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Empagliflozin is a potential treatment for outpatients with chronic hyponatremia due to the syndrome of inappropriate antidiuresis (SIAD), new data suggest. 

The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance), licensed for the treatment of type 2 diabetes, raised serum sodium levels and improved neurocognitive function without major adverse effects in a 4-week trial of 14 outpatients with chronic SIAD-induced hyponatremia.

The findings were recently presented at ENDO 2022: The Endocrine Society Annual Meeting, by Sophie Monnerat, MD-PhD candidate in clinical research, zidovudine food interactions Department of Endocrinology, University Hospital Basel, Switzerland.

The Basel group had previously published a paper showing that empagliflozin increased plasma sodium levels in patients hospitalized with SIAD who were also treated with fluid restriction.

In an interview with Medscape Medical News, session moderator Mark E. Molitch, MD, called the new data on empagliflozin “exciting” and said it’s enough to merit use.

“Empagliflozin is relatively cheap compared to tolvaptan [a vasopressin receptor antagonist]. It’s likely that all the SGLT2 inhibitors would work. It’s well-tolerated…Obviously, they need to do a longer-term study and look at people with more severe hyponatremia, so they need to expand their studies, but it’s really promising,” he said.

“Based on even these data, we should be able to use it clinically now,” said Molitch, professor emeritus of medicine (endocrinology) at Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Hyponatremia: More Than Meets the Eye

Hyponatremia, defined as a serum sodium level below 135 mmol/L, is the most common electrolyte disorder in both the inpatient and outpatient settings. SIAD is one of its main causes, whereby impaired antidiuretic hormone regulation leads to a reduction in free water excretion and water retention in the kidney, with subsequent hypotonic hyponatremia.

There are many causes of SIAD, including central nervous system and pulmonary disorders, cancer, and certain drugs. But it’s also often idiopathic and ongoing. In those situations, it’s commonly overlooked but shouldn’t be, Monnerat said.

“Hyponatremia is a common and clinically relevant issue…Acute hyponatremia is inarguably considered an emergency, whereas chronic hyponatremia is often seen as asymptomatic. However, there’s accumulating evidence that these patients have cognitive impairments such as attention deficit, that they are unstable when walking with a propensity to fall, and that they have increased risk for osteoporosis and fractures, and even death, she said.

Indeed, Molitch noted, “With idiopathic inappropriate vasopressin secretion, if there’s a distinct cause you always try to fix it, but a lot of people have low sodium levels for unclear reasons. We don’t know why, and we pretty much ignore them. We work them up and if the sodium is 128-130 [mmol/L] and they seem to be okay, we haven’t really been paying attention.”

But he said that several studies have shown that “these people really aren’t normal. They have cognitive issues, gait issues, they’re unsteady, and if you correct the hyponatremia those things improve.”

Empagliflozin: An Alternative to Current Unsatisfactory Treatments?

Current treatments for chronic hyponatremia involve addressing the underlying cause, if possible, along with fluid restriction, but long-term compliance with that is a problem. Oral urea works by increasing free water clearance through osmotic diuresis, but it has a bitter taste that patients dislike, Monnerat observed.  

Vasopressin receptor antagonists (vaptans) are very effective, but also very expensive and carry the risk of overly rapid correction.

“So, overall, those treatments are unsatisfactory and we need alternative treatments,” she said.

The investigators chose to study empagliflozin. SGLT2 inhibitors work by promoting osmotic diuresis via urinary glucose excretion, with loss of free water.

“We thought that this water clearance was of greatest interest for the treatment of hyponatremia,” Monnerat said, noting that this initial effort led to their 2020 publication of 87 patients hospitalized with acute SIAD.

For the new study, they enrolled 14 outpatients with chronic SIAD in a randomized, double-blind, placebo-controlled crossover trial comparing 25 mg/day of empagliflozin versus a daily placebo tablet for 28 days, followed by a washout period and crossover to the other treatment group.

The participants, seven men and seven women, were a mean age of 71.5 years and had a body mass index of 24.4 kg/m2. Their causes of SIAD were central nervous system disorders in two, chronic pain/stress in one, drug-induced in four, pulmonary disease in three, and idiopathic in four. The average SIAD duration was 45.5 months.

Serum sodium levels remained stable with placebo while increasing from 130 mmol/L to 134 mmol/L with empagliflozin, giving a corresponding treatment effect of 4.1 mmol/L (P = .004). The increase took place during the first week of treatment and plasma sodium levels remained stable through subsequent weeks, Monnerat reported.

The Montreal Cognitive Assessment, a very sensitive test for mild cognitive impairment, was used to evaluate neurocognition. At baseline, the patients had a pathological score of 22.7 points, with normal being 26 points or greater. At end of treatment, the empagliflozin-treated group improved by 1.16 points compared to placebo (P = .042), with a particular effect seen in executive function.

However, no differences were seen in quality of life, gait test, or muscle strength. During the question-and-answer period, Molitch commented that these parameters may take longer to resolve following recovery of normal sodium levels, pointing out that “long-term therapy will be important.”  

There were no serious adverse events and no differences between the treatment groups in terms of thirst, vertigo, headache, or nausea. There were no episodes of hypoglycemia, hypotension, acute kidney injury, or urogenital infection.

The Basel team is now conducting a larger multicenter trial called EMPOWER (Empagliflozin in Patients With Euvolemic and Hypervolemic Hyponatremia). Results are expected early 2023.

Monnerat and Molitch have reported no relevant financial relationships.

ENDO 2022. Presented June 14, 2022.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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