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

According to the Global Burden of Disease Study, the incidences of basal cell carcinomas (BCC), squamous cell carcinomas (SCC), and melanoma have increased by 77%, 309%, and 161%, respectively, from 1990 to 2017 [1]. Identification and avoidance of modifiable risk factors may mitigate this increasing trend. One risk factor is the interaction of sunlight with medications, leading to photosensitivity responses in susceptible patients, potentially increasing the risk of skin cancer [2, 3].

Among first-line antihypertensives [4], thiazide diuretics have photosensitizing properties with a biologically plausible causal association with skin cancers [5]. Previous Danish studies have suggested an increased risk for non-melanoma skin cancers (NMSC) and some melanoma subtypes associated with hydrochlorothiazide [6, 7]. Several systematic reviews have indicated overall thiazide uses increased the risk of skin cancers [5, 8, 9]. However, the risk profiles may vary between different individual thiazides. For example, indapamide and bendroflumethiazide did not pose additional risk of skin cancers, based on a recent study by Schneider et al. [10]. Furthermore, studies from Asian countries have shown findings inconsistent with those from non-Asian countries which indicated ethnic differences between Caucasians and Asians with regard to adverse effects of medications. For example, hydrochlorothiazide appears safe for use in Taiwanese and Korean populations [11, 12], while Australian and Icelandic studies have found significant associations of thiazide use with skin cancers [13, 14]. Thus, this study aimed to examine the associations of individual thiazide use with skin cancer risk, differentiated by subtypes of skin cancers, geographic regions, and cumulative doses of individual thiazides.

We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines [15, 16]. Two authors (CCL and YHC) independently performed study selection, data extraction, and risk of bias (RoB) assessments. Two senior authors (SCS and CCC) helped resolve disagreements. The protocol was registered with PROSPERO (CRD42021234317).

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]. Taken together, healthcare professionals and patients should recognize that more aggressive and appropriate photoprotective behaviours (e.g., use of adequate amounts of broad-spectrum sunscreen with a sun-protection factor of ≥ 30) should be re-emphasized to eliminate the carcinogenicity of thiazides [49]. The risk-benefit evaluation in prescribing thiazides must be individually assessed.

The inconsistent risk profiles for skin cancers among individual drugs within the same chemical class of thiazides are possibly due to varying photosensitizing effects under different molar concentrations of the drugs and differences in wavelengths responsible for various histologic types of skin cancers [7]. For example, we found associations of NMSC only with hydrochlorothiazide use, but not with bendroflumethiazide use, possibly due to the shorter half-life of bendroflumethiazide, given the lower molar concentrations of therapeutically equivalent doses [50, 51]. Indapamide has more absorbance in the UV-B spectrum than hydrochlorothiazide in the UV-A spectrum, which plays an essential role in NMSC carcinogenesis [52‐54]. In addition, our study suggests that cumulative doses of hydrochlorothiazide under 25,000 mg are relatively safe with regard to BCC, SCC, and melanoma, based on case-control studies. These data could provide an important reference for the selection and dosing of appropriate thiazide drugs taking into consideration the risks for skin cancers.

A similar biological mechanism to NMSC may extend the carcinogenic effects of hydrochlorothiazide to the development of various melanoma subtypes associated with high sun exposure [6, 55]. Previous studies have indicated that different ethnicities have varying risk profiles for melanoma; the risk typically being higher in Caucasians (incidence: 7.6–18.9 per 10,000 people) than in Asians (incidence: 0.5–1.5 per 10,000 people) [56]. Our subgroup analysis on geographic regions revealed reduced melanoma risk associated with hydrochlorothiazide in one case-control study in Taiwan [11], compared with increased risks in five case-control studies in Europe and Australia. Although the dosage of hydrochlorothiazide prescribed in Taiwan is generally lower than that in other non-Asian countries [11], the dose-response analysis found no increased risk of melanoma, especially with medium and high cumulative doses of hydrochlorothiazide, in Taiwan. As thiazide diuretics are not metabolized in the human body [57], possible genetic polymorphisms are unlikely to explain risk differences across populations. Skin photosensitivity reactions are considered important in hydrochlorothiazide carcinogenicity [5]; thus, contradicting results noted between Asian and non-Asian countries may be explained by ethnic differences. For example, ultraviolet exposure plays an important role in the carcinogenesis of melanoma in Caucasians, but not in Asians [56], which is supported by a previous study indicating that acral melanoma, which usually occurs in areas with little to no sun exposure, accounted for 50%–58% of melanoma in Asians [58]. Since a previous study suggested trauma and physical pressure as a risk factor for acral melanoma, the mechanisms of melanoma may vary between Asian and non-Asian populations [59]. Similarly, our subgroup analysis found oppositely directed risks of hydrochlorothiazide-associated NMSC between Asian and non-Asian countries, which may be explained by ethnic differences in skin phototypes. Asian populations typically have larger amounts of melanin (Fitzpatrick skin phototype III or IV), and DNA repair mechanisms are probably more efficient than in fair-skinned Northern European populations [11, 60]. Considering ethnicity as an effect modifier, our findings suggest that hydrochlorothiazide use does not appear to pose a clinically meaningful risk for skin cancers in Asians.

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. Consequently, our findings could be geographically more generalizable. Our meta-analysis is also the first to evaluate skin cancer risk associated with individual thiazides, instead of pooling all thiazides into one pharmacologic entity. For those with a potential risk of skin cancers, physicians may consider prescribing alternative thiazides such as bendroflumethiazide and indapamide. Furthermore, we conducted subgroup analyses on geographic regions on hydrochlorothiazide and skin cancers. A higher risk for hydrochlorothiazide-associated skin cancers was observed in non-Asian countries than in Asian countries; however, further studies are still needed to understand the aetiology and develop different preventative strategies for Asian skin cancers. Our findings for the different geographic regions support the biological mechanism whereby more sun exposure combined with photosensitizing drugs leads to increased skin cancer risk [61]. The causal link between hydrochlorothiazide and skin cancer was further strengthened by our subgroup analysis on cumulative doses. Notably, no dose-response effect was found between bendroflumethiazide and indapamide use and NMSC, suggesting that skin cancer risk profiles vary with different individual thiazides.

This study has several limitations. First, since we found no eligible RCTs, our findings may be biased through unmeasured confounding, such as lifestyle, diet, amounts of sun exposure, and sun-protective behaviours. Second, high heterogeneity among the studies for NMSC and melanoma was observed in the main analysis, probably due to varying thiazide prescribing patterns and skin cancer incidences across different countries. To identify the sources of heterogeneity across the studies, we performed multiple subgroup analyses to evaluate skin cancer risk, based on different regions and cumulative doses. However, the subgroup analysis did not fully diminish the statistical heterogeneity among the included studies. Third, some results from the meta-analysis were inconsistent between case-control studies and cohort studies on the same outcomes, probably because shorter follow-up durations in the cohort studies may have led to underestimation of the risk estimates [47]. Fourth, the skin cancer risk associated with the use of chlorothiazide, methyclothiazide, and metolazone is unclear due to the lack of relevant data.

Current evidence supports an increased risk for SCC and melanoma among patients receiving hydrochlorothiazide, but no significant or clinically meaningful risk for those receiving bendroflumethiazide or indapamide. Dermatology consultation and optimal photo-protection may be considered for hydrochlorothiazide users.