Effects of Empagliflozin on Right Ventricular Function in Heart Failure with Reduced Ejection Fraction

Objectives To investigate the effect of empagliflozin on right ventricular (RV) function in patients with HFrEF.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes and reverse left ventricle (LV) remodeling in heart failure with reduced ejection fraction (HFrEF). The impact on RV function remains uncertain.

The Empire HF trial was a randomized, double-blind trial of 190 participants with HFrEF (LVEF ≤40%) randomized (1:1) to empagliflozin (10mg/daily) or matching placebo for 12 weeks. The primary endpoint was changes in RV free wall strain (RVFWS) across the whole cohort. RVFWS was also stratified into tertiles based on baseline RVFWS. Secondary endpoints included changes in TAPSE and RV S’ velocity.

Baseline characteristics were balanced between the groups (mean age of 64±11 years, 86% male, mean LVEF 29±8%, 79% in NYHA class II). The overall mean RVFWS was −16.7±6.1%, with the empagliflozin group at −16.4±6.2% and the placebo group at −16.9±5.9%. No differences were observed in RVFWS between the groups. When stratified by baseline RVFWS into tertiles, patients in the lowest tertile demonstrated a significant improvement with empagliflozin (treatment effect: −2.9% [95% CI: −5.0 to −0.3]; P=0.027), independent of LVEF, plasma volume, or weight loss changes. No significant treatment effect was observed in the middle or highest tertiles of RVFWS, nor in the overall or lowest tertiles of TAPSE or RV S’.

Empagliflozin exerted no overall effect on RV function in stable HFrEF patients, but significantly improved RVFWS in patients in the lowest tertile of RVFWS after 12 weeks of treatment. Trial Registration ClinicalTrials.gov, Unique Identifier: NCT03198585 Competing Interest Statement The authors have declared no competing interest. Clinical Trial NCT03198585 Funding Statement This funding source had no role in the design of the study, its execution, analysis, interpretation of the data, or decision to submit results. There was no interference or financial support from the manufacturer of empagliflozin. This work was supported by the Danish Heart Foundation (grant numbers 17-R116-A7714-22076, 18-R124-A8573-22107); Steno Diabetes Center Odense, Denmark (grant number 3363); A.P. Møller Foundation for the Advancement of Medical Science (grant numbers 17-L-0339, 17-L-0002); The Research Council at Herlev and Gentofte University Hospital, Denmark (institutional research grant); The Research and Innovation Foundation of the Department of Cardiology (FUHAS, formerly FUKAP), Herlev and Gentofte University Hospital, Denmark (institutional research grant); The Capital Region of Denmark (grant number A6058). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Danish National Committee on Health Research Ethics (reference no. H-17010756). All participants provided written informed consent prior to inclusion. The study was conducted in accordance with the Declaration of Helsinki and applicable national regulations. The trial is registered at ClinicalTrials.gov (Unique Identifier: NCT03198585). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability The data that support the findings of this study are available from the corresponding author upon reasonable request. Abbreviations - HF - Heart Failure - HFrEF - Heart Failure with Reduced Ejection Fraction - LV - Left Ventricle - LVEF - Left ventricular Ejection Fraction - RV - Right Ventricle - RVFWS - Right Ventricular Free Wall Strain - RV S’ - Right ventricular peak systolic tissue velocity - SGLT2 - Sodium-Glucose cotransporter-2 - TAPSE - Tricuspid Annular Plane Systolic Excursion - T2DM - Type 2 Diabetes Mellitus