TOPLINE

A cohort study found that the use of proton pump inhibitors (PPIs) was associated with a more than twofold higher risk for profound hyponatraemia (serum sodium levels < 125 mmol/L) than the use of histamine-2 receptor antagonists (H2RAs) over a 90-day follow-up period.

METHODOLOGY

• Researchers conducted a retrospective cohort study, analysing data from 2006 to 2018, to compare the risk for hyponatraemia between PPI users and H2RA users.
• They assessed 451,676 adults (mean age, 55.8 years; 41% men) who initiated PPI therapy (omeprazole, pantoprazole, esomeprazole, rabeprazole, or lansoprazole) and 41,318 adults who started H2RA treatment, with participants categorised according to their initial prescription.
• Individuals with profound hyponatraemia (serum sodium levels < 125 mmol/L) before the initiation of therapy were excluded.
• Inverse probability of treatment weighting based on propensity scores was used to account for baseline imbalances between the two groups.
• The primary outcome was the incidence of profound hyponatraemia during the 90 days after starting treatment; secondary outcomes were the incidence of hyponatraemia at milder thresholds (serum sodium levels < 130 mmol/L and < 135 mmol/L) over the same period.

TAKEAWAY

• The PPI group had a more than twofold higher risk for profound hyponatraemia (hazard ratio [HR], 2.57) than the H2RA group; smaller, though still significant, increases in risk were observed at the milder hyponatraemia thresholds (HR, 1.72 for sodium levels < 130 mmol/L and HR, 1.43 for sodium levels < 135 mmol/L).
• A sensitivity analysis accounting for death as a competing event confirmed the association.
• The 90-day risk for profound hyponatraemia was 0.24% in the PPI group vs 0.09% in the H2RA group, corresponding to one additional case for every 680 people treated with a PPI.
• Most cases of profound hyponatraemia occurred early after treatment began, particularly within the first month.

IN PRACTICE

"PPI initiation was associated with an increased risk of profound hyponatremia, with consistent findings across secondary analyses and clinical subgroups. This supports a strong independent association between use of PPIs and profound hyponatremia," the authors wrote.

SOURCE

This study was led by Issa Issa, MD, Karolinska Institutet, Stockholm, Sweden. It was published online on October 12, 2026, in Kidney360.

LIMITATIONS

The study relied on laboratory measurements of sodium levels, which may have led to surveillance bias. About two thirds of patients had no sodium measurement during the 90-day follow-up period. In addition, residual confounding could not be ruled out as factors such as fluid intake, dietary habits, and over-the-counter drug use were not included in the analysis. 

DISCLOSURES

The study was funded by the Tore Nilsons Stiftelse för Medicinsk Forskning and Region Stockholm ALF funding. Some authors reported being employed by various academic and healthcare institutions. One author reported receiving honoraria from Neurocrine Inc. and speakers' fees from Frost Pharma and Medscape.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.