Treatment Effect of the SGLT2 Inhibitor Empagliflozin on Chronic Syndrome of Inappropriate Antidiuresis: Results of a Randomized, Double-Blind, Placebo-Controlled, Crossover Trial

Significance Statement The syndrome of inappropriate antidiuresis (SIAD) is a major cause of hypotonic hyponatremia. Despite its prevalence, treatment options are sparse, and data on their effect on hyponatremia-associated morbidity such as neurocognitive impairment are largely lacking. New treatment options are needed. The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin promotes osmotic diuresis via urinary glucose excretion and could be used as a treatment for chronic SIAD. This randomized, double-blind, placebo-controlled, crossover trial with 14 participants revealed that empagliflozin is well tolerated and effective compared with placebo. In addition, treatment with empagliflozin possibly led to an improvement in neurocognitive function. The results set the stage for further studies evaluating empagliflozin as a treatment option in patients with SIAD-induced hyponatremia. Background The syndrome of inappropriate antidiuresis (SIAD) is characterized by a reduction of free water excretion with consecutive hypotonic hyponatremia and is therefore challenging to treat. The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin promotes osmotic diuresis via urinary glucose excretion, likely leading to increased electrolyte free water clearance. Methods In this randomized, double-blind, placebo-controlled, crossover trial, we compared 4-week treatment with empagliflozin 25 mg/d to placebo in outpatients with chronic SIAD-induced hyponatremia. At baseline and after both treatment cycles, patients underwent different assessments including neurocognitive testing (Montreal Cognitive Assessment [MoCA]). The primary end point was the difference in serum sodium levels between treatments. Results Fourteen patients, 50% female, with a median age of 72 years (interquartile range [IQR], 65–77), completed the trial. Median serum sodium level at baseline was 131 mmol/L (IQR, 130–132). After treatment with empagliflozin, median serum sodium level rose to 134 mmol/L (IQR, 132–136), whereas no increase was seen with placebo (130 mmol/L; IQR, 128–132), corresponding to a serum sodium increase of 4.1 mmol/L (95% confidence interval [CI], 1.7 to 6.5; P =0.004). Exploratory analyses showed that treatment with empagliflozin led to improved neurocognitive function with an increase of 1.16 (95% CI, 0.05 to 2.26) in the MoCA score. Treatment was well tolerated; no serious adverse events were reported. Conclusion The SGLT2 inhibitor empagliflozin is a promising new treatment option for chronic SIAD-induced hyponatremia, possibly improving neurocognitive function. Larger studies are needed to confirm the observed treatment effects. Clinical Trial registration number: ClinicalTrials.gov NCT03202667.