Hydrochlorothiazide use and risk of keratinocyte carcinoma and melanoma: a multi-site population-based cohort study

Background — The association between hydrochlorothiazide (HCTZ) and skin cancer remains controversial.

Objective — To determine whether HCTZ is associated with an increased risk of skin cancer compared with angiotensin-converting enzyme inhibitors (ACEIs) and calcium channel blockers (CCBs).

Methods — Two new-user, active comparator cohorts were assembled using six Canadian databases. Site-specific hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using standardized morbidity ratio weighted Cox proportional hazard models and pooled using random-effects meta-analysis.

Results — HCTZ was not associated with an overall increased risk of keratinocyte carcinoma compared with ACEIs or CCBs, although increased risks were observed with longer durations (≥10 years; HR: 1.12; 95% CI: 1.03-1.21) and higher cumulative doses (≥100,000 mg; HR: 1.49; 95% CI: 1.27-1.76). For melanoma, there was no association with ACEIs, but a 32% increased risk with CCBs (crude incidence rates: 64.2 vs. 58.4 per 100,000 person-years; HR: 1.32; 95% CI: 1.19-1.46; estimated number needed to harm at 5 years of follow-up: 1,627 patients), with increased risks with longer durations and cumulative doses.

Limitations — Residual confounding due to the observational design.

Conclusions — Increased risks of keratinocyte carcinoma and melanoma were observed with longer durations of use and higher cumulative doses of HCTZ.