A new meta-analysis shows increased risk of some skin cancers with thiazide diuretics, but considering they also reduce mortality in people with hypertension, the latest EBM Focus discusses how this risk is not likely to change clinical practice. EBM Focus — provides concise summaries of clinical trials most likely to inform clinical practice and is curated by the DynaMed® editorial team.
Thiazide diuretics have the strongest evidence for mortality benefit and reduction of stroke and cardiovascular disease among patients with hypertension (Cochrane 2018). Given the reasonable side effect profile and high-quality evidence for efficacy, thiazide diuretics are one of the most commonly prescribed anti-hypertensive agents worldwide. It has been postulated that thiazide diuretics can result in increased photosensitivity and may increase the risk of skin cancer through a series of complex chemical reactions and resulting generation of reactive oxygen species.
A recent meta-analysis of observational studies published in the Journal of Clinical Medicine Research examined the association between thiazide diuretic use and the development of skin cancer. The authors identified seven case-control and two cohort studies investigating this association. Three of the nine studies included data from a single Danish registry; one of the studies overlapped in time with the other two. Most study samples included a high percentage of non-Hispanic white men, and just three of nine included data about prior sun exposure and sunburns. The study found an increased risk of squamous cell carcinoma (SCC) of the skin among thiazide users compared to non-users (adjusted odds ratio 1.86 [aOR], 95% CI 1.23-2.8), a finding that is limited by significant heterogeneity among the studies and the lack of control for some covariates such as cigarette smoking. There was a small increased risk of basal cell carcinoma (BCC) (aOR 1.19, 95% CI 1.02-1.38) and malignant melanoma (MM) (aOR 1.14, 95% CI 1.01-1.29). Subgroup analysis examining hydrochlorothiazide (HCTZ) or HCTZ combination medications found an increased risk of SCC (aOR 2.04, 95% CI 1.79-2.33) but no association with BCC or MM. Thiazide use for more than four and a half years also appeared to increase the risk of SCC, although this association was also heterogeneous among included studies.
Although this study is unlikely to change our choice of antihypertensive medications, clinicians can use questions about this association as an opportunity to highlight the long-term benefit of thiazide therapy and encourage all patients to protect themselves from sun damage.
Patients are often the first to bring up studies that make the news cycle, as friends, advertisements, and internet searches can alert them to potential medication risks. As clinicians, it is our job to carefully analyze the available evidence, weighing the risks and benefits with our patients in the exam room. It is important to keep in mind the demonstrated mortality benefit of thiazide diuretics for treatment of hypertension (risk ratio 0.89, 95% CI 0.82-0.97, NNT 51-303, Cochrane 2018) as we assess the possibility that they may also increase the risk of non-fatal skin cancer. While it might seem easy for clinicians to more heavily weight the high-quality data suggesting improved overall survival against weaker data from observational studies, easing patients’ fears around the term ‘cancer’ can be challenging. Although this study is unlikely to change our choice of antihypertensive medications, clinicians can use questions about this association as an opportunity to highlight the long-term benefit of thiazide therapy and encourage all patients to protect themselves from sun damage.
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