Empagliflozin and fluid balance: results from the SiRENA project

Sodium-glucose co-transporter 2 inhibitors (SGLT2is) exert cardiorenal benefits in type 2 diabetes (T2D) 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.

Employing a randomized, double-blind, placebo-controlled crossover design, we conducted three identical trials examining patients with T2D with and without CKD and non-diabetic CKD, respectively. A total of 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-h ambulatory blood pressure (BP) and several markers of fluid and electrolyte balance.

In the combined cohort, empagliflozin reduced extracellular body water by 0.29 l [95% confidence interval (CI) -0.54 to -0.03, P = .03] and tended towards reducing overhydration [-0.23 l (95% CI -0.51-0.05), P = .10]. Change in overhydration was correlated to changes in BP (R = 0.38, P = .008). Sodium excretion and urine volume was unchanged, but copeptin, a surrogate of antidiuretic hormone (ADH), increased by 30% (P > .0001), aquaporin-2 excretion increased by 8% (P = .04) and free water clearance decreased (P = .0001). Renin levels increased (P = .02) with non-significant increases in aldosterone (P = .05) and epithelial sodium channel excretion (P = .08).

SGLT2i could exert diuretic effects that, although compensated for by increased ADH and renin-angiotensin-aldosterone system activity, causes lasting changes in fluid balance.

EU Clinical Trials Register 2019-004303-12, 2019-004447-80 and 2019-004467-50.