Reduced tissue sodium content is related to improvement of vascular function in patients with chronic heart failure treated with the SGLT2 inhibitor empagliflozin
Authors: Kolwelter J , Kannenkeril D , Linz P , Jung S , Nagel A.M , Bosch A , Ott C , Bramlage P , Uder M , Achenbach S , Schmieder R.E 
Published: October 2021

Abstract

Background
Large randomized controlled trials have demonstrated that SGLT2 inhibitors produce cardiovascular benefits beyond their metabolic effects. One of the assumed underlying mechanisms is the reduction of the left ventricular afterload. Factors aggravating the afterload are impaired vascular function (ventricular-arterial coupling) as well as high tissue sodium content, which exerts enhanced hypertrophic stimuli and exaggerated response to vasoconstrictors.

Purpose
We hypothesized that the SGLT2 inhibitor empagliflozin leads to afterload reduction in patients with chronic heart failure (CHF) by reducing tissue sodium content and improving vascular function and that these changes are related to each other.

Methods
In a randomized (2:1), investigator initiated, double-blind, placebo controlled, parallel-group, prospective clinical study, patients with CHF NYHA II-III and an ejection fraction of 49% or less were randomized to empagliflozin 10mg once daily or placebo. In each patient, we assessed vascular parameters under resting conditions (Sphygmocor) and 24-hour daily life conditions (Mobilograph), including central systolic pressure (cSBP) and central pulse pressure (cPP) among others. In parallel, we measured tissue (skin and muscle) sodium content of the lower leg by Sodium-MRI, at baseline and after 1 month of therapy.

Results
A total of 74 patients (men: n=62), aged 66±9 years, with a mean ejection fraction of 39±9% were included. Only 24% of the patients had type 2 diabetes. After 1 month treatment with empagliflozin, a decrease of skin sodium content was observed (22.8±6.1 vs. 21.6±6.0 mmol/l, p=0.039), while there was no significant change in muscle sodium and muscle water content. A decrease of cSBP (117.1±14.5 vs. 110.7±11.3 mmHg, p&lt;0.001) and cPP (41.4±8.8 vs. 38.4±8.5 mmHg, p=0.004) under resting conditions was observed after 1 month treatment with empagliflozin, while changes in the placebo group were not significant for cSBP (117.0±18.1 vs. 116.3±15.0 mmHg, p=0.759) and cPP (40.6±9.1 vs. 39.4±8.6 mmHg, p=0.422). Similarly, there was a decrease of cSBP and cPP in patients with empagliflozin treatment under ambulatory conditions, but not in the placebo group. In the whole group, we observed a significant correlation between change in skin sodium content and change in vascular parameters such as cSBP (r=0.364, p=0.004) and cPP (r=0.250, p=0.054) after 1 month of treatment with empagliflozin or placebo.

Conclusion(s)
Significant changes in skin sodium content induced by empagliflozin and a significant correlation between changes in skin sodium content and vascular function suggest that a reduction of tissue sodium content may be one of the mechanisms underlying the beneficial effects of SGLT2 inhibitors in heart failure.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): Boehringer Ingelheim International GmbH.