A study published online Aug. 6 in the journal Archives of Internal Medicine showed that commonly used photosensitizing antihypertensive drugs can increase the risk of lip cancer by 1 to 3 times. Hydrochlorothiazide, tranylcypromine and nifedipine were included, and lenopril was also suspected. In this study, which included 23,616 non-Hispanic white hypertensive patients, hydrochlorothiazide diuretics, hydrochlorothiazide-amfetidil and the calcium channel blocker nifedipine were associated with at least a 1-fold increase in the risk of developing lip cancer. Although angiotensin-converting enzyme inhibitor (ACEI) lenopril is also a photosensitizing antihypertensive agent, the association of this drug with lip cancer is “ambiguous. The beta-blocker atenolol, which is also a photosensitizing antihypertensive agent, was not associated with an increased risk of lip cancer. Lead investigator Gary D. Friedman, MD, of Kaiser Permanente, noted, “Lip cancer is a rare disease, and the benefits of antihypertensive drugs for hypertension clearly outweigh this potential risk. However, clinicians should ensure that patients are not at high risk for lip cancer (fair complexion, prolonged sun exposure) before prescribing photosensitizing antihypertensive medications, and should discuss lip protection with patients.” A few simple protective measures may be effective: wearing hats with wide edges that shield the lips from the sun, and applying sunscreen to the lips. Dr. Friedman and colleagues conducted this case-control study using information from the Kaiser Permanente pharmacy database and cancer registry for the period 1994 to 2008, with the aim of assessing the association between four classes of antihypertensive drugs and lip cancer. The aforementioned database covers residents of different races and social classes in the San Francisco and Central Valley of California. Because of the small number of lip cancer cases among non-whites, this analysis was performed on white patients only. In addition, HIV-infected patients and patients on immunosuppressive drugs after organ transplantation were excluded to reduce potential confounding factors. Subjects in this study included 712 patients with lip cancer and 22,904 age-matched controls. Almost all of the lip cancers were squamous cell carcinomas. As expected by the investigators, smokers were more likely to develop lip cancer in both groups of subjects. The association between specific types of antihypertensive drugs and the risk of lip cancer was dose-dependent, with the risk of lip cancer increasing as the duration of drug use increased. For patients treated with hydrochlorothiazide for 5 years, the OR for the risk of lip cancer was 4.22; for patients taking the hydrochlorothiazide-amlodipine combination, the OR was 2.82; for those taking nifedipine, the OR was 2.50; and for those taking lenopril, the OR was only marginally significant (1.42). In contrast, patients who took atenolol for ≥5 years had a reduced risk of lip cancer, with an OR of 0.54. As to why previous large clinical trials failed to find such an association, the investigators believe the main reason is that lip cancer is rare. For example, in a study of antihypertensive drugs that included more than 33,000 patients with an average follow-up of five years, only a total of seven cases of lip cancer could theoretically be found after excluding non-white patients, correcting for the much lower incidence of lip cancer in women, and taking into account their very low background incidence. “Despite the relatively high ratio, the specificity of the evidence, and the consistency of the biological mechanism with causality, causality cannot usually be established from one observational study alone. We need to further investigate the association of photosensitizing antihypertensive drugs with lip cancer.” A limitation of the study is that the researchers were unable to calculate the subjects’ exposure to sunlight, which is the most important risk factor for lip cancer. “However, there was no indication that sunlight exposure was greater in patients with lip cancer who were taking antihypertensive drugs.” The study was supported by the National Cancer Institute. dr. Friedman reported an association with Allergan, and his colleagues reported links with Genentech, Merck, Sanofi-Aventis, and Takeda, among others.