The Governing Board of the Croatian Society of Hypertension held an e-meeting on December 12, 2018, where the observed increase in risk of non-melanoma skin cancer associated with hydrochlorothiazide treatment was discussed, and the following statement was prepared.

On October 1, 2018, the European Medicines Agency (EMA) published a warning on the increased risk of non-melanoma skin cancer associated with higher cumulative hydrochlorothiazide doses (1). Their recommendation was to inform the patients of the risk and that patients receiving this treatment should undergo regular skin examinations. Other recommended preventive measures include avoiding exposure to sunlight, ultraviolet (UV) radiation, and the use of appropriate protection. Continued hydrochlorothiazide treatment should be reconsidered in patients who were previously treated for non-melanoma skin cancer.

The Agency for Medical Products and Medical Devices of Croatia (HALMED; Hrvatska agencija za lijekove i medicinske proizvode) has published a statement on November 22, 2018 in which they warn of the slightly increased risk of non-melanoma skin cancer due to exposure to high cumulative doses of hydrochlorothiazide, with the conclusion that the benefits of hydrochlorothiazide application outweigh the potential risks (2). HALMED’s recommendation is for patients to continue with the application of the prescribed treatment and that self-induced treatment termination can cause serious harm to patients. The advice is for patients to regularly check their skin for possible manifestations of any new lesions or changes in existing ones. It is also recommended that patients limit exposure to sunlight and UV radiation. HALMED provided a list of medications containing hydrochlorothiazide that are on the market in the Republic of Croatia (2), as shown in Table 1.

This warning is a result of the publication of the results obtained from data analysis performed on a Danish registry (3, 4). However, there had been earlier papers reporting the possible association between thiazide diuretics and risk of skin and lip carcinoma (5-7). What caused special attention in the Danish results was confirmation of the importance of cumulative doses, i.e. that the risk is greater for higher cumulative doses. A cause for concern and caution is also the fact that with a dose of 12.5 mg daily, which is the most commonly applied dose in our region, the cumulative dose after five years of treatment is equal to 22.812 mg, with an OR for risk of lip carcinoma of 3.9 (3.0-4.9) and the risk of skin cancer after ten years at OR 1.29 (1.23-1.35) for basal-cell carcinoma and OR 3.98 (3.68-4.31) for squamous cell carcinoma (3, 4). Similar data, but with a lower level of significance, were also obtained in the Kaiser Permanente Northern California US cohort (8).

Although these studies have certain strengths, they have limitations as well. The fact that increased risk of these carcinomas with cumulative doses of hydrochlorothiazide has been observed cannot and must not be ignored. However, we must also be aware of the fact that the benefits of the application of thiazide diuretics is several times greater than the risk of carcinoma, which is especially evident in elderly persons, patients with heart failure, and those with a shorter life expectancy (9).

It is also important to note that these carcinomas can be diagnosed early and in a timely manner if the patients are properly informed on how to monitor changes on the skin and lips.