The SGLT2 inhibitor empagliflozin reduces tissue sodium content in patients with chronic heart failure: results from a placebo-controlled randomised trial

Abstract

Introduction: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have cardiovascular protective properties in addition to the metabolic effects and represent a cornerstone of treating patients with chronic heart failure (CHF). We hypothesised that empagliflozin reduces tissue sodium content in patients with CHF.

Methods: In a double-blind, randomised (2:1), placebo-controlled, parallel-group, clinical trial, 74 patients with NYHA class II-III CHF and an ejection fraction of 49% or less received empagliflozin 10 mg once daily or placebo for 3 months. In each patient, tissue sodium content of the lower leg was assessed non-invasively by sodium-MRI (23Na-MRI) at baseline, after 1 and 3 months of treatment.

Results: After 1 and 3 months treatment with empagliflozin (n = 48), a significant decrease in skin sodium content was observed (1 month: 22.8 ± 6.1 vs. 21.6 ± 6.0 AU, p = 0.039; 3 months: 22.9 ± 6.1 vs. 21.6 ± 6.1 AU, p = 0.013), while there was no change in muscle sodium and muscle water content. In direct comparison, the change in skin sodium content between baseline and 3 months was - 1.3 ± 3.5 AU in the empagliflozin group versus 0.6 ± 3.5 AU in the placebo group (p for between-group difference = 0.022). No significant difference regarding change in muscle sodium and in muscle water content was observed after 3 months treatment between the two groups.

Conclusion: This trial showed a significant decrease in skin sodium content after 1 and 3 months of treatment with empagliflozin. The decrease in skin sodium content may reflect a decrease in subclinical micro-oedema or/and in non-osmotic bound tissue sodium, both reported to impair left ventricular function.

Trial registration number: NCT03128528 ( http://www.

Clinicaltrials: gov ).

Trial registration date: 25th April 2017.

Keywords: Chronic heart failure; Empagliflozin; Magnetic resonance imaging; SGLT2 inhibitor; Sodium; Tissue sodium content.

Conflict of interest statement

RES received speaker fees and advisory board fees and PB has received research funding (related and unrelated to the present work) from Boehringer Ingelheim Pharma GmbH & Co. KG during the conduct of the trial. All other authors declare that there is no conflict of interest.

© 2022. The Author(s).

Figures

Fig. 1

Trial design: summary of study visits and tests performed in each visit

Fig. 2

Sample of 1H-MRI and 23Na-MRI image acquisition of the lower leg at baseline (left) and after 3 months treatment with empagliflozin (right). The calibration tubes 1–4 are placed in the phantom holder underneath the calf. Calibration tubes – 1: 20 mmol Nacl + 5% agarose gel, 2: 20 mmol NaCl, 3: 40 mmol NaCl + 5% agarose gel, 4: 40 mmol NaCl

Fig. 3

Primary endpoint: Change in skin sodium content after 3 months treatment with empagliflozin in the two groups—individual trajectories and boxplot showing the change from baseline to 3 months in each group

Fig. 4

Forest Plot of subgroup analysis for the primary endpoint: change in skin sodium content after 3 months treatment with empagliflozin versus placebo. eGFR estimated glomerular filtration rate; mean difference = skin sodium content at 3 months minus skin sodium content at baseline, NTproBNP N-terminal prohormone of brain natriuretic peptide, 95% CI 95% confidence interval, median age = 67 years; median NTproBNP = 444 pg/ml

Fig. 5

Relationship between change in skin sodium content and change in muscle sodium content a as well as change in muscle water content, b after 3 months treatment with empagliflozin. *After ignoring the potential outlier (left lower corner of the graph), the correlation between change in muscle sodium content and change in skin sodium content was still significant (r = 0.445, p = 0.002) and the correlation between change in muscle water and change in skin sodium content was still not significant (r = − 0.066, p = 0.673)