研究背景：
隨著高血壓的盛行率越來越高，降血壓藥物的使用率也隨之逐年上升；然而於先前之丹麥研究1指出，Hydrochlorothiazide (HCTZ)的暴露可能會增加非黑色素皮膚癌之風險；然而有鑑於皮膚癌風險具有種族差異，且先前台灣之研究2指出Hydrochlorothiazide之使用並不會增加非黑色素皮膚癌發生，但該研究缺乏非黑色素皮膚癌組織學之分組，因此可能造成統計結果低估；本研究透過連結健保資料庫與癌症登記資料庫來取得組織學資料並分析HCTZ暴露與皮膚癌之相關性。

研究目的：
探討使用HCTZ與皮膚癌風險之相關性分析，本研究並額外將皮膚癌分成不同組織學包含鱗狀上皮細胞癌(Squamous cell carcinoma, SCC)、基底細胞癌(Basal cell carcinoma, BCC)以及惡性黑色素癌(Malignant melanoma, MM)來進行分析。

研究方法：
本研究納入2004-2015年間年齡大於20歲且初次使用降血壓藥物之患者，患者被納入後會計算前兩年藥物之降血壓藥物持有率(Medication possession ratio, MPR)，並排除MPR小於80%之患者後，再分別根據降血壓藥物使用狀況分成下面四組 1) HCTZ、2)非HCTZ之thiazide類利尿劑、3) 非thiazide類利尿劑、4) 其他降血壓藥物，此外我們亦透過隨機抽樣之方式取得100萬人作為5) 控制組用來與治療組比較；各組納入後，再排除用藥前兩年發生排除條件之診斷以及使用免疫抑制劑大於6個月之患者；本研究的主要結果為非黑色素皮膚癌(BCC、SCC)在各組別之風險，另次要結果為各類別皮膚癌(SCC、BCC、MM)在不同組別之風險；患者自首次使用降血壓藥物兩年後開始追蹤，直到發生研究終點、死亡或是研究結束，且不同組別風險比會透過Cox-proportional hazard model進行分析。

研究結果：
本研究最後共納入828,375位患者於降血壓藥物組以及890,492位患者於控制組，於研究結果發現，HCTZ組相較於控制組具有較高之非黑色素皮膚癌風險(adjusted HR: 2.02; 95% CI, 1.48-2.75)，於次要結果也發現HCTZ組對比控制組有較高之SCC(adjusted HR: 2.26; 95% CI 1.43-2.58)以及BCC風險(adjusted HR: 1.81; 95% CI 1.19-2.75)，但相反的，在MM則無發現對比控制組有較高之風險(adjusted HR: 1.23, 95% 0.37-4.09)；另外，本研究也發現HCTZ組在與其他降血壓藥物組之比較並無較高之NMSC風險，不論於HCTZ組對比其他非HCTZ之thiazide類利尿劑(adjusted HR: 1.00, 95% CI 0.70-1.42)、非thiazide類利尿劑(adjusted HR: 1.08, 95% CI 0.69-1.70)或是其他降血壓藥物(adjusted HR:1.02, 95% CI 0.80-1.30)。

結論：
本研究發現在台灣族群使用HCTZ對比其他降血壓藥物而言並不會增加NMSC之發生，此外亦發現台灣人皮膚癌發生率較高加索人種低，因此在考量藥物之潛在效果或風險時，不同種族之差異應一併納入考慮。

Rationale and background:
Studies predominantly based on Caucasian populations have reported that the use of hydrochlorothiazide (HCTZ) was associated with increased risk of non-melanoma skin cancer (NMSC), especially in squamous cell carcinoma. The assessment on HCTZ and associated risk of NMSC in Asian population are scarce. A case-control study from Taiwan has suggested no association between the use of HCTZ and skin cancers; however, it lacked the detailed analyses based on subtypes of skin cancers by histology.

Research question and objectives:
To evaluate the association between HCTZ and risk of skin cancers by various histologic subtypes, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and malignant melanoma (MM).

Method:
A cohort of patients aged 20 years and older and newly receiving antihypertensive agents are identified from 2004 to 2015. Patients were classified into five groups: 1) hydrochlorothiazide (HCTZ), 2) thiazide diuretics other than HCTZ, 3) all diuretics other than thiazide group, 4) other antihypertensive agents other than diuretics, and 5) a control cohort comprising one million randomly sampled patients which are not be included in above cohort were selected for comparison. After patients enrolled, we excluded patients meet the exclusionary diagnosis and received immunosuppressants for above 6 months in the first 2 years of antihypertensive treatment. The primary endpoints were the non-melanoma skin cancer (NMSC) which includes basal cell carcinoma (BCC), squamous cell carcinoma (SCC). The secondary endpoints were the subtypes of skin cancers (SCC, BCC, and MM). We also performed intention-to-treat analysis and followed patients from 2 years after medication initiation until occurrence of study endpoints, death, or the end date of the database. Hazard ratios (HR) and 95% confidence intervals (CI) derived from Cox-proportional hazard models was used to compare the risks of study endpoints among the different groups.

Result:
We total identified 828,375 patients who received antihypertensive agents and 890,492 patients who are selected from NHID as our control cohort and we noted the risk of NMSC was higher in patients receiving HCTZ (adjusted HR: 2.02; 95% CI, 1.48-2.75) comparing with control cohort. The risks of SCC (adjusted HR: 2.26; 95% CI 1.43-2.58) and BCC (adjusted HR: 1.81; 95% CI 1.19-2.75) were also higher in patients receiving HCTZ comparing with control cohort. However, there is no difference on the risk of MM (adjusted HR: 1.23, 95% 0.37-4.09) between HCTZ group and control group. Specifically, we found there was no difference when comparing HCTZ group with other thiazide diuretics group (adjusted HR: 1.00, 95% CI 0.70-1.42), non-thiazide diuretics group (adjusted HR: 1.08, 95% CI 0.69-1.70), and other antihypertensive agents group (adjusted HR: 1.02, 95% CI 0.80-1.30) regarding the risk of NMSC.

Conclusion:
We found patients receiving HCTZ were not associated with an increased risk of NMSC comparing with those with other antihypertensive agents in Taiwan. The incidence rate of skin cancer was lower in the Taiwanese population comparing with Caucasians. The findings highlight the difference in drug effects among races and ethnicities.

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