Dataset Information

A Randomized Trial of Empagliflozin to Increase Plasma Sodium Levels in Patients with the Syndrome of Inappropriate Antidiuresis.

ABSTRACT:

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.

SUBMITTER: Refardt J

PROVIDER: S-EPMC7062212 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

A Randomized Trial of Empagliflozin to Increase Plasma Sodium Levels in Patients with the Syndrome of Inappropriate Antidiuresis.

Refardt Julie J Imber Cornelia C Sailer Clara O CO Jeanloz Nica N Potasso Laura L Kutz Alexander A Widmer Andrea A Urwyler Sandrine A SA Ebrahimi Fahim F Vogt Deborah R DR Winzeler Bettina B Christ-Crain Mirjam M

Journal of the American Society of Nephrology : JASN 20200204 3

<h4>Background</h4>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 <i>via</i> urinary glucose excretion and therefore, might offer a novel treatment option for SIAD.<h4>Methods</h4>In this double-blind, randomized trial, we recruited 88 hospitalized patients with SIAD-induced hyponatremia <130 mmol/L at the University Hospital Bas ...[more]

PMID: 32019783

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Project description:BackgroundThe stimulatory G-protein α-subunit encoded by GNAS exons 1-13 (GNAS-Gsα) mediates signal transduction of multiple G protein-coupled receptors, including arginine vasopressin receptor 2 (AVPR2). Various germline-derived loss-of-function GNAS-Gsα variants of maternal and paternal origin have been found in pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism, respectively. Specific somatic gain-of-function GNAS-Gsα variants have been detected in McCune-Albright syndrome and may result in phosphate wasting. However, no germline-derived gain-of-function variant has been identified, implying that such a variant causes embryonic lethality.MethodsWe performed whole-exome sequencing in two families with dominantly inherited nephrogenic syndrome of inappropriate antidiuresis (NSIAD) as a salient phenotype after excluding a gain-of-function variant of AVPR2 and functional studies for identified variants.ResultsWhole-exome sequencing revealed two GNAS-Gsα candidate variants for NSIAD: GNAS-Gsα p.(F68_G70del) in one family and GNAS-Gsα p.(M255V) in one family. Both variants were absent from public and in-house databases. Of genes with rare variants, GNAS-Gsα alone was involved in AVPR2 signaling and shared by the families. Protein structural analyses revealed a gain-of-function-compatible conformational property for p.M255V-Gsα, although such assessment was not possible for p.F68_G70del-Gsα. Both variants had gain-of-function effects that were significantly milder than those of McCune-Albright syndrome-specific somatic Gsα variants. Model mice for p.F68_G70del-Gsα showed normal survivability and NSIAD-compatible phenotype, whereas those for p.M255V-Gsα exhibited severe failure to thrive.ConclusionsThis study shows that germline-derived gain-of-function rare variants of GNAS-Gsα exist and cause NSIAD as a novel Gsα-mediated genetic disease. It is likely that AVPR2 signaling is most sensitive to GNAS-Gsα's gain-of-function effects.

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Dataset Information

A Randomized Trial of Empagliflozin to Increase Plasma Sodium Levels in Patients with the Syndrome of Inappropriate Antidiuresis.

Background

Methods

Results

Conclusions

Publications

A Randomized Trial of Empagliflozin to Increase Plasma Sodium Levels in Patients with the Syndrome of Inappropriate Antidiuresis.

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