A Randomized Trial of Empagliflozin to Increase Plasma Sodium Levels in Patients with the Syndrome of Inappropriate Antidiuresis
Authors: Refardt Julie , Imber Cornelia , Sailer Clara O. , Jeanloz Nica , Potasso Laura , Kutz Alexander , Widmer Andrea , Urwyler Sandrine A. , Ebrahimi Fahim , Vogt Deborah R. , Winzeler Bettina , Christ-Crain Mirjam 
Published: February 2020

Significance Statement
Treatment options for the syndrome of inappropriate antidiuresis (SIAD), the predominant cause of hyponatremia, are inadequate. The authors studied the effects of the sodium glucose cotransporter 2 inhibitor empagliflozin, which promotes osmotic diuresis via urinary glucose excretion, in a randomized trial of 87 hospitalized patients with SIAD-induced hyponatremia who were also treated with standard fluid restriction. Patients who received 4 days of empagliflozin had a significantly larger increase in plasma sodium compared with those who received placebo (10 versus 7 mmol/L, respectively). Profound hyponatremia (<125 mmol/L) and lower baseline osmolality levels increased the likelihood of response to treatment with empagliflozin. These findings suggest that further investigation of empagliflozin as a treatment option for hospitalized patients with SIAD-induced hyponatremia is warranted.

Background
Treatment options to address the hyponatremia induced by the syndrome of inappropriate antidiuresis (SIAD) are inadequate. The sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin promotes osmotic diuresis via urinary glucose excretion and therefore, might offer a novel treatment option for SIAD.

Methods
In this double-blind, randomized trial, we recruited 88 hospitalized patients with SIAD-induced hyponatremia <130 mmol/L at the University Hospital Basel from September 2016 until January 2019 and assigned patients to receive, in addition to standard fluid restriction of <1000 ml/24 h, a once-daily dose of oral empagliflozin or placebo for 4 days. The primary end point was the absolute change in plasma sodium concentration after 4 days of treatment. Secondary end points included predisposing factors for treatment response and safety of the intervention.

Results
Of the 87 patients who completed the trial, 43 (49%) received treatment with empagliflozin, and 44 (51%) received placebo. Baseline plasma sodium concentrations were similar for the two groups (median 125.5 mmol/L for the empaflozin group and median 126 mmol/L for the placebo group). Patients treated with empagliflozin had a significantly higher increase of median plasma sodium concentration compared with those receiving placebo (10 versus 7 mmol/L, respectively; P=0.04). Profound hyponatremia (<125 mmol/L) and lower baseline osmolality levels increased the likelihood of response to treatment with empagliflozin. Treatment was well tolerated, and no events of hypoglycemia or hypotension occurred among those receiving empagliflozin.

Conclusions
Among hospitalized patients with SIAD treated with fluid restriction, those who received empagliflozin had a larger increase in plasma sodium levels compared with those who received placebo. This finding indicates that empagliflozin warrants further study as a treatment for the disorder.