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

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Omar reports grants from the Danish Heart Foundation, the Steno Diabetes Center Odense, Odense University Hospital Denmark, and the A.P. Møller Foundation for the Advancement of Medical Science, Denmark during the conduct of the study. Dr Jensen reports grants from the Research Council at Herlev and Gentofte University Hospital, the Research and Innovation Foundation of the Department of Cardiology, Herlev and Gentofte University Hospital, and the A.P. Møller Foundation for the Advancement of Medical Science during the conduct of the study. Dr Kistorp reports personal fees from scientific advisory panels and speaker fees from Boehringer Ingelheim, Merck, Sharp & Dohme, AstraZeneca, Amgen, Novartis, Novo Nordisk, and Shire outside the submitted work. Dr Gustafsson reports personal fees from Boehringer Ingelheim during the conduct of the study and personal fees from Novartis Orion Pharma Abbott, Bayer, AstraZeneca, and Carmat and grants and personal fees from Pfizer outside the submitted work. Dr Køber reports speaker honoraria from Novartis, AstraZeneca, Novo, and Boehringer Ingelheim outside the submitted work. Dr Shou reports grants from the Capital Region of Denmark and the Danish Heart Foundation during the conduct of the study and personal fees and nonfinancial support from AstraZeneca and personal fees from Novo Nordisk and Boehringer Ingelheim outside the submitted work. Dr Møller reports grants from Danish Heart Foundation during the conduct of the study and grants and personal fees from Abiomed and personal fees from Novartis and Orion Pharma outside the submitted work. No other disclosures were reported.

Figures

Figure.. Changes From Baseline to 12 Weeks in Primary Efficacy Measures

Error bars indicate 95% CIs. LAVI indicates left atrial volume index; LVEDVI, left ventricular end-diastolic volume indexes; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end-systolic volume indexes.