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Randomized Controlled Trial
. 2023 Feb 1;34(2):322-332.
doi: 10.1681/ASN.2022050623. Epub 2022 Nov 17.

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

Julie Refardt  1   2 , Cornelia Imber  1   2 , Rianne Nobbenhuis  1   2 , Clara O Sailer  1   2 , Aaron Haslbauer  3 , Sophie Monnerat  1   2 , Cemile Bathelt  1   2 , Deborah R Vogt  2 , Manfred Berres  4 , Bettina Winzeler  1   2 , Stephanie A Bridenbaugh  3 , Mirjam Christ-Crain  1   2
Affiliations
Randomized Controlled Trial

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

Julie Refardt et al. J Am Soc Nephrol. .

Abstract

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.

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Conflict of interest statement

All authors have nothing to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Study flow diagram.
Figure 2
Figure 2
Course of serum sodium levels from baseline to end of treatment. (A) Serum sodium levels before (baseline) and after (week 4) treatment with empagliflozin or placebo. (B) Course of serum sodium from baseline to end of treatment according to treatment phase. Boxes contain the 25% and 75% quartiles (spanning the interquartile range); the thick horizontal line is the median. Whiskers indicate the most extreme values lying within the box edge and 1.5 times the interquartile range. All eventual further values are plotted as individual points (outliers).
Figure 3
Figure 3
Time course of different parameters under treatment with empagliflozin or placebo. Results are shown for (A) serum glucose, (B) serum creatinine, (C) urine glucose, and (D) urine sodium. Boxes contain the 25% and 75% quartiles (spanning the interquartile range); the thick horizontal line is the median. Whiskers indicate the most extreme values lying within the box edge and 1.5 times the interquartile range. All eventual further values are plotted as individual points (outliers).
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References

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