Association between Use of Hydrochlorothiazide and Nonmelanoma Skin Cancer: Common Data Model Cohort Study in Asian Population

Abstract

Although hydrochlorothiazide (HCTZ) has been suggested to increase skin cancer risk in white Westerners, there is scant evidence for the same in Asians. We analyzed the association between the use of hydrochlorothiazide and non-melanoma in the Asian population using the common data model. Methods: A retrospective multicenter observational study was conducted using a distributed research network to analyze the effect of HCTZ on skin cancer from 2004 to 2018. We performed Cox regression to evaluate the effects by comparing the use of HCTZ with other antihypertensive drugs. All analyses were re-evaluated using matched data using the propensity score matching (PSM). Then, the overall effects were evaluated by combining results with the meta-analysis. Results: Positive associations were observed in the use of HCTZ with high cumulative dose for non-melanoma skin cancer (NMSC) in univariate analysis prior to the use of PSM. Some negative associations were observed in the use of low and medium cumulative doses. Conclusion: Although many findings in our study were inconclusive, there was a non-significant association of a dose-response pattern with estimates increasing in cumulative dose of HCTZ. In particular, a trend with a non-significant positive association was observed with the high cumulative dose of HCTZ.

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

“…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.…”

“…Eight case-control studies [ 7 , 11 , 13 , 37 – 40 , 43 ] and four cohort studies [ 10 , 12 , 45 , 46 ] provided risk estimates for hydrochlorothiazide-associated NMSC. The meta-analysis demonstrated increased odds for NMSC among patients receiving hydrochlorothiazide in case-control studies (pooled OR 1.16, 95% CI 1.08–1.24, I 2 = 96%) and cohort studies (pooled HR 1.26, 95% CI 1.04–1.54, I 2 = 100%) (Fig.…”

“…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).…”

“…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.…”