Use of Thiazide Diuretics and Risk of All Types of Skin Cancers: An Updated Systematic Review and Meta-Analysis

SIMPLE SUMMARY: By examining evidence from 30 non-randomized studies, we found that thiazide diuretic users have a higher risk of skin cancer than non-thiazide diuretic users. A small but consistent risk was identified across all types of skin cancers, including the more dangerous malignant melanoma (all subtypes, superficial spreading melanoma, nodular melanoma, and lentigo maligna melanoma) and non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma). The high cancer risk associated with thiazides, especially the risk of malignant melanoma, is concerning. Individual skin cancer risk assessment, monitoring, and consideration of suitable drug alternatives are needed before the long-term use of these agents. Our findings suggest that to promote the rational use of anti-hypertensive medication, the benefits of thiazide diuretics must be weighed against potential safety concerns in terms of skin cancer risks. ABSTRACT: Background: The use of thiazide diuretics is associated with skin cancer risk; however, whether this applies to all skin cancer types is unclear. Methods: In this meta-analysis, we searched multiple electronic databases and gray literature up to 10 April 2022, with no language restrictions, to identify relevant randomized controlled trials (RCTs) and non-randomized studies (cohort, case-control) that investigated the association between thiazide diuretics and skin cancer. The primary outcomes of interest were malignant melanoma and non-melanoma skin cancer (basal cell carcinoma [BCC], squamous cell carcinoma [SCC]). Secondary outcomes included other skin cancers (lip cancer, Merkel cell carcinoma, malignant adnexal skin tumors, oral cavity cancer, and precursors of skin cancer). We used a random-effects meta-analysis to estimate pooled adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results: Thirty non-randomized studies (17 case-control, 13 cohort, no RCTs) were included. Thiazide diuretic users had a higher risk of malignant melanoma (17 studies; n = 10,129,196; pooled adjusted OR, 1.10; 95% CI, 1.04–1.15; p < 0.001; strength of evidence, very low; very small harmful effect), BCC (14 studies; n = 19,780,476; pooled adjusted OR, 1.05; 95% CI, 1.02–1.09; p = 0.003; strength of evidence, very low; very small harmful effect), and SCC (16 studies; n = 16,387,862; pooled adjusted OR, 1.35; 95% CI, 1.22–1.48; p < 0.001; strength of evidence, very low; very small harmful effect) than non-users. Thiazide diuretic use was also associated with a higher risk of lip cancer (5 studies; n = 161,491; pooled adjusted OR, 1.92; 95% CI, 1.52–2.42; p < 0.001; strength of evidence, very low; small harmful effect), whereas other secondary outcomes were inconclusive. Conclusions: Thiazide diuretics are associated with the risk of all skin cancer types, including malignant melanoma; thus, they should be used with caution in clinical practice.