Empagliflozin reduces the risk for heart failure hospitalization and slows kidney function decline in patients with heart failure with markedly reduced ejection fraction, including those with concomitant diabetes, according to new study findings published in the New England Journal of Medicine.
In the EMPEROR-Reduced trial (NCT03057977), investigators randomly assigned 3730 patients to receive empagliflozin (10 mg daily), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, or placebo, along with recommended therapy. The patients had a mean age of 67 years, 71% were White, and 24% were female. They had New York Heart Association (NYHA) class II, III, or IV heart failure and an ejection fraction of 40% or less. Half of the patients had diabetes, 73% had a left ventricular ejection fraction of 30% or less, 79% had a N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level of at least 1000 pg/mL, 48% had an estimated glomerular filtration (eGFR) of less than 60 mL/min/1.73 m2, and nearly 20% were receiving an angiotensin receptor-neprilysin inhibitor.
Over a median 16 months, a smaller proportion of empagliflozin than placebo recipients experienced the primary composite outcome of cardiovascular death or new hospitalization for heart failure: 19.4% vs 24.7%, respectively. Empagliflozin reduced the risk for the primary outcome by a significant 25% (P <.001), mostly driven by a 31% decline in the risk for heart failure hospitalization, Milton Packer, MD, of Baylor Heart and Vascular Institute in Dallas, Texas, and colleagues reported. Investigators observed the benefit regardless of diabetes status, ejection fraction, or eGFR.
Empagliflozin also reduced the risk for total heart failure hospitalizations (including the first and subsequent hospitalizations) by a significant 30% (P <.001).
With respect to renal outcomes, the empagliflozin group had significantly slower annual eGFR decline than the placebo group: -0.55 vs -2.28 mL/min/1.73 m2, respectively (P <.001). In addition, a smaller proportion of empagliflozin than placebo recipients experienced the composite endpoint of a sustained reduction in eGFR, dialysis, or kidney transplantation: 1.6% vs 3.1%, respectively. Empagliflozin recipients had a 50% lower risk for the composite of serious renal events.
Notably, uncomplicated genital infections occurred more with empagliflozin than placebo.
The recent DAPA-HF trial examined dapagliflozin, another SGLT2 inhibitor, in heart failure patients with mild to moderately reduced ejection fraction with favorable results. EMPEROR-Reduced included more patients with an ejection fraction of 30% or less and increased levels of natriuretic peptides than the DAPA-HF trial.
“Our trial thus extends the benefits of SGLT2 inhibitors to patients with more advanced but stable heart failure,” Dr Packer’s team stated.
In an accompanying editorial, John A. Jarcho, MD, of Brigham and Women’s Hospital, in Boston, Massachusetts, and deputy editor of the New England Journal of Medicine noted that empagliflozin appeared beneficial even in patients taking sacubitril-valsartan, according to subgroup analyses.
Dr Jarcho also questioned whether the purported benefit for cardiovascular death was real (only an 8% reduction in risk was found with empagliflozin). He recommended a subgroup analysis of cardiovascular death according to ejection fraction, baseline NT-proBNP level, or NYHA class, and a future trial.
“The results of the EMPEROR-Reduced trial confirm that the findings in DAPA-HF were no fluke and substantially strengthen the rationale for the use of SGLT2 inhibitors in patients with heart failure and a reduced ejection fraction,” Dr Jarcho wrote.
This clinical trial was supported by Boehringer Ingelheim and Eli Lilly. Please see the original reference for a full list of authors’ disclosures.
Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. Published online August 29, 2020. doi:10.1056.NEJMoa2022190
Jarcho JA. More evidence for SGLT2 inhibitors in heart failure. N Engl J Med. Published online August 29, 2020. doi:10.1056/NEJMe2027915