Phosphodiesterase 5 Inhibitor Use and Risk of Conventional and Serrated Precursors of Colorectal Cancer

Phosphodiesterase 5 inhibitors (PDE5) have been hypothesized to have anticancer activity and have potential in the prevention of colorectal cancer. PDE5 inhibitors inhibited tumorigenesis in mice with reduction of the number of polyps up to 50% (1). Currently, population-based evidence remains lacking. Only three studies were conducted and found conflicting results (2–4), and no study has yet evaluated the association between PDE5 inhibitors and precursors of colorectal cancer.

We prospectively evaluated the association between PDE5 inhibitors and risk of conventional adenoma and serrated lesion, among 18,123 men in the Health Professionals Follow-up Study (HPFS), who had no diagnosis of polyps or cancer before 2000, had exposure information and have undergone at least one lower gastrointestinal endoscopy during the follow up period between 2000 and 2010. The HPFS is an ongoing prospective cohort of men initiated in 1986 among 51,529 health professionals of age 40–75 years in the United States at baseline. Briefly, participants provided detailed information on demographics and lifestyle every 2 years and diet every 4 years. Endoscopic examinations and diagnosis of colorectal cancer and polyp in the past 2 years were acquired on each biennial questionnaire and validated by medical records. If a participant had more than one endoscopy during the study period, multiple records from the same participant were included in the analysis.

The primary exposure was sildenafil use for erectile dysfunction. In 2000, participants were queried as to whether they had undergone surgery or treatment to correct problems with erections during the past 3 months, including sildenafil, shots or penile injection, vacuum suction, alprostadil, and other treatments, and whether they had ever received any treatment of erectile dysfunction before, including sildenafil. However, no information on the dose or frequency of sildenafil was collected. In the same questionnaire, participants were asked to rate their ability during the past 3 months to have and maintain an erection adequate for intercourse without treatment (very poor, poor, fair, good, or very good). Men with poor or very poor ability were considered to have erectile dysfunction at baseline (5).

We evaluated recent sildenafil use at baseline (in the past 3 months, which was reported in 2000) as the main exposure. As sildenafil was mainly prescribed to treat erectile dysfunction, we stratify the population into three groups by erectile dysfunction status (no erectile dysfunction, erectile dysfunction with PDE5 inhibitors, erectile dysfunction without PDE5 inhibitors) to account for potential “confounding by indication.” To account for possible multiple records per participant and handle time-varying covariates, we used an Andersen-Gill data structure with a new record for each 2-year follow-up period during which a participant underwent an endoscopy (6). Men were censored at the diagnosis of any colorectal polyp or colorectal cancer, at the time of death, or end of the follow-up (January 1, 2010), whichever occurred first. Multivariable-adjusted logistic regressions were used for cluster data with generalized estimating equations (GEE) to account for repeated observations and to calculate ORs and 95% confidence interval (CI; ref. 6). We also examined the associations by polyp type (conventional adenomas only, serrated lesions only, or any polyps) and for advanced conventional adenomas (≥10 mm, high-grade dysplasia, or tubulovillous or villous histology).

The study protocol was approved by the institutional review boards of the Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health (Boston, MA), and those of participating registries as required.

Among 41,295 person-endoscopies, we documented 1,395 cases of serrated polyps and 2,595 cases of conventional adenomas. Among the three groups, participants who had erectile dysfunction and reported no PDE5 inhibitor use were older and more likely to have diabetes mellitus, smoke, and use aspirin regularly. Participants who had erectile dysfunction and reported using PDE5 inhibitors were more likely to drink alcohol and consume more folate, calcium, and vitamin D (Table 1).

Overall, no apparent association was observed between recent sildenafil use at baseline and polyps after adjusting for repeated observations and multiple lifestyle risk factors. Using people without erectile dysfunction as reference group, recent PDE5 inhibitor use at baseline was not associated with lower risk of serrated lesions, conventional adenoma, any polyps or advanced conventional adenomas (Table 2). We also evaluated sildenafil use ever before (all recent and prior users) as exposure and no apparent association was found (Supplementary Table S1).

PDE5 inhibitors have been proposed as a potential drug for chemoprevention of colorectal cancer. Animal models and gene expression studies suggested its potential role in anticancer activity and prolonged survival. However, population-based studies are limited. Only one study, based on Swedish Hospital Discharge Register, found a significant inverse association between PDE5 inhibitor use and risk of colorectal cancer (adjusted HR, 0.65; 95% CI, 0.49–0.85; ref. 2) among men with benign neoplasms. In the same database, the authors further found that postdiagnostic use of PDE5 inhibitors was associated with decreased risk of colorectal cancer–specific mortality and metastasis (4). Both of the studies, however, had several key limitations. First, data on several key lifestyle risk factors for colorectal cancer, such as smoking and dietary factors, were not available. Second, the low polypectomy rate recorded in the registers raised concerns about other potential uncontrolled confounding

In contrast, we found no evidence of an association between PDE5 inhibitor use and precursors of colorectal cancer after adjusting for main lifestyle risk factors and stratified by erectile dysfunction status. Similarly, a recent case–control study nested in the Health Improvement Network primary care database in the United Kingdom also reported no association between use of PDE5 inhibitors and colorectal cancer among men with erectile dysfunction (3).

The strengths of our study include prospective design with large sample size, long-term follow-up, comprehensive profiling of colorectal cancer risk factors, detailed and repeated data collection, as well as confirmation of polyp diagnosis with detailed recording of histopathologic information based on pathology reports. Because the men are highly educated health professionals, the validity of the self-reported information is high. However, we do not have information on the dose or frequency of sildenafil and only included one type of PDE5 inhibitor. Future population studies with detailed measure of PDE5 inhibitors, comprehensive colorectal cancer risk factors as well as accurate updated outcome diagnosis are warranted to further address the potential preventive role of PDE5 inhibitors in colorectal cancer.

No disclosures were reported.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Y. Zhang: Conceptualization, resources, data curation, software, formal analysis, investigation, methodology, writing–original draft, project administration, writing–review and editing. C.-H. Lo: Data curation, formal analysis. E.L. Giovannucci: Conceptualization, supervision, funding acquisition, validation, methodology, project administration, writing–review and editing.

The authors thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. The Health Professionals Follow-up Study was supported by grant number U01 CA167552.

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