The erectile dysfunction agents sildenafil, vardenafil, and tadalafil showed a modest but significant association with increased risk of malignant melanoma in a large Swedish cohort study, but the pattern of the association suggests that the association is not causal, a report published online June 23 in JAMA shows.
These phosphodiesterase type 5 (PDE5) inhibitors target a part of the signaling pathway that has been implicated in the development of malignant melanoma, and the findings of a small cohort study (14 cases) suggested that the drugs might raise the risk of the malignancy. “It has been suggested that PDE5 inhibitors represent an important part of the medical history for dermatologists, and that melanoma screening could be performed by the physician when a sildenafil prescription is written for an older man with a history of sunburns,” said Dr. Stacy Loeb, of the department of urology and population health, and the Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, and her associates.
To examine this possible association, the investigators performed a case-control study using information from nationwide Swedish drug and cancer registries. They focused on 4,065 previously cancer-free men who developed malignant melanoma during the 6-year study period and 20,325 control subjects who did not develop melanoma.
Eleven percent of the men with melanoma had filled prescriptions for PDE5 inhibitors, compared with only 8% of the control subjects, for a crude odds ratio of 1.31. Further multivariable analysis showed a persistently increased risk of melanoma among users of ED drugs (OR, 1.21). This translates to 7 additional cases of melanoma for every 100,000 ED drug users in Sweden, Dr. Loeb and her associates said (JAMA 2015 June 23 [doi:10.1001/jama.2015.6604]).
However, no dose-response relationship was found when the data were analyzed according to the number of prescriptions filled or the different exposure levels of the three PDE5 inhibitors. Men who filled the highest number of prescriptions did not have a higher risk of melanoma, and neither did men who took vardenafil or tadalafil, which have a longer half-life and thus a greater exposure time than sildenafil. This “raises questions about whether this association is causal. Rather, [it] may reflect confounding by lifestyle factors associated with both PDE5 inhibitor use and melanoma,” the researchers said.
Men who used ED agents were younger, and had fewer comorbidities, higher education levels, and higher incomes than those who did not. Malignant melanoma is known to be associated with higher SES and lower comorbidity burden. So it is possible that the association found in this study reflects residual confounding from “differences in lifestyle factors (such as leisure travel with ensuing sunburns) and health care seeking behavior,” they added.
This study was supported by several entities, including the Swedish Research Council, the Swedish Cancer Foundation, and the Laura and Isaac Perlmutter Cancer Center at the NYU Langone Medical Center. Dr. Loeb reported receiving personal fees from Bayer and Sanofi-Aventis, and her associates reported ties to Pfizer, Ferring, and AstraZeneca.