Empagliflozin shows promise for chronic SIAD-induced hyponatremia

The sodium-glucose cotransporter 2 inhibitor empagliflozin showed potential as a treatment alternative for hyponatremia due to chronic syndrome of inadequate antidiuresis (SIAD), according to a trial presented at ENDO 2022.

Fluid restriction is the recommended first-line treatment for SIAD-induced hyponatremia; however, this is mostly unsuccessful in correcting the condition. [J Intern Med 2016;280:609-617] Other treatment alternatives (eg, urea, vaptans) are costly or poorly tolerated thus impairing compliance, while some carry the risk of overcorrection in sodium levels. [Eur J Endocrinol 2014;170:G1-G47; Am J Kidney Dis 2018;71:772-782; Clin Endocrinol (Oxf) 2016;84:620-626] As such, other options for managing this condition are warranted.

Empagliflozin, an antidiabetic drug, may have the potential to manage hyponatremia due to its ability to induce pronounced glucosuria, which leads to osmotic diuresis with subsequent increase in free water excretion. [Clin Pharmacol Drug Dev 2013;2:152-161; Int J Endocrinol 2017;2017:7815690]

“We have previously shown that … empagliflozin is a promising short-term treatment option in hospitalized patients with SIAD-induced hyponatremia,” said the researchers. [J Am Soc Nephrol 2020;31:615-624] “[B]ut so far, there are no data on prolonged treatment in outpatients nor on its effect on neurocognitive function.”

Fourteen outpatients (50 percent female, median age 72 years) with chronic SIAD-induced hyponatremia (serum sodium <135 mmol/L) participated in the trial. They were randomized to receive daily treatment with either empagliflozin 25 mg or placebo for 4 weeks, on top of fluid restriction of ≤1.5 L/24 hours. Neurocognitive testing was measured using the Montreal Cognitive Assessment (MoCA) test.

At baseline, median serum sodium level was 131 mmol/L. After 4 weeks of treatment, the empagliflozin arm saw an increase (134 mmol/L), whereas for placebo, no notable change was noted (130 mmol/L). This led to a 4.1-mmol/L difference between the empagliflozin and the placebo arms, yielding a p value of p=0.004. “This effect was independent of severity of SIAD,” said the researchers.

Moreover, neurocognitive function appeared to have improved with empagliflozin, as reflected by the 1.2-point increase in the MoCA test in the empagliflozin arm (p=0.042).

Hyponatremia is the most common electrolyte disorder, with SIAD being one of its main causes. “However, treatment options for chronic SIAD-induced hyponatremia are inadequate, [and this is] … challenging but crucial due to its association with neurocognitive defects, [with] little data on its reversibility,” said the researchers.

“[Our findings suggest that] empagliflozin is a promising new treatment option for outpatients with chronic SIAD-induced hyponatremia, leading to improvement in neurocognitive function,” said the researchers. “[Furthermore,] treatment with empagliflozin was generally well tolerated, with no serious adverse events occurring during the observation period.”

The investigators also highlighted in their previous report that empagliflozin trumps the other currently available treatment alternatives for chronic SIAD-induced hyponatremia due to its established long-term cardiovascular and renoprotective effects, safety and tolerability profile, and wide availability. [N Engl J Med 2015;373:2117-2128; N Engl J Med 2016;375:323-334]