Systemic Effects of Phosphodiesterase Type 5 Inhibitors Beyond Erectile Dysfunction: A Narrative Review

Abstract

Phosphodiesterase type 5 inhibitors (PDE5Is) are widely prescribed for erectile dysfunction; however, growing evidence indicates that their pharmacological effects extend beyond urological indications and involve multiple organ systems. This narrative review aims to synthesize and critically evaluate current evidence on the systemic effects of PDE5 inhibitors across cardiovascular, renal, neurological, and urological domains, as well as emerging therapeutic indications. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science for studies published up to May 2024, including preclinical studies, clinical trials, observational studies, systematic reviews, and meta-analyses. The reviewed evidence demonstrates that PDE5 inhibitors are associated with reduced cardiovascular morbidity and mortality, improvements in cardiac and pulmonary hemodynamics, preservation of renal function in diabetic populations, potential neuroprotective effects against cognitive decline and ischemic stroke, and symptomatic improvement in benign prostatic hyperplasia and lower urinary tract symptoms. Additional benefits have been reported in conditions characterized by vascular dysfunction, such as angina pectoris and Raynaud’s phenomenon. Overall, PDE5 inhibitors represent a pharmacologically versatile drug class with clinically relevant systemic effects beyond erectile dysfunction, supporting their potential role as adjunctive therapies in broader disease management, although further well-designed randomized controlled trials are needed to inform clinical guidelines.

Keywords
  • Phosphodiesterase Type 5 Inhibitors
  • Erectile Dysfunction
  • Cardiovascular Disease
  • Renal Function
  • Neuroprotection
Lisensing Information
Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

