Empagliflozin and fluid balance: Results from the SiRENA project

Background and Hypothesis Sodium-glucose-cotransporter-2 inhibitors (SGLT2i) exert cardiorenal benefits in type 2 diabetes (DM2) and chronic kidney disease (CKD), possibly mediated by natriuresis and changes in fluid balance. We examined the effects of empagliflozin on fluid and electrolyte balance. Methods Employing a randomized double-blind, placebo controlled cross-over design, we conducted 3 identical trials examining patients with DM2 with and without CKD and non-diabetic CKD, respectively. 49 participants were randomized to 4 weeks of empagliflozin 10 mg/day or matching placebo and crossed over to the opposite treatment after a wash-out. We measured body composition, 24-hour ambulatory blood pressure (BP) and several markers of fluid and electrolyte balance. Results In the combined cohort empagliflozin reduced extracellular body water by 0.29 L (95% CI: -0.54; -0.03 L, p = 0.03) and tended towards reducing overhydration (-0.23 L, 95% CI: -0.51; 0.05 L, p = 0.10). Change in overhydration was correlated to changes in BP (R = 0.38, p = 0.008). Sodium excretion and urine volume was unchanged, but copeptin, a surrogate of antidiuretic hormone (ADH), increased by 30% (p > 0.0001), aquaporin-2 excretion by 8% (p = 0.04) and free water clearance decreased (p = 0.0001). Renin levels increased (p = 0.02) with non-significant rises in aldosterone (p = 0.05) and epithelial sodium channel excretion (p = 0.08). Conclusion SGLT2i could exert diuretic effects which, although compensated by increased ADH and renin-angiotensin-aldosterone system activity, causes lasting changes in fluid balance.