Commonly used photosensitizing antihypertensive drugs increase the risk for lip cancer by two- to fourfold, according to a study published online Aug. 6 in Archives of Internal Medicine.
"Lip cancer is rare, and an increased risk of its development is generally outweighed by the benefits of drugs that are effective for other conditions. However, physicians prescribing photosensitizing drugs should ascertain whether patients are at high risk of lip cancer because of their fair skin and long-term sun exposure, and discuss lip protection with them," wrote Dr. Gary D. Friedman of the division of research, Kaiser Permanente Medical Care Program, Oakland Calif., and his colleagues. "Likely preventive measures are simple: a hat with a sufficiently wide brim to shade the lips, and lip sunscreens," they added.
The diuretics hydrochlorothiazide and hydrochlorothiazide-triamterene, as well as the calcium channel blocker nifedipine, were associated with at least a doubling in the risk for lip cancer in a study involving 23,616 hypertensive non-Hispanic white adults. The association between lip cancer and the ACE inhibitor lisinopril, which also is photosensitizing, was characterized as "equivocal." And atenolol, a beta-adrenergic blocker that is not photosensitizing, was not linked to a higher risk.
Dr. Friedman and his colleagues used prescription data from the Kaiser Permanente pharmacy database and information from its cancer registry to perform a case-control study examining the relationship between the four classes of antihypertensive medications and lip cancer. They assessed the period from 1994 through 2008. The database includes an ethnically and socioeconomically diverse population of residents in the San Francisco and central valley regions of California.
There were few cases of lip cancer among nonwhite patients, so the analysis was restricted to white patients. Those with human immunodeficiency virus infection and those taking immunosuppressants after receiving organ transplants also were excluded because these factors were likely to be confounders.
The study population comprised 712 patients with lip cancer and 22,904 age-matched control patients. Nearly all malignancies were squamous cell. As expected, cigarette smokers in both study groups were more likely than nonsmokers to develop lip cancer.
The risk of developing lip cancer showed a dose-response relationship with the use of certain antihypertensive drugs, with the risk increasing as the duration of drug use increased. For patients treated with hydrochlorothiazide for 5 years or more, the odds ratio of developing lip cancer was 4.22. The OR for the combination drug hydrochlorothiazide-triamterene was 2.82, and the OR for nifedipine was 2.50. The OR was of borderline significance for lisinopril (1.42).
In contrast, for patients treated with atenolol for 5 years or more, the risk of developing lip cancer was reduced, with an odds ratio of 0.54, the investigators reported (Arch. Intern. Med. 2012 Aug. 6 [doi:10.1001/archinternmed.2012.2754]).
It should not be surprising that previous large clinical trials of these drugs’ efficacy failed to find an association with lip cancer, because of the rarity of the malignancy, they added.
For example, one study of antihypertensive medications involved more than 33,000 patients followed for a mean of 5 years. And after the investigators excluded the nonwhite patients, adjusted for the much lower incidence of lip cancer in women (who comprised half of the study population) than in men, and considered the low background incidence of the malignancy, they found that only seven lip cancers would have been expected to be detected in all the treatment groups combined, reported Dr. Friedman, also of the department of health research and policy, Stanford (Calif.) University, and his associates.
"Although the relatively high odds ratios, the evidence for specificity, and the biological mechanism are consistent with a causal relationship, causality cannot usually be established by a single observational study such as ours. Further investigations are needed to confirm and characterize relationships between photosensitizing antihypertensive agents and lip cancer," the researchers noted.
The study was limited because the researchers were unable to account for patients’ sun exposure, which is the most important factor contributing to lip cancer risk. "However, it does not seem likely that users of the antihypertensive drugs associated with lip cancer experience a great deal more sun exposure than nonusers or than users of atenolol," they wrote.
This study was supported by the National Cancer Institute. Dr. Friedman reported ties to Allergan, and his associates reported ties to Genentech, Merck, Sanofi-Aventis, and Takeda.