Association between hydrochlorothiazide exposure and different incident skin, lip and oral cavity cancers: A series of population‐based nested case–control studies

Abstract

Hydrochlorothiazide-induced photosensitivity may increase squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and lip cancer risk. The aim was to quantify these risks.Methods: Nested case-control studies using data from the UK THIN database from 01 January 1999 to 01 May 2016. Adults with incident SCC, BCC, melanoma, lip cancer and oral cancer were matched (on age, sex and calendar year of cohort entry) to controls using incidence density sampling. Incidence rate ratios (IRR) for each outcome were calculated for ever and cumulative hydrochlorothiazide exposure, measuring the impact of additionally adjusting for smoking and body mass index (BMI). Adjusted rate differences were estimated, including the number needed to harm.Results: Cumulative hydrochlorothiazide doses ≥50 000 mg were associated with a significantly increased risk of SCC IRR = 3.05 (1.93-4.81) and BCC IRR = 1.34 (1.06-1.69).Using a 5-year lag-period, hydrochlorothiazide exposure was also associated with a significantly increased risk of lip cancer (IRR 2.85, 95% confidence interval 1.32-6.15). No significantly increased risk of melanoma or oral cavity cancer was observed. Following adjustment for smoking and BMI, which had inverse associations with several skin cancer types, associations for hydrochlorothiazide remained significant. The overall number needed to harm with high-dose cumulative hydrochlorothiazide exposure was: 804 for SCC; 2463 for BCC, and 200 000 for lip cancer but varied by age and sex. Conclusion:Hydrochlorothiazide exposure was associated with an increased risk of SCC, BCC and lip cancer that is not explained following adjustment for smoking and BMI. These findings may support clinical and regulatory decision making.

Risk of squamous cell carcinoma of the lip and cutaneous melanoma in older Australians using hydrochlorothiazide: A population‐based case‐control study

“…In this population‐based study nested within Australia's most populous state, we found elevated risks of both lip cancer and malignant melanoma associated with HCTZ use. Our findings are in line with those reported from Denmark, 11,12 the UK, 10 and the United States, 13 and further support the existence of an association between HCTZ use and increased risks of skin cancer. This association is particularly relevant in Australia, as it is home to the highest incidence of skin cancer in the world and the use of HCTZ is widespread.…”

“…Most SCC diagnoses are not recorded in the NSWCR, and the only reportable SCC diagnosis for which we had sufficient numbers to examine was SCC of the lip. Still, we observed a small number of lip cancer cases, and while our risk estimates are similar to those reported in previous studies, 10,12,13 our findings should be interpreted with this limitation in mind. The cancer diagnosis data we used in our study go back as far as 1972, but our dispensing records began in 2004.…”

“…We observed a twofold increase in the risk of lip cancer associated with ever‐use of HCTZ, similar to risks reported from Denmark (OR: 2.1; 95% CI: 1.7‐2.6), 12 the UK (IRR: 2.9; 95% CI: 1.3‐6.2), 10 and the United States (OR: 2.2; 95% CI: 1.7‐2.8) 13 . Two of these studies also noted an increased risk of lip cancer associated with higher use of HCTZ 12,13 .…”

“…Cutaneous basal cell carcinomas and SCC are not notifiable diagnoses in NSW—with the exceptions of SCC of the skin of anus, vulva, penis, scrotum and vermilion surface, and border of the lip—and do not appear in NSWCR data. We chose to examine SCC of the lip as previous studies have also examined this cancer 10,12,13 and because it is the only cutaneous SCC diagnosis that appears in sufficient numbers in our data set. The NSWCR receives information from pathology laboratories, public and private hospitals, radiotherapy and medical oncology departments, aged care facilities, day procedure centres and the NSW Registry of Births, Deaths and Marriages 22 .…”

“…Thiazide diuretics are known to possess photosensitising properties 7 ; in 2013, the International Agency for Research on Cancer classified HCTZ as “possibly carcinogenic to humans” (Group 2B) 8 . Recent studies reported HCTZ increased the risk of developing a range of skin cancers, particularly squamous cell carcinomas (SCCs), 2,7,9‐13 and warnings from medicines regulatory agencies in Europe, 14 the UK, 15 Canada, 16 Singapore 17 and New Zealand 18 followed from October 2018. These findings and regulatory warnings are particularly relevant for Australia, which has the highest incidence of skin cancer in the world 19…”