title: Risk of hyponatremia with diuretics: chlorthalidone versus hydrochlorothiazide.
abstract: 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.
authors.affiliation: Department of Medical Informatics, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. Electronic address: j.vanblijderveen@erasmusmc.nl.
authors.forename: Jan C
authors.initials: JC
authors.lastname: van Blijderveen
authors.affiliation: Department of Medical Informatics, Erasmus Medical Center, Rotterdam, the Netherlands; Dutch Medicines Evaluation Board, Utrecht, the Netherlands.
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Straus
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Eline M
authors.initials: EM
authors.lastname: Rodenburg
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Zietse
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Drug Safety Unit, Inspectorate of Healthcare, The Hague, the Netherlands.
authors.forename: Bruno H
authors.initials: BH
authors.lastname: Stricker
authors.affiliation: Department of Medical Informatics, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Miriam C
authors.initials: MC
authors.lastname: Sturkenboom
authors.affiliation: Department of Medical Informatics, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Katia M
authors.initials: KM
authors.lastname: Verhamme
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002752:Chlorthalidone / Q000009:adverse effects*; D004232:Diuretics / Q000009:adverse effects*; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide / Q000009:adverse effects*; D007010:Hyponatremia / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D012307:Risk Factors; D055815:Young Adult
chemical_list: D004232:Diuretics; D006852:Hydrochlorothiazide; D002752:Chlorthalidone
keywords: adverse drug reaction; chlorthalidone; hydrochlorothiazide; hyponatremia; matched case-control study