Thiazides and Risk of Hyponatremia by Age and Sex

Importance: Thiazide diuretics are a cornerstone for the treatment of hypertension, but their use is associated with development of hyponatremia. Women and older adults are particularly vulnerable, but population-based estimates of absolute risk are largely absent. Such data are a prerequisite for a robust risk-benefit assessment in the clinical setting. Objective: To compare new use of thiazide diuretics with calcium channel blockers (CCBs) and subsequent risk of hyponatremia among different age groups and between the sexes. Design, Setting, and Participants: This propensity score-matched cohort study included 159 080 individuals 18 years or older in the Stockholm Sodium Cohort, a research database established to investigate the association between thiazide and hyponatremia among individuals in Stockholm, Sweden, between July 1, 2006, and December 31, 2018. Statistical analysis was performed between January 2025 and January 2026. Exposure: Newly initiated treatment with thiazide diuretics and CCBs. Main Outcomes and Measures: The primary outcome was profound hyponatremia (ie, a sodium concentration <125 mEq/L). Secondary outcomes were sodium concentrations less than 130 mEq/L and less than 135 mEq/L. Results: A total of 79 540 individuals (median age, 63 years [IQR, 54-72 years]; 41 275 women [51.9%]) initiating thiazide treatment were propensity score matched with 79 540 individuals (median age, 63 years [IQR, 54-72 years]; 41 168 women [51.8%]) receiving CCBs. The cumulative incidence of profound hyponatremia was 0.80% (95% CI, 0.74%-0.87%) for thiazide users and 0.46% (95% CI, 0.41%-0.51%) for CCB users during the first 2 years of treatment. The occurrence of profound hyponatremia with thiazide treatment was higher among women (cumulative incidence, 1.04% [95% CI, 0.94%-1.15%) and individuals 80 years or older (cumulative incidence, 2.40% [95% CI, 2.07%-2.73%]). Thus, among women 80 years or older, the number needed to harm (NNH) was 53 (95% CI, 41-73) for developing sodium concentrations less than 125 mEq/L, 28 (95% CI, 22-38) for concentrations less than 130 mEq/L, and 16 (95% CI, 13-20) for concentrations less than 135 mEq/L. This was in marked contrast with women younger than 65 years, for whom the corresponding NNH was 790 (95% CI, 408-11 966) for developing sodium concentrations less than 125 mEq/L, 818 (95% CI, 303-∞) for concentrations less than 130 mEq/L, and 120 (95% CI, 78-261) for concentrations less than 135 mEq/L. Conclusions and Relevance: In this cohort study comprising 159 080 individuals, the association between newly initiated thiazide diuretics and hyponatremia was negligible among individuals younger than 65 years of age. In contrast, among older adults, especially among women, the association was substantial. The results may incentivize the prescriber toward choosing an alternative antihypertensive treatment. If thiazides are initiated, subsequent monitoring of serum sodium concentrations should be considered.