Abstract
Introduction
There are concerns that hydrochlorothiazide may increase the risk of incident nonmelanoma (cutaneous squamous cell carcinoma [cSCC], basal cell carcinoma [BCC]) and melanoma skin cancer, with regulatory agencies and societies calling for additional studies.
Methods
We conducted a propensity score-matched population-based cohort study using the United Kingdom Clinical Practice Research Datalink. A total of 20,513 new users of hydrochlorothiazide were propensity score matched, in a 1:1 ratio, to new users of other thiazide diuretics between January 1, 1988 and March 31, 2018, with follow-up until March 31, 2019. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for cSCC, BCC, and melanoma, comparing use of hydrochlorothiazide with use of other thiazide diuretics overall, by cumulative duration of use, and cumulative dose.
Results
After an 8.6-year median follow-up, hydrochlorothiazide was associated with an increased risk of cSCC (HR 1.50, 95% CI 1.06–2.11). HRs increased with cumulative duration of use, with evidence of an association after 5–10 years (HR 2.10, 95% CI 1.20–3.67) and highest after > 10 years (HR 3.70, 95% CI 1.77–7.73). Similarly, HRs increased with cumulative dose, with higher estimates for ≥ 100,000 mg (HR 4.96, 95% CI 2.51–9.81). In contrast, hydrochlorothiazide was not associated with an increased risk of BCC (HR 1.01, 95% CI 0.91–1.13) or melanoma (HR 0.82, 95% CI 0.63–1.08), with no evidence of duration– or dose–response relationships.
Conclusions
Use of hydrochlorothiazide was associated with an increased risk of cSCC and with evidence of a duration– and dose–response relationship. In contrast, no association was observed for BCC or melanoma.
Similar content being viewed by others
References
Williams B, et al. 2018 Practice Guidelines for the management of arterial hypertension of the European Society of Hypertension and the European Society of Cardiology: ESH/ESC Task Force for the Management of Arterial Hypertension. J Hypertens. 2018;36(12):2284–309.
Whelton PK, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2018;138(17):e426–83.
Wang YR, Alexander GC, Stafford RS. Outpatient hypertension treatment, treatment intensification, and control in Western Europe and the United States. Arch Intern Med. 2007;167(2):141–7.
Bendinelli B, et al. Do thiazide diuretics increase the risk of skin cancer? A critical review of the scientific evidence and updated meta-analysis. Curr Cardiol Rep. 2019;21(9):92.
Kreutz R, Algharably EAH, Douros A. Reviewing the effects of thiazide and thiazide-like diuretics as photosensitizing drugs on the risk of skin cancer. J Hypertens. 2019;37(10):1950–8.
IARC. IARC monographs on the evaluation of carcinogenic risks to humans, vol 108. Some drugs and herbal products. Lyon: IARC; 2016.
Friedman GD, et al. Antihypertensive drugs and lip cancer in non-Hispanic whites. Arch Intern Med. 2012;172(16):1246–51.
Pottegard A, et al. Hydrochlorothiazide use is strongly associated with risk of lip cancer. J Intern Med. 2017;282(4):322–31.
Pedersen, S.A., et al., Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-control study from Denmark. J Am Acad Dermatol, 2018; 78(4):673–81e9.
Morales DR, et al. Association between hydrochlorothiazide exposure and different incident skin, lip and oral cavity cancers: a series of population-based nested case-control studies. Br J Clin Pharmacol. 2020;86(7):1336–45.
Jensen AO, et al. Use of photosensitising diuretics and risk of skin cancer: a population-based case-control study. Br J Cancer. 2008;99(9):1522–8.
Pottegard A, et al. Association of hydrochlorothiazide use and risk of malignant melanoma. JAMA Intern Med. 2018;178(8):1120–2.
McNally RJ, et al. A review of the prescribing trend of thiazide-type and thiazide-like diuretics in hypertension: a UK perspective. Br J Clin Pharmacol. 2019;85(12):2707–13.
NICE. Hypertension in adults: diagnosis and management (NG136). 2019 [cited 2020 April 03]. https://www.nice.org.uk/guidance/ng136.
Herrett E, et al. Data resource profile: clinical practice research datalink (CPRD). Int J Epidemiol. 2015;44(3):827–36.
Bhaskaran K, et al. Representativeness and optimal use of body mass index (BMI) in the UK Clinical Practice Research Datalink (CPRD). BMJ Open. 2013;3(9):e003389.
