Level 2 [mid-level] evidence

Thiazide-type diuretics reduce the risk for mortality, stroke, and cardiovascular disease among patients with hypertension.1 Given the reasonable adverse effect profile and high-quality evidence for efficacy, thiazide-type diuretics are one of the most commonly prescribed antihypertensive agents worldwide.

It has been postulated that thiazide-type diuretics can result in increased photosensitivity and may increase the risk for skin cancer through a series of complex chemical reactions and resulting generation of reactive oxygen species. As clinicians, it is our job to carefully analyze the available evidence and weigh the risks and benefits with our patients.

A recent meta-analysis of observational studies examined the association between thiazide-type diuretic use and the development of skin cancer.2 The authors identified 7 case-control and 2 cohort studies investigating this association. Three of the 9 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 3 of 9 included data about prior sun exposure and sunburns.

The analysis found an increased risk for squamous cell carcinoma of the skin among thiazide users compared with nonusers (adjusted odds ratio [aOR], 1.86; 95% CI, 1.23-2.80), a finding that is limited by significant heterogeneity among the studies. There was also a small increased risk for basal cell carcinoma (aOR, 1.19; 95% CI 1.02-1.38) and malignant melanoma (aOR, 1.14; 95% CI, 1.01-1.29). Subgroup analysis examining hydrochlorothiazide or hydrochlorothiazide combination medications found an increased risk for squamous cell carcinoma (aOR, 2.04; 95% CI, 1.79-2.33) but no association with basal cell carcinoma or malignant melanoma. Use of a thiazide diuretic for more than 4.5 years also appeared to increase the risk for squamous cell carcinoma, although this association was also heterogeneous among included studies.

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) as we assess the possibility that they may also increase the risk for nonfatal skin cancer.1 Although it might seem easy for clinicians to more heavily weigh the high-quality data suggesting improved overall survival against weaker data from observational studies, easing patients’ fears around the term “cancer” can be challenging.

Related Articles

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 diurectic therapy and encourage all patients to protect themselves from sun damage in the coming summer months.

References

1. Wright JM, Musini VM, Gill R. First-line drugs for hypertension. Cochrane Database Syst Rev. 2018;4:CD001841.

2. Shin D, Lee ES, Kim J, Guerra L, Naik D, Prida X. Association between the use of thiazide diuretics and the risk of skin cancers: a meta-analysis of observational studies. J Clin Med Res. 2019;11(4):247-255.