Short- and long-term effects of empagliflozin on sodium balance and fluid regulation in chronic heart failure

Abstract Introduction Sodium-glucose co-transporter 2 (SGLT2) inhibitors have become a central pillar in the management of chronic heart failure (CHF). While their immediate impact on urinary glucose-, and sodium excretion is well-established, it remains unclear whether these effects persist over time. Purpose Our analysis aims to explore the effects of empagliflozin treatment on fluid- and sodium balance in patients with CHF over a period of 3 months in a double-blind, placebo-controlled trial. Methods A cohort of 74 patients with NYHA class II-III CHF and ejection fraction (EF) ≤49% were randomized (2:1) to receive empagliflozin 10mg daily (n=48) or placebo (n=26). 24-hour urine was collected using standardized protocols. Sodium, potassium, glucose, and urea were measured in both serum and 24-hour urine samples, along with urine volume and body weight. Subsequently, free water clearance, plasma-, and urine osmolality were calculated. A Sodium magnetic resonance imaging (23Na-MRI) of the lower leg for the quantification of tissue Na+ content was performed at baseline, after 1 and 3 months of treatment. All parameters were assessed at baseline (visit 1), after 1 month (short-term; visit 2), and after 3 months (long-term; visit 3) of treatment (see table). Results The mean patient age was 66.4 years, 84% were male, the mean EF was 40%, and the mean NT-proBNP was 444pg/ml. In patients treated with empagliflozin natriuresis increased significantly during the first month (p=0.040) of treatment, and returned to baseline levels by month 3 (p=0.190). Skin sodium content decreased at 1 month (p=0.039) and remained reduced at 3 months (p=0.013). In contrast, muscle sodium content did not show significant changes. Persistent glucosuria was observed throughout the study period (p0.001), resulting in an increased estimated urine osmolality in the empagliflozin group compared to placebo at 3 months follow-up (p=0.003). Urine volume increased at 1 month (p=0.046) but returned to baseline at 3 months, with no significant difference from placebo. Empagliflozin-treated patients showed a reduction in free water clearance at 1 and 3 months (p0.001). Body weight decreased over the same period (p=0.010), while serum sodium, potassium, and urea levels remained unchanged. Conclusion Empagliflozin induces a transient but not sustained natriuretic effect in patients with CHF, whereas skin sodium content remains reduced. Glucosuria and subsequent osmotic diuresis were evident after 1 and 3 months compared to baseline. Compensatory, free water clearance was reduced to maintain plasma osmolality. These findings suggest that the reduced skin sodium content was mediated by natriuresis, while osmotic diuresis and compensatory downregulation of free water clearance maintained euvolemia in CHF patients, indicating the kidneys' adaptive response to preserve volume homeostasis.