozin and placebo groups. 

The primary endpoint (time to adjudicated HHF or CV death) was reduced by 21% in the empagliflozin group. This observed benefit was consistent across the pre-specified subgroups of sex, ejection fraction, and presence of diabetes. Additionally, patients receiving empagliflozin experienced a 27% decrease in risk of total HHFs over the time period as well as a reduced slope of decline of eGFR over time (a difference of 1.36 ml/min/1.73m2/year). There was no observed benefit in all-cause mortality. Patients receiving empagliflozin also experienced a significant increase in their Kansas City Cardiomyopathy Questionnaire Clinical Summary Score over a year (indicating an improvement in health status), and were also more likely to experience an improvement in NYHA functional class at 32 weeks and one year. Patients with diabetes receiving empagliflozin experienced a significant reduction in HbA1c relative to placebo (-0.19%), and patients with or without diabetes experienced a reduction in NT-proBNP (geometric mean ratio of 0.95), body weight (-1.28kg), and systolic BP (-1.2mm Hg). A large set of adverse events were evaluated, including but not limited to hypotension, hypoglycemia, ketoacidosis, and urinary tract infections. 47.9% of patients receiving empagliflozin experienced serious adverse events compared to 51.6% in the placebo group (significance not provided).

When discussing the rationale for the study with Cardiology Now News, Dr. Anker stated that “heart failure with preserved ejection fraction affects many millions of patients, and so far there are no evidence-based treatments.” With regards to the most important implications of the study, Dr. Anker continued: “the main outcome is the cardiovascular event reduction, and this is accompanied by quality of life improvement and also by improvements in New York Heart class.”

While the observed benefit in the primary composite outcome appears to be driven largely by HHF, this trial establishes empagliflozin as one of the first medications with clear improvement in clinically significant cardiovascular outcomes in the HFpEF population. Further studies are needed to establish whether this represents a larger class effect for SGLT-2 inhibitors.

The associated manuscript will be published in the New England Journal of Medicine.