A history of high cumulative exposure to hydrochlorothiazide (HCTZ) was associated with an increased risk of developing nonmelanoma skin cancer, according to results of a large observational study. These findings were reported in the British Journal of Clinical Pharmacology.

Preclinical evidence, as well as findings from observational studies, have suggested that HCTZ use can cause photosensitivity and may increase skin cancer risk, although only a limited number of studies have investigated this association.

In this nested case-control study, data relating to a cohort of patients with and without different types of cancer, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), melanoma, lip cancer, and oral cavity cancer, were accessed from The Health Improvement Network (THIN) database which includes hundreds of electronic medical records of patients in the United Kingdom (UK).

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Cases were defined as those patients with a specific form of skin cancer, and the index date was the date of skin cancer diagnosis. Multiple control patients, defined as those without a diagnosis of skin cancer by the index date, were randomly selected and matched with each patient case by sex, birth year, and year of entry into the study cohort. For each patient included in the study, exposure to HCTZ was determined based on prescriptions prior to the index date, but to allow for a lag-time for cancer induction, HCTZ prescriptions within 2 years before the index date were not included in the cumulative dose.

Regarding the cancers selected for investigation in this study, the study authors explained that “given that the mechanism of action for this risk is alleged to be photosensitivity, oral cavity cancer was included as a negative control testing for unmeasured confounding because cancers arising within the oral cavity and pharynx

will not be exposed to significant UV light whilst potentially sharing similar risk factors for cancer development and in particular for lip cancer. Any observed association between HCTZ and oral cavity cancers would raise doubt about the validity of an association between HCTZ and skin cancer due to UV light exposure.”

A key finding from this study was that the incidence rate ratios (IRR) of SCC and BCC were 2.93 (95% CI, 1.85-4.62) and 1.30 (95% CI, 1.03-1.65), respectively, for those with a cumulative exposure to HCTZ of 50,000 mg or higher.

Regarding lip cancer, the IRR was 2.23 for those with a cumulative HCTZ exposure history corresponding to 25,000 to 49,999 mg, although the 95% CI (0.54–9.16) indicated that this association did not reach statistical significance. However, when the HCTZ lag-time was extended to 5 years as part of a secondary analysis, the IRR of lip cancer was 2.59 (95% CI, 1.20-5.60) with ever-use of HCTZ.

The risk of these skin cancers in patients with HCTZ exposure remained significantly elevated following adjustment for smoking history and body mass index.

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No significant increase in the incidence of melanoma or oral cavity cancers were found for patients with a history of exposure to high doses of HCTZ.

In their concluding remarks, the study authors commented that “this information may be useful to healthcare professionals for assessing the benefit–risk and communicating the risk of these medicines to patients,” although they also noted that “further studies examining the risk of skin cancer with HCTZ in different UV-susceptible skin susceptible populations [outside of the UK] are required to assess whether these effects are more generalizable.”


Morales DR, Pacurariu A, Slattery J, Kurz X. Association between hydrochlorothiazide exposure and different incident skin, lip and oral cavity cancers: a series of population-based nested case-control studies [published online February 18, 2020]. Br J Clin Pharmacol. doi: 10.1111/bcp.14245

This article originally appeared on Oncology Nurse Advisor