Endocrine Abstracts

Introduction: Hyponatremia is the most common electrolyte disorder and the syndrome of inappropriate antidiuresis (SIAD) is one of its main causes. However, treatment options for chronic SIAD-induced hyponatremia are inadequate. This is problematic because hyponatremia has been associated with neurocognitive deficits, although there is little data on its reversibility. We previously showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin is a promising short-term treatment option for hospitalized patients with SIAD-induced hyponatremia, promoting osmotic diuresis via urinary glucose excretion. However, there are no data on long-term treatment in outpatients nor its effect on neurocognitive function.

Material and Methods: In this double-blind, randomized, placebo-controlled, crossover trial we compared 4-week treatment with empagliflozin 25 mg/day to placebo in addition to fluid restriction of ≤1.5L/24h in outpatients with chronic SIAD-induced hyponatremia (serum sodium <135 mmol/l). At baseline and after both treatment cycles, patients underwent neurocognitive testing (Montreal Cognitive Assessment (MoCA) test). There was a 2-week wash-out period between the two treatment cycles, and a follow-up visit was scheduled 30 days after completion of the treatment phase. The primary endpoint was the difference in serum sodium levels (mmol/l) after 4 weeks of treatment with empagliflozin or placebo, calculated using a linear mixed-effects model.

Results: 14 patients, 50% female, with a median (IQR) age of 72 years (65-77) completed the trial. Median (IQR) serum sodium level at baseline was 131 mmol/l (130-132). Under treatment with empagliflozin, median (IQR) serum sodium level increased to 134 mmol/l (132-136), while no notable change was seen under placebo (130 mmol/l (128-132)). This resulted in a 4.1 mmol/l (95% CI 1.7-6.5) higher serum sodium level after 4 weeks of empagliflozin treatment compared to placebo (P=0.004). This effect was independent of severity of SIAD. In addition, treatment with empagliflozin led to improved neurocognitive function, as shown by an increase of 1.2 points (SE 0.5) in the MoCA test (P=0.042). Treatment with empagliflozin was generally well tolerated, no serious adverse events occurred during the observation period.

Conclsion: This trial shows that the SGLT-2 inhibitor empagliflozin is a promising new treatment option for outpatients with chronic SIAD-induced hyponatremia. Furthermore, hyponatremia treatment led to an improvement of neurocognitive function.