How to Cite
Daniszewski, W., Knobelsdorf, W., Furtak, G., Łagódka, M., Pogoda, M., Zając, K., … Karchut, W. (2025). Systemic Effects of Phosphodiesterase Type 5 Inhibitors Beyond Erectile Dysfunction: A Narrative Review. JITSS (Journal of Innovation and Trend in Social Sciences), 2(2), 87–100. https://doi.org/10.63203/jitss.v2i2.376
Endnote/Zotero/Mendeley (RIS) BibTeX
References
  1. Abouelmagd, M. E., Abdelmeseh, M., Elrosasy, A., Saad, Y. H., Alnajjar, A. Z., & Eid, M. (2024). Phosphodiesterase-5 inhibitors use and the risk of Alzheimer’s disease. Neurological Sciences, 45(11), 5261–5270. https://doi.org/10.1007/s10072-024-07583-9
  2. Adhikari, G., Baral, N., Rauniyar, R., Tse, G., Karki, S., & Abdelazeem, B. (2022). Meta-analysis examining phosphodiesterase-5 inhibitors in heart failure with preserved ejection fraction. Proceedings (Baylor University Medical Center), 35(5), 643–648. https://doi.org/10.1080/08998280.2022.2078633
  3. Al-Amin, M. M., Hasan, S. M., Alam, T., Hasan, A. T., Hossain, I., & Didar, R. R. (2014). Tadalafil enhances working memory and reduces hippocampal oxidative stress in both young and aged mice. European Journal of Pharmacology, 745, 84–90. https://doi.org/10.1016/j.ejphar.2014.10.026
  4. AlRuwaili, R., Al-Kuraishy, H. M., Alruwaili, M., Khalifa, A. K., Alexiou, A., & Papadakis, M. (2024). The potential therapeutic effect of phosphodiesterase 5 inhibitors in the acute ischemic stroke (AIS). Molecular and Cellular Biochemistry, 479(5), 1267–1278. https://doi.org/10.1007/s11010-023-04793-1
  5. Arancio, O., Zuccarello, E., Fiorito, J., & Acquarone, E. (2022). PDE5 inhibitors against synaptic and cognitive impairment in Alzheimer’s disease and related dementia. Alzheimer’s & Dementia, 18(2), 149–158. https://doi.org/10.1002/alz.062170
  6. Caglayan, E., Axmann, S., Hellmich, M., Moinzadeh, P., & Rosenkranz, S. (2012). Vardenafil for the treatment of raynaud phenomenon. Archives of Internal Medicine, 172(15), 1182–1184. https://doi.org/10.1001/archinternmed.2012.2271
  7. Chang, W. T., Su, C. C., Chang, Y. C., Cheng, C. L., & Hsu, C. H. (2022). The Impact of Sildenafil on Ischemic Outcomes in Patients with Pulmonary Hypertension. Acta Cardiologica Sinica, 38(5), 623–630. https://doi.org/10.6515/ACS.202209_38(5).20220401A
  8. Cheng, F., Fang, J., Zhang, P., Zhou, Y., Chiang, C. W., & Pieper, A. A. (2021). Sildenafil reduces the incidence of Alzheimer’s disease. Alzheimer’s & Dementia, 17(12), 1175–1178. https://doi.org/10.1002/alz.051847
  9. Delhaye, S., & Bardoni, B. (2021). Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders. Molecular Psychiatry, 26(9), 4570–4582. https://doi.org/10.1038/s41380-020-00997-9
  10. Haque, A., & Hughes, M. (2020). Raynaud’s phenomenon. Clinical Medicine, 20(6), 580–587. https://doi.org/10.7861/clinmed.2020-0754
  11. Hegazy, S. K., Amaar, W. A., & Hegab, W. S. M. (2024). Tadalafil versus pentoxifylline in the management of diabetic kidney disease. Diabetology & Metabolic Syndrome, 16(1), 138. https://doi.org/10.1186/s13098-024-01363-3
  12. Hinze, A., & Wigley, F. (2018). Pharmacotherapy options in the management of Raynaud’s phenomenon. Current Treatment Options in Rheumatology, 4(4), 367–382. https://doi.org/10.1007/s40674-018-0102-6
  13. Hwang, I. C., Kim, Y. J., Park, J. B., Yoon, Y. E., Lee, S. P., & Kim, H. K. (2017). Pulmonary hemodynamics and effects of phosphodiesterase type 5 inhibition in heart failure. BMC Cardiovascular Disorders, 17(1), 150. https://doi.org/10.1186/s12872-017-0576-4
  14. Khouri, C., Lepelley, M., Bailly, S., Blaise, S., Herrick, A. L., & Matucci-Cerinic, M. (2019). Comparative efficacy and safety of treatments for secondary Raynaud’s phenomenon. Seminars in Arthritis and Rheumatism, 51(3), 653–662. https://doi.org/10.1016/S2665-9913(19)30079-7
  15. Kloner, R. A., Stanek, E., Crowe, C. L., Singhal, M., Pepe, R. S., & Bradsher, J. (2023). Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality. Journal of Sexual Medicine, 20(1), 38–48. https://doi.org/10.1093/jsxmed/qdac005
  16. Kones, R. (2010). Recent advances in the management of chronic stable angina II. Vascular Health and Risk Management, 6, 749–774. https://doi.org/10.2147/VHRM.S11100
  17. Li, T., Zhang, Y., Zhou, Z., Guan, L., Wang, W., & Zhou, X. (2024). Phosphodiesterase type 5 inhibitor tadalafil reduces prostatic fibrosis via MiR-3126-3p/FGF9 axis in benign prostatic hyperplasia. Biology Direct, 19(1), 61. https://doi.org/10.1186/s13062-024-00504-y
  18. Maurice, D. H., Ke, H., Ahmad, F., Wang, Y., Chung, J., & Manganiello, V. C. (2014). Advances in targeting cyclic nucleotide phosphodiesterases. Nature Reviews Drug Discovery, 13(4), 290–314. https://doi.org/10.1038/nrd4228
  19. Nemr, M. T. M., Abdelaziz, M. A., Teleb, M., Elmasry, A. E., & Elshaier, Y. A. A. M. (2024). An overview on pharmaceutical applications of phosphodiesterase enzyme 5 (PDE5) inhibitors. Molecular Diversity. https://doi.org/10.1007/s11030-024-11016-2
  20. Omori, K., & Kotera, J. (2007). Overview of PDEs and their regulation. Circulation Research, 100(3), 309–327. https://doi.org/10.1161/01.RES.0000256354.95791.f1
  21. Paronetto, M. P., & Crescioli, C. (2024). Rethinking of