Empagliflozin is a potential treatment for outpatients with chronic hyponatremia due to syndrome of inappropriate antidiuresis (SIAD), new data suggest.
The sodium-glucose cotransporter 2 inhibitor (SGLT2) inhibitor empagliflozin (Jardiance), approved for the treatment of type 2 diabetes, increased serum sodium levels and improved neurocognitive function without major adverse effects in a 4-week study 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, 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 Newssession moderator Mark E. Molitch, MD, called the new data on empagliflozin “exciting” and said it’s enough to use it.
“Empagliflozin is relatively inexpensive compared to tolvaptan [a vasopressin receptor antagonist]† It is likely that all SGLT2 inhibitors would work. It’s well tolerated… Obviously they need to do a long-term study and look at people with more severe hyponatremia, so they need to expand their studies, but it’s really promising,” he said.
“Even based on this data, we should now be able to use it clinically,” said Molitch, a 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 disturbance in both the inpatient and outpatient setting. SIAD is one of the main causes, with impaired regulation of antidiuretic hormone leading to a decrease in free water excretion and water retention in the kidney, resulting in hypotonic hyponatremia.
There are many causes of SIAD, including disorders of the central nervous system and lung disease, cancer, and certain medications. But it is also often idiopathic and persistent. In those situations, it’s often overlooked, but it shouldn’t be, Monnerat said.
“Hyponatraemia is a common and clinically relevant problem… Acute hyponatremia is undeniably considered an emergency, while chronic hyponatremia is often seen as asymptomatic. However, there is mounting evidence that these patients have cognitive impairments, such as attention deficit, that they are unstable when walking with a tendency to fall, and that they have an increased risk of osteoporosis and fractures, and even death, she said.
Indeed, Molitch noted, “With idiopathic inappropriate vasopressin secretion, you always try to fix it if there is an obvious cause, 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 fine, we didn’t really pay attention.”
But he said several studies have shown that “these people are really not normal. They have cognitive problems, they have walking difficulties, they are unsteady, and if you correct the hyponatremia, those things improve.”
Empagliflozin: an alternative to electricity †unsatisfactory† treatments?
Current treatments for chronic hyponatremia involve addressing the underlying cause, if possible, along with fluid restriction, but long-term compliance is an issue. Oral urea works by increasing the clearance of free water through osmotic diuresis, but it has a bitter taste that patients don’t like, Monnerat noted.
Vasopressin receptor antagonists (vaptans) are very effective, but also very expensive and carry the risk of over-correction.
“So in general those treatments are unsatisfactory and we need alternative treatments,” she said.
The researchers chose to study empagliflozin. SGLT2 inhibitors work by promoting osmotic diuresis via urinary glucose excretion, with loss of free water.
“We thought this water clearance was paramount 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 study comparing 25 mg/day of empagliflozin with 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 on average 71.5 years old and had a body mass index of 24.4 kg/m2.2† Their causes of SIAD were central nervous system disorders in two, chronic pain/stress in one, drug-induced in four, lung disease in three, and idiopathic in four. The mean 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, yielding a corresponding treatment effect of 4.1 mmol/L (p = .004). The increase occurred during the first week of treatment and plasma sodium levels remained stable over the following weeks, Monnerat reported.
The Montreal Cognitive Assessment, a highly sensitive test for mild cognitive impairment, was used to evaluate neurocognition. At baseline, patients had a pathological score of 22.7 points, with the normal score being 26 points or greater. At the end of treatment, the empagliflozin-treated group improved by 1.16 points compared to placebo (p = .042), with some effect seen in the executive function.
However, no differences were seen in quality of life, walking test or muscle strength. During the question-and-answer period, Molitch noted that these parameters may take longer to resolve after recovery of normal sodium levels, pointing out that “long-term therapy will be important.”
There were no serious side effects and there were no differences between the treatment groups in terms of thirst, dizziness, headache, or nausea. There were no episodes of hypoglycaemia, hypotension, acute renal injury, or genitourinary infection.
The Basel team is now conducting a larger multicenter study called EMPOWER (Empagliflozin in Patients With Euvolemic and Hypervolemic Hyponatremia). The results are expected in early 2023.
Monnerat and Molitch have not reported any relevant financial relationships.
ENDO 2022. Presented on June 14, 2022.
Miriam E. Tucker is a freelance journalist based in the Washington, DC area. She is a regular contributor to Medscape, and other work appears in The Washington Post, NPR’s Shots blog, and Diabetes Forecast magazine. She’s on Twitter: @MiriamETucker.
For more news on diabetes and endocrinology, follow us Twitter and Facebook.