Geographical Differences in Hydrochlorothiazide Associated Risk of Skin Cancer Balanced Against Disability Related to Hypertensive Heart Disease

Abstract BACKGROUND Hypertension affects 25%–30% of the world population. Hydrochlorothiazide (HCTZ) is among the most used and cheapest medications but was in 2018 labeled with a warning stating the increased risk of nonmelanoma skin cancer (NMSC). This study describes geographical differences in the association between HCTZ and NMSC from the perspective of hypertensive heart disease (HHD). METHODS We conducted a systematic literature search (PubMed, Embase, Clinicaltrial.gov, and Clinicaltrial.eu) using PICO/PECO acronyms, including case–control, cohort, and randomized controlled trials. We constructed a rate ratio of disability-adjusted life years (DALY) for HHD/NMSC in the global burden of disease (GBD) regions. RESULTS No increased risk of NMSC with the use of HCTZ was found in Taiwan, India, and Brazil. A small (hazard ratio (HR)/odds ratio (OR) ≤1.5) but significantly increased risk was seen in Canada, the United States, and Korea. An increased risk (1.5< HR/OR ≤2.5) in Iceland, Spain, and Japan and a highly increased risk (HR/OR >2.5) in the United Kingdom, Denmark, the Netherlands, and Australia. HHD is associated with a more than tenfold DALY rate compared with NMSC in 13 of 21 GBD regions, corresponding to 77.2% of the global population. In none of these 13 regions was there an increased risk of HCTZ-associated NMSC. CONCLUSIONS Despite limited information from many countries, our data point to large geographical differences in the association between HCTZ and NMSC. In all GBD regions, except Australasia, HHD constitutes a more than fivefold DALY rate compared to NMSC. This disproportionate risk should be considered before avoiding HCTZ from the antihypertensive treatment.