Short-term effects of an SGLT2 inhibitor on divalent ions in autosomal dominant polycystic kidney disease: a randomized crossover trial

Abstract

ABSTRACT Background Sodium–glucose cotransporter 2 (SGLT2) inhibitors are a cornerstone of chronic kidney disease therapy, reducing disease progression, cardiovascular events, and mortality. Autosomal dominant polycystic kidney disease (ADPKD) patients were excluded from major trials, and data on electrolyte handling with SGLT2 inhibitors, in combination with tolvaptan, are lacking. Methods SIDIA was a randomized, double-blind, placebo-controlled, two-period crossover trial in 15 adults with ADPKD (mean estimated glomerular filtration rate (eGFR) 68 ml/min/1.73 m²; median age 43 years). Participants received empagliflozin 10 mg or placebo for 14 days, separated by a 2-week washout. The primary endpoint was 24 h urinary and fractional excretion of phosphate, calcium, and magnesium. Exploratory secondary endpoints included markers of kidney stone propensity, inflammation, vitamin D metabolism, and tolerability. Treatment effects were estimated using generalized linear mixed models. Given the small sample size, analyses were exploratory and focused on effect estimation. Results For the primary endpoint, neither 24 h urinary nor fractional excretion of phosphate, calcium, or magnesium differed between empagliflozin and placebo. Empagliflozin lowered serum uric acid (–26%), increased serum magnesium (+5.7%) and urinary citrate (+78.6%), and reduced blood pressure (–4/–7 mmHg). An expected decline in eGFR (–7.1%) was observed, with no major short-term safety signals observed. Copeptin levels increased with empagliflozin (+26%). Conclusions In this exploratory mechanistic trial, no substantial short-term difference in urinary or fractional excretion of divalent ions were detected with empagliflozin. The observed changes in serum magnesium, urinary citrate, uric acid, and copeptin are hypothesis-generating and require confirmation in larger, longer-term studies.