Risk of hyponatremia with diuretics: chlorthalidone versus hydrochlorothiazide

Am J Med. 2014 Aug;127(8):763-71. doi: 10.1016/j.amjmed.2014.04.014. Epub 2014 May 5.


Background: Chlorthalidone and hydrochlorothiazide are often considered as interchangeable. However, greater (nighttime) blood pressure reduction, and alleged pleiotropic effects have renewed the interest in chlorthalidone. A recent study showed an increased risk of adverse events with chlorthalidone, including hyponatremia.

Methods: To investigate differences in risk of hyponatremia between chlorthalidone and hydrochlorothiazide, adjusted for daily dose, we conducted a population-based case-control study within the Dutch IPCI (Integrated Primary Care Information) database. The study population included all subjects ≥18 years without diabetes mellitus, heart failure, liver failure, and malignancy, who were registered in the IPCI database from 1996 to 2011. Cases were subjects with a serum sodium <130 millimoles per liter or hospitalization due to hyponatremia. Controls were matched on practice, age within 5 years, sex, and date of onset.

Results: A total of 1033 cases of hyponatremia were identified. Hyponatremia was more common with chlorthalidone than with hydrochlorothiazide at equal dose per day: adjusted odds ratio was 2.09 (95% confidence interval [CI], 1.13-3.88) for 12.5 milligrams per day and 1.72 (95% CI, 1.15-2.57) for 25 milligrams per day. Risks were not significantly increased with chlorthalidone compared with twice the dose per day of hydrochlorothiazide.

Conclusions: This is the first study that shows an increased risk of hyponatremia with chlorthalidone relative to hydrochlorothiazide at equal milligram-to-milligram dose per day. The need for a lower dose of chlorthalidone than hydrochlorothiazide to achieve similar blood pressure reduction likely compensates for the increased risk of hyponatremia at equal dose.

Keywords: adverse drug reaction; chlorthalidone; hydrochlorothiazide; hyponatremia; matched case-control study.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Case-Control Studies
  • Chlorthalidone / adverse effects*
  • Diuretics / adverse effects*
  • Female
  • Humans
  • Hydrochlorothiazide / adverse effects*
  • Hyponatremia / chemically induced*
  • Male
  • Middle Aged
  • Odds Ratio
  • Risk Factors
  • Young Adult


  • Diuretics
  • Hydrochlorothiazide
  • Chlorthalidone