Risk of Nonmelanoma Skin Cancer in Association With Use of Hydrochlorothiazide-Containing Products in the United States

Abstract

Background: European studies reported an increased risk of nonmelanoma skin cancer associated with hydrochlorothiazide (HCTZ)-containing products. We examined the risks of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) associated with HCTZ compared with angiotensin-converting enzyme inhibitors (ACEIs) in a US population.

Methods: We conducted a retrospective cohort study in the US Food and Drug Administration's Sentinel System. From the date of HCTZ or ACEI dispensing, patients were followed until a SCC or BCC diagnosis requiring excision or topical chemotherapy treatment on or within 30 days after the diagnosis date or a censoring event. Using Cox proportional hazards regression models, we estimated the hazard ratios (HRs), overall and separately by age, sex, and race. We also examined site- and age-adjusted incidence rate ratios (IRRs) by cumulative HCTZ dose within the matched cohort.

Results: Among 5.2 million propensity-score matched HCTZ and ACEI users, the incidence rate (per 1000 person-years) of BCC was 2.78 and 2.82, respectively, and 1.66 and 1.60 for SCC. Overall, there was no difference in risk between HCTZ and ACEIs for BCC (HR = 0.99, 95% confidence interval [CI] = 0.97 to 1.00), but there was an increased risk for SCC (HR = 1.04, 95% CI = 1.02 to 1.06). HCTZ use was associated with higher risks of BCC (HR = 1.09, 95% CI = 1.07 to 1.11) and SCC (HR = 1.15, 95% CI = 1.12 to 1.17) among Caucasians. Cumulative HCTZ dose of 50 000 mg or more was associated with an increased risk of SCC in the overall population (IRR = 1.19, 95% CI = 1.05 to 1.35) and among Caucasians (IRR = 1.27, 95% CI = 1.10 to 1.47).

Conclusions: Among Caucasians, we identified small increased risks of BCC and SCC with HCTZ compared with ACEI. Appropriate risk mitigation strategies should be taken while using HCTZ.

Figure 1.

Incidence rate ratio for squamous cell carcinoma by cumulative hydrochlorothiazide dose using angiotensin-converting enzyme inhibitor use as reference within the 1:1 propensity score–matched population. A) Incidence rate ratio for squamous cell carcinoma by cumulative hydrochlorothiazide-containing products (HCTZ) dose for all HCTZ users. B) Incidence rate ratio for squamous cell carcinoma by cumulative HCTZ dose for Caucasian HCTZ users. One small data partner did not contribute data to the cumulative dose analyses (18 409 patients, 133 basal cell carcinoma events, 55 squamous cell carcinoma events).

Figure 2.

Incidence rate ratio for basal cell carcinoma by cumulative hydrochlorothiazide dose using angiotensin-converting enzyme inhibitor use as reference within the 1:1 propensity score–matched population. A) Incidence rate ratio for squamous cell carcinoma by cumulative hydrochlorothiazide-containing products (HCTZ) dose for all HCTZ users. B) Incidence rate ratio for squamous cell carcinoma by cumulative HCTZ dose for Caucasian HCTZ users. One small data partner did not contribute data to the cumulative dose analyses (18 409 patients, 133 basal cell carcinoma events, 55 squamous cell carcinoma events).