BACKGROUND: SGLT2 inhibitors are a promising treatment option in patients with heart failure and reduced ejection fraction. We aimed to investigate the effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate (GFR) in patients with heart failure and reduced ejection fraction.

METHODS: Empire HF Renal was a prespecified substudy of the investigator-initiated, double-blind, randomised, placebo-controlled Empire HF trial. The study was done at Herlev and Gentofte University Hospital (Herlev, Denmark), with patients recruited from four Danish heart failure outpatient clinics. Patients with New York Heart Association class I-III symptoms, with a left ventricular ejection fraction of 40% or lower, and on guideline-directed heart failure therapy were randomly assigned (1:1) to receive either oral empagliflozin 10 mg or matched placebo once daily for 12 weeks. The allocation sequence was computer-generated. Patients and study investigators were masked to treatment allocation. The coprimary prespecified renal outcomes were the between-group difference in the changes in estimated extracellular volume, estimated plasma volume, and measured GFR from baseline to 12 weeks. All analyses were done in the intention-to-treat population (apart from safety analyses, which were done in patients who received at least one dose of study drug), with no interim analyses done during the trial. The Empire HF trial is registered with ClinicalTrials.gov, NCT03198585, and EudraCT, 2017-001341-27.

FINDINGS: Between June 29, 2017, and July 15, 2019, we assessed 391 patients for eligibility, of whom 120 (31%) were randomly assigned to empagliflozin or placebo, including 105 (88%) without diabetes. In intention-to-treat analyses, 60 (100%) patients in the empagliflozin group and 59 (98%) patients in the placebo group were included for estimated extracellular volume and estimated plasma volume, and 59 (98%) patients in the empagliflozin group and 58 (97%) patients in the placebo group were included for measured GFR. Empagliflozin treatment resulted in reductions in estimated extracellular volume (adjusted mean difference -0·12 L, 95% CI -0·18 to -0·05; p=0·00056), estimated plasma volume (-7·3%, -10·3 to -4·3; p<0·0001), and measured GFR (-7·5 mL/min, -11·2 to -3·8; p=0·00010) compared with placebo. Five (8%) of 60 patients in the empagliflozin group and three (5%) of 60 patients in the placebo group had one or more serious adverse events.

INTERPRETATION: In patients with heart failure and reduced ejection fraction, empagliflozin reduced estimated extracellular volume, estimated plasma volume, and measured GFR after 12 weeks. Fluid volume changes might be an important mechanism underlying the beneficial clinical effects of SGLT2 inhibitors.

FUNDING: Research Council at Herlev and Gentofte University Hospital, Research and Innovation Foundation of the Department of Cardiology at Herlev and Gentofte University Hospital, Capital Region of Denmark, Danish Heart Foundation, and AP Møller Foundation for the Advancement of Medical Science.