Erectile Dysfunction Drug Lacks Effect on AMD Prevention, Study Finds

New evidence identified no significant association between the use of sildenafil, a common treatment for men with erectile dysfunction (ED), and the prevention of age-related macular degeneration (AMD) development.¹

The pharmacoepidemiologic study, using real-world data in the United Kingdom, revealed the lack of association remained consistent when accounting for age and type 2 diabetes (T2D) status and the pre-2018 period when sildenafil was unavailable as an over-the-counter drug in the UK.

“The lack of a significant association between sildenafil use and AMD in our study suggests that sildenafil is unlikely to have a clinically meaningful preventive effect on AMD,” wrote the investigative team led by Nicola Jaime Adderley, PhD, MPH, Institute of Applied Research, University of Birmingham.

Owing to a global, rapidly aging population, AMD is anticipated to impact nearly 300 million people by 2040, with its treatment remaining a consistent, major area of unmet need in eye care.² Intravitreal treatments for the dry- and wet- form of AMD, while effective, carry high costs, the potential for adverse events, and a significant treatment burden for both patients and providers.

Originally developed as an antihypertensive drug, sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, later found success in treating ED, with approval for this indication in 1998.³ Its broad, favorable safety and therapeutic versatility is considered a successful example of drug repurposing.

Prior findings have linked choroidal ischemia with AMD development, with a recent study suggesting that PDE5 inhibitors may prevent AMD by increasing retinal blood flow.⁴ Given the significant global burden, reducing the risk of AMD development could be significant for public health concerns. In this analysis, Adderley and colleagues assessed the potential association between the use of sildenafil and AMD risk in men with ED in the UK.¹

The retrospective matched open-cohort study compared new users of sildenafil to non-users of the drug from January 2000 to September 2019. Data were collected from the IQVIA Medical Research Data (IMRD-UK) primary care database, accounting for approximately 6% of the UK population.

As research points to a trend of increasing ED prevalence with age, men aged ≥40 years with a clinically coded ED diagnosis were included for analysis. Those with a diagnosis of AMD on or before the index data were excluded from the study. To confirm those in the exposed group were consistently taking sildenafil, the analysis required a minimum of four records of prescription within 12 months, for ≥1 prescription per quarter.

To minimize potential confounding, investigators included demographic variables, including age at index, ethnicity, and Townsend deprivation quintile, lifestyle factors, including smoking status, and body mass index (BMI), and baseline comorbidities, including hypertension and T2D, in the analysis.

Overall, the study cohort collected data on 307,384 male patients aged ≥40 years with an ED diagnosis, of whom 31,575 patients were prescribed sildenafil. The exposure cohort was matched to 62,155 male patients without any history of sildenafil prescription. Individuals in the sildenafil cohort demonstrated a higher proportion of comorbidities, including hypertension and T2D, compared with non-users.

During a total follow-up of 393,426 person-years, 234 patients in the sildenafil group and 398 patients in the non-sildenafil user group developed AMD. After adjusting for confounders, including age, ethnicity, Townsend deprivation quintile, BMI, and comorbidities, investigators identified no significant differences in AMD incidence between the sildenafil users and the non-users (adjusted hazard ratio [aHR], 0.99; 95% CI, 0.84 to 1.16).

A subgroup analysis restricted to the period before the availability of over-the-counter sildenafil further (before January 2018) revealed a lack of association between sildenafil use and the risk of developing AMD (aHR, 0.98; 95% CI, 0.83 to 1.15; P = .776).

Adderley and colleagues noted a key limitation of the analysis was the classification of sildenafil relying on prescriptions issued by primary care practitioners in the UK, potentially leading to exposure misclassification in some men, particularly those who may have used the drug without a prescription.

“Overall, our findings contribute to the growing body of evidence on the potential effects of commonly prescribed medications on the development of AMD,” they wrote.

References

1. _{Han JED, Subramanian A, Lee WH, et al Association of sildenafil use with age-related macular degeneration: a retrospective cohort study BMJ Open Ophthalmology 2024;9:e001525. doi: 10.1136/bmjophth-2023-001525}
2. _{Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106-e116. doi:10.1016/S2214-109X(13)70145-1}
3. _{Smith BP. Sildenafil. StatPearls [Internet]. February 14, 2023. Accessed March 18, 2024. https://www.ncbi.nlm.nih.gov/books/NBK558978/.}
4. _{Yiu, G., Vuong, V.S., Tran, S. et al. Vascular Response to Sildenafil Citrate in Aging and Age-Related Macular Degeneration. Sci Rep 9, 5049 (2019). https://doi.org/10.1038/s41598-019-41509-2}