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 non-melanoma skin cancer associated with hydrochlorothiazide (HCTZ)-containing products. We examined the risks of basal cell (BCC) and squamous cell carcinoma (SCC) associated with HCTZ compared to 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 1,000 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% CI = 0.97–1.00), but an increased risk for SCC (HR = 1.04, 95% CI = 1.02–1.06). HCTZ use was associated with higher risks of BCC (HR = 1.09, 95% CI = 1.07–1.11) and SCC (HR = 1.15, 95% CI = 1.12–1.17) among Caucasians. Cumulative HCTZ dose ≥50,000mg was associated with an increased risk of SCC in the overall population (IRR =1.19, 95% CI = 1.05–1.35) and among Caucasians (IRR = 1.27, 95% CI = 1.10–1.47). Conclusions Among Caucasians, we identified small increased risks of BCC and SCC with HCTZ compared to ACEI. Appropriate risk mitigation strategies should be taken while using HCTZ.

Associations of thiazide use with skin cancers: a systematic review and meta-analysis

“…Eight case-control studies [ 7 , 11 , 13 , 37 – 40 , 43 ] and four cohort studies [ 10 , 12 , 45 , 46 ] provided risk estimates for hydrochlorothiazide-associated NMSC. The meta-analysis demonstrated increased odds for NMSC among patients receiving hydrochlorothiazide in case-control studies (pooled OR 1.16, 95% CI 1.08–1.24, I 2 = 96%) and cohort studies (pooled HR 1.26, 95% CI 1.04–1.54, I 2 = 100%) (Fig.…”

“…Earlier systematic reviews have reported that thiazides are associated with an increased risk of skin cancers [ 5 , 8 , 9 ]. In comparison with previous reviews, we included more recent studies, with 13 published from February 2019 to January 2022 [ 10 – 14 , 36 – 40 , 43 , 45 , 46 ]. More importantly, our analyses covered a broader range of recent nationwide data, including data from the Brazil, Netherlands, USA, UK, Iceland, Spain, Australia, Taiwan, and Korea.…”

Increasing Trust in Real-World Evidence Through Evaluation of Observational Data Quality

“…It is our vision that this becomes the way data quality is shared among networks, with reviewers, and with regulators. The most recent papers published using the PEDSnet, PCORNet, and Sentinel networks [38][39][40] either do not mention how the data used were assessed for quality or they touch on it very briefly. Instead, with a tool like the DQD, a JSON file(s) can be shared as additional material to a publication detailing all data quality checks that were run on the database in which the study was executed.…”

Hydrochlorothiazide use, sun exposure, and risk of keratinocyte cancer

“…Concerns about HCTZ and sun interactions are well founded. High UV exposure has long been known to increase the risk of severe sunburn and skin cancer [ 9 , 10 ] and, in response to recent evidence from very large observational studies [ 14 , 28 , 29 ], HCTZ labeling in the U.S. now has overt warnings of increased KC risks [ 30 ]. KC is fast becoming a disease (primarily) of the elderly [ 10 , 31 ], likely reflecting accrued exposures to KC risk factors (e.g., sun seeking, ozone depletion) over longer lifetimes [ 32 , 33 ].…”

“…Studies on this topic have been limited by indirect markers of sun exposure such as the self-reported number of lifetime painful sunburns or residential address information indicative of living in sunnier regions. While some studies have adjusted for said markers of sun exposure in their examination of HCTZ use [ 13 , 14 ], analyses of HCTZ effect modification by sun exposure are lacking, with just one known case–control study showing enhanced risk of squamous cell carcinoma among users of photosensitizing medications who also have a tendency to sunburn [ 15 ].…”