Hydrochlorothiazide and chlorthalidone use and glaucoma risk: pharmacovigilance analysis and nationwide cohort study

Hydrochlorothiazide and chlorthalidone are widely used thiazide diuretics, and pharmacovigilance reports have suggested a possible link between their use and glaucoma. Therefore, this study aims to evaluate whether the use of hydrochlorothiazide or chlorthalidone is associated with an increased risk of glaucoma in a nationwide population-based claims cohort to clarify the true risk and guide clinical practice. Pharmacovigilance disproportionality analyses of the Food and Drug Administration Adverse Event Reporting System (FAERS) reports were conducted to identify candidates for glaucoma-related diuretics. In the nationwide Korean Health Insurance Review and Assessment (HIRA) cohort of new users of hydrochlorothiazide or chlorthalidone, incidence of overall and subtype-specific glaucoma was assessed, and pre- and post-exposure incidence rate ratios (IRRs) were calculated. Multivariate Cox proportional hazards models were used to estimate hazard ratios (HRs) for clinical risk factors. Hydrochlorothiazide and chlorthalidone demonstrated positive disproportionality signals for glaucoma (ROR, 3.34; 95% confidence interval [CI], 2.85-3.91 and 11.37; 95% CI, 7.67-16.86, respectively). In the HIRA cohort of new users of hydrochlorothiazide (n = 250,296) or chlorthalidone (n = 10,005) from January 2019 to December 2020, the cumulative incidence of glaucoma/ocular hypertension rose gradually for both drugs, reaching approximately 2%-3% by study end. Pre- versus post-exposure IRRs for overall glaucomatous conditions were 1.02 (95% CI 0.98-1.06) for hydrochlorothiazide and 1.03 (95% CI 0.84-1.26) for chlorthalidone; IRRs for ocular hypertension were 1.02 (95% CI 0.97-1.07) and 1.09 (95% CI 0.87-1.37), respectively. Multivariate analyses found no significant association between the drugs and overall glaucomatous conditions (adjusted HR 1.01; 95% CI 0.86-1.19). In dose-stratified analyses, hydrochlorothiazide showed a modest increase in glaucoma risk in the highest cumulative exposure group (for overall glaucomatous conditions, HR 1.21; 95% CI 1.12-1.31; log-rank <i>P</i> < 0.01), whereas chlorthalidone showed no consistent dose-response trends. Although the FAERS pharmacovigilance suggested a potential glaucoma risk with hydrochlorothiazide and chlorthalidone, population-based validation found no significant association. Pharmacovigilance signals should be confirmed with population-based data to identify true drug-glaucoma associations.