A 12-week treatment with empagliflozin was associated with reductions in extracellular volume, estimated plasma volume, and glomerular filtration rate (GFR) in patients with heart failure with reduced ejection fraction (HFrEF), according to a study published in the Lancet Diabetes Endocrinology.

This was a prespecified substudy of the Empire HF Renal double-blind, randomized, placebo-controlled trial conducted at Herlev and Gentofte University Hospital in Denmark between 2017 and 2019. Patients (N=120) with HFrEF were randomly assigned at a 1:1 ratio to receive empagliflozin (10 mg orally; 78% men; 95% White) or placebo (n=60 in each group) for 12 weeks. Study participants were instructed to adhere to a sodium-restricted diet and were assessed for clinical outcomes, safety, and mortality.

Patients receiving empagliflozin and placebo were on angiotensin converting enzyme inhibitors or equivalent (92% and 98%, respectively), b-blockers (97% in both groups), loop diuretics (65% and 58%, respectively),  had New York Heart Association Functional Class II (78% and 83%, respectively), and had never been admitted to the hospital for HF (40% in each group).


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At 12 weeks, estimated extracellular volume was reduced in patients receiving empagliflozin (adjusted mean difference [AMD], -0.12; 95% CI, -0.18 to -0.05 L; P =.00056) and remained unchanged in the placebo group (mean, baseline: 16.9 L; 12 weeks, 17.0 L). Estimated plasma volume (AMD, -7.3%; 95% CI, -10.3% to -4.3%; P <.0001) and estimated GFR (AMD, -7.5; 95% CI, -11.2 to -3.8 mL/min; P =.00010) were reduced in participants receiving empagliflozin vs placebo, respectively.

Treatment with empagliflozin significantly reduced uric acid concentrations (adjusted relative mean difference [ARMD], -20.4%; 95% CI, -25.7% to -15.2%; P <.0001), bodyweight (ARMD, -1.7%; 95% CI, -2.5% to -0.8%; P =.00022), glycated hemoglobin levels (ARMD, -3.9%; 95% CI, -6.8% to -1.1%; P =.0062), and systolic blood pressure (ARMD, -4.2%; 95% CI, -7.4% to -1.1%; P =.0085) and significantly increased hemoglobin (ARMD, 4.2%; 95% CI, 2.3%-6.2%; P <.0001) and hematocrit (ARMD, 5.2%; 95% CI, 3.2%-7.2; P <.0001) concentrations, compared with placebo.

The treatment and placebo groups had 5 and 3 serious adverse events, respectively:  urinary tract infection (n=7) and a bone fracture (n=1). No deaths occurred during the study.

Study limitations include the fact that few participants had diabetes. It remains unclear whether empagliflozin may be an effective treatment for patients with HFrEF and comorbid diabetes.

“A reduction in fluid volumes might be an important mechanism that underlies the clinical benefits of SGLT2 inhibitors in heart failure,” concluded the study authors.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.

Reference

Jensen J, Omar M, Kistorp C, et al. Effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate in patients with heart failure (Empire HF Renal): a prespecified substudy of a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2021;9(2):106-116. doi:10.1016/S2213-8587(20)30382-X