Reduced tissue sodium content is related to improvement of vascular function in patients with chronic heart failure treated with the SGLT2 inhibitor empagliflozin

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 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.