Hydrochlorothiazide and risk of melanoma subtypes

Abstract

Background Hydrochlorothiazide (HCTZ), a common diuretic known to be photosensitizing and previously associated with non‐melanoma skin cancer, was recently reported to be associated with two melanoma subtypes, nodular and lentigo, among residents of Denmark. Our goal was to examine whether Danish findings could be replicated in a US cohort, using a similar study design and analysis. Methods Among non‐Hispanic White enrollees of Kaiser Permanente Northern California, we conducted an analysis of 9176 melanoma cases and 264 781 controls, matched on age, sex and time in health plan. We examined use of HCTZ prior to cancer diagnosis (cases) or comparable date for controls, categorized as never use, ever use and high use (≥50 000 mg). Electronic health records provided data on prescriptions, cancer diagnoses, and covariates. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for education, income and number of dermatology, internal medicine and urgent care visits. Results We observed a small increase in risk of melanoma, all types combined, associated with high use (≥50 000 mg) of HCTZ (OR = 1.11, 95% CI 1.00–1.23) and no evidence of a dose–response. Risk was more elevated for lentigo subtype (OR = 1.57, 95% CI 1.01–2.42). The somewhat elevated risk for nodular subtype was not statistically significant (OR = 1.22, 95% CI 0.78–1.90). There was very little association of high use with the superficial spreading subtype (OR = 1.05, 95% CI 0.80–1.37). Conclusions Our findings support a recent report of an association between high use of HCTZ and increased risk of the lentigo subtype of melanoma.

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

“…Our study indicated an increased risk for NMSC associated with the use of hydrochlorothiazide but not with bendroflumethiazide or indapamide. Specifically, we found a higher risk for SCC than for BCC associated with thiazide use, consistent with evidence that cumulative UV exposure plays a greater role in the aetiology of SCC than of BCC [ 35 , 36 ]. The minimum average daily UV exposure level to induce skin cancers among thiazide users is unclear; however, one Icelandic study indicated that relatively low levels of average daily UV exposure were sufficient to cause 1.24-fold and 1.14-fold increases in the risks of SCC in situ and BCC, respectively, following hydrochlorothiazide use [ 13 ].…”

“…Briefly, because hydrochlorothiazide was less likely to be prescribed as the drug of choice for antihypertensive treatment, following up patients from the first date of hydrochlorothiazide may lead to a spurious protective effect against skin cancers because participants were free from the outcome of skin cancer (i.e., immortal time) until they received hydrochlorothiazide. Finally, 13 case-control studies [ 6 , 7 , 11 , 13 , 14 , 36 – 43 ] and 5 cohort studies [ 10 , 12 , 44 – 46 ] with a total of 17,848,313 participants, with 6,790,008 exposed to thiazides, were included, and most of the studies analysed hydrochlorothiazide-containing drugs. The summary for the inclusion of thiazides is presented in Additional file 1 : Table S3.…”

“…No relevant RCTs were found. We found 15 [ 6 , 7 , 10 – 14 , 36 – 40 , 43 , 45 , 46 ], 5 [ 7 , 10 , 41 , 42 , 44 ], and 5 observational studies [ 7 , 10 , 14 , 37 , 42 ] on skin cancer risk associated with hydrochlorothiazide, bendroflumethiazide, and indapamide use, respectively. These studies were from 17 countries, and the study characteristics are listed in Table 1 and Additional file 1 : Table S4.…”

“…Six case-control studies [ 6 , 11 , 14 , 36 , 37 , 40 ] and two cohort studies [ 10 , 12 ]examined the association of hydrochlorothiazide use with melanoma. The meta-analysis revealed increased odds for melanoma among patients who received hydrochlorothiazide (pooled OR 1.11, 95% CI 1.02–1.20, I 2 = 83%) in case-control studies, whereas no significant differences were observed in the cohort studies (HR 1.03, 95% CI 0.93–1.14, I 2 = 0%) (Fig.…”

“…We found two studies (one case-control study [ 11 ] and one cohort study [ 12 ]) and six studies (five case-control studies [ 6 , 14 , 36 , 37 , 40 ] and one cohort study [ 10 ]) on the association of hydrochlorothiazide with melanoma from Asian and non-Asian regions, respectively. One Taiwanese study with 317,845 subjects revealed reduced OR for hydrochlorothiazide-associated melanoma (OR 0.90; 95% CI 0.82–0.99), contradicting the results of five other non-Asian studies (pooled OR 1.14; 95% CI 1.10–1.19; I 2 = 0%; test for subgroup differences: P < 0.00001; Additional file 1 : Figure S11), whereas no risk for melanoma was observed both from Asian and non-Asian cohort studies (Additional file 1 : Figure S12).…”