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

Abstract

BackgroundThe 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 diuresisviaurinary glucose excretion, likely leading to increased electrolyte free water clearance.MethodsIn 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.ResultsFourteen 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.ConclusionThe 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.govNCT03202667.

Prevalence of Admission Hyponatremia in Patients With Diabetes Treated With and Without an SGLT2 inhibitor

“…Therefore, findings should be cautiously interpreted [ 48 ]. The incongruence between our retrospective observational results and our prospective randomized data [ 25 , 26 ] underlines this limitation.…”

“…Furthermore, we showed in a randomized, double-blind, placebo-controlled trial in 87 hospitalized euvolemic hyponatremic patients with the syndrome of inappropriate antidiuresis (SIAD) that a 4-day treatment with empagliflozin combined with fluid restriction led to a higher plasma sodium increase than fluid restriction alone [ 25 ]. We recently confirmed these findings in a randomized, double-blind, placebo-controlled, crossover trial in 14 outpatients with chronic SIAD [ 26 ].…”

“…However, hyponatremia is not a side effect of SGLT2 inhibitors, mainly because the pathophysiology of hyponatremia relies more on a relative water excess than an absolute sodium deficit [ 39 ]. Interestingly, our data showed no difference in urine sodium concentration and fractional excretion of sodium between patients with SIAD treated with empagliflozin or a placebo [ 25 , 26 ]. In patients with T2DM, natriuresis seems to be transient as well [ 40 ].…”

“…Two of our randomized, double-blind, placebo-controlled trials provided evidence that empagliflozin is an effective treatment: first, in hospitalized patients with SIAD [ 25 ], and, second, in outpatients with chronic SIAD [ 26 ]. Furthermore, a post hoc analysis in patients with HFrEF [ 46 ] and case reports in patients with liver cirrhosis [ 47 ] suggests that SGLT2 inhibitors might represent an effective option for these hyponatremic subgroups.…”

“…These findings do not support their use as hyponatremia prophylaxis in at-risk patients. Prospective randomized data suggest their efficacy at a higher dosage in overt SIAD [ 25 , 26 ], but their efficacy in other hyponatremia subtypes remains to be demonstrated. An ongoing randomized, placebo-controlled study will help better define the role of empagliflozin in overt euvolemic and hypervolemic hyponatremia (NCT04447911).…”