Mathur R, et al. Completeness and usability of ethnicity data in UK-based primary care and hospital databases. J Public Health (Oxf). 2014;36(4):684–92.
Service, NH. Read codes. 2020 [cited 2020 March 1];. https://digital.nhs.uk/services/terminology-and-classifications/read-codes.
Boggon R, et al. Cancer recording and mortality in the General Practice Research Database and linked cancer registries. Pharmacoepidemiol Drug Saf. 2013;22(2):168–75.
Margulis AV, et al. Validation of cancer cases using primary care, cancer registry, and hospitalization data in the United Kingdom. Epidemiology. 2018;29(2):308–13.
Chiesa Fuxench ZC, Troxel AB, Gelfand JM. Validity of diagnostic codes for identifying cutaneous squamous cell carcinoma in The Health Improvement Network. Br J Dermatol. 2017;176(5):1363–5.
Meal A, et al. Validation of THIN data for non-melanoma skin cancer. Qual Prim Care. 2008;16(1):49–52.
Ding P, VanderWeele TJ. Sensitivity analysis without assumptions. Epidemiology. 2016;27(3):368–77.
Adalsteinsson JA, et al. Association between hydrochlorothiazide and the risk of in situ and invasive squamous cell skin carcinoma and basal cell carcinoma: a population-based case-control study. J Am Acad Dermatol. 2020. https://doi.org/10.1016/j.jaad.2020.08.025
Pottegard A, et al. Use of hydrochlorothiazide and risk of skin cancer: a nationwide Taiwanese case-control study. Br J Cancer. 2019;121(11):973–8.
Daniels B, et al. Risk of squamous cell carcinoma of the lip and cutaneous melanoma in older Australians using hydrochlorothiazide: a population-based case-control study. Basic Clin Pharmacol Toxicol. 2020;127(4):320–28.
Faconti L, et al. Hydrochlorothiazide and the risk of skin cancer. A scientific statement of the British and Irish Hypertension Society. J Hum Hypertens. 2019;33(4):257–8.
Pirie K, et al. Heterogeneous relationships of squamous and basal cell carcinomas of the skin with smoking: the UK Million Women Study and meta-analysis of prospective studies. Br J Cancer. 2018;119(1):114–20.
McCormack T, Cappuccio FP. 10 steps before you refer for hypertension. Br J Cardiol. 2008;15:254–7.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
This work was supported by a Foundation Scheme grant from the Canadian Institutes of Health Research (FDN-143328). JR is the recipient of a Doctoral Award from the Canadian Institutes of Health Research (FRN-152254). LA holds a Chercheur-Boursier Senior Award from the Fonds de Recherche du Québec—Santé and is the recipient of a William Dawson Scholar award from McGill University. Researchers were independent from the funding sources. The funding sources had no influence on the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Conflicts of interest
JR received consulting fees for work unrelated to this project from Biogen. LA received consulting fees from Janssen and Pfizer for work unrelated to this paper. AP reports participation in research projects funded by Alcon, Almirall Astellas, AstraZeneca, Boehringer-Ingelheim, Novo Nordisk, Servier and LEO Pharma, all with funds paid to the institution where he was employed (no personal fees) and with no relation to the work reported in this paper. KN received research funding from AstraZeneca, Vifor and CSL Behring and personal fees from MSD, Sanofi and Boehringer Ingelheim, all unrelated to this study. HY has no conflicts of interest to disclose.
Ethical approval
The study protocol was approved by the Independent Scientific Advisory Committee of the CPRD (protocol number 19_279A) and the Research Ethics Board of the Jewish General Hospital, Montreal, Canada (number 2020-2207).
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Availability of data and materials
The data cannot be shared publicly due to patients’ privacy, as per the Clinical Practice Research Datalink policy.
Code availability
The codes cannot be shared publicly, as per the Lady Davis Institute—Centre for Clinical Epidemiology policy.
Author contributions
Conception and planning of the work that led to the manuscript (JR, HY, LA). Acquisition, analysis and interpretation of the data (JR, HY, AP, KN, LA). Drafting and/or critical revision of the manuscript for important intellectual content (JR, HY, AP, KN, LA). Approval of the final submitted version of the manuscript (JR, HY, AP, KN, LA).
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Rouette, J., Yin, H., Pottegård, A. et al. Use of Hydrochlorothiazide and Risk of Melanoma and Nonmelanoma Skin Cancer. Drug Saf 44, 245–254 (2021). https://doi.org/10.1007/s40264-020-01015-1
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40264-020-01015-1