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Brief Report
January 6, 2021

Associations of Empagliflozin With Left Ventricular Volumes, Mass, and Function in Patients With Heart Failure and Reduced Ejection Fraction: A Substudy of the Empire HF Randomized Clinical Trial

Author Affiliations
  • 1Research Unit of Cardiology, Department of Cardiology, Odense University Hospital, Odense, Denmark
  • 2Steno Diabetes Centre Odense, Odense University Hospital, Odense, Denmark
  • 3Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
  • 4Department of Cardiology, Herlev and Gentofte University Hospital, Copenhagen, Denmark
  • 5Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
  • 6Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark
  • 7Department of Cardiology, Odense University Hospital, Odense, Denmark
  • 8Department of Cardiology, Bispebjerg and Frederiksberg University Hospital, Copenhagen, Denmark
  • 9Department of Clinical Research, Odense University Hospital, Odense, Denmark
  • 10Department of Cardiology, Rigshospitalet, Copenhagen, Denmark
JAMA Cardiol. Published online January 6, 2021. doi:10.1001/jamacardio.2020.6827
Key Points

Question  What are the pathophysiologic mechanisms behind the clinical outcomes of the sodium-glucose cotransporter-2 inhibitor empagliflozin in patients with heart failure and reduced ejection fraction (HFrEF)?

Findings  This exploratory post hoc substudy of the Empagliflozin in Heart Failure Patients with Reduced Ejection Fraction (Empire HF) randomized clinical trial of 190 patients with HFrEF found that when empagliflozin was compared with placebo, treatment caused a modest but statistically significant reduction in left ventricular and atrial volumes, but not ejection fraction, after 12 weeks of treatment. These findings were consistent across subgroups, including patients with type 2 diabetes.

Meaning  In this analysis, empagliflozin caused a decrease in cardiac volume after 12 weeks compared with placebo.


Importance  Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve outcomes in patients with heart failure and a reduced ejection fraction (HFrEF). The association with cardiac remodeling has not been investigated.

Objective  To investigate the outcome of the SGLT2i empagliflozin, compared with placebo, on cardiac remodeling in patients with HFrEF.

Design, Setting, and Participants  This exploratory post hoc analysis included participants with stable HFrEF and ejection fractions of 40% or less, who were randomly enrolled in an investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trial in Denmark. Enrollment commenced on June 29, 2017, and continued through September 10, 2019, with the last participant follow-up on December 20, 2019.

Interventions  Randomization (1:1) to empagliflozin (10 mg once daily) or matching placebo in addition to recommended heart failure therapy for 12 weeks.

Main Outcomes and Measures  Efficacy measures were changes from baseline to week 12 in left ventricular end-systolic and end-diastolic volume indexes, left atrial volume index, and left ventricular ejection fraction adjusted for age, sex, type 2 diabetes, and atrial fibrillation. Secondary efficacy measures included changes in left ventricular mass index, global longitudinal strain, and relative wall thickness.

Results  A total of 190 patients were randomized (95 each receiving empagliflozin and placebo), with a mean (SD) age of 64 (11) years; 162 were men (85.3%), 97 (51.1%) had ischemic HFrEF, 24 (12.6%) had type 2 diabetes, and the mean (SD) latest recorded left ventricular ejection fraction was 29% (8%). Of the 190, 186 completed the study. Empagliflozin significantly reduced left ventricular end-systolic volume index (−4.3 [95% CI, −8.5 to −0.1] mL/m2; P = .04), left ventricular end-diastolic volume index (−5.5 [95% CI, −10.6 to −0.4] mL/m2; P = .03), and left atrial volume index (−2.5 [95% CI, −4.8 to −0.1] mL/m2; P = .04) compared with placebo at 12 weeks’ follow-up, with no change in left ventricular ejection fraction (1.2% [95% CI, −1.2% to 3.6%]; P = .32). These findings were consistent across subgroups. Of secondary efficacy measures, left ventricular mass index was significantly reduced by empagliflozin (−9.0 [95% CI, −17.2 to −0.8] g/m2; P = .03).

Conclusions and Relevance  In this small, randomized, short-term study, empagliflozin was associated with modest reductions in left ventricular and left atrial volumes with no association with ejection fraction. Effects beyond 12 weeks of SGLT2i use require further study.

Trial Registration  ClinicalTrials.gov Identifier: NCT03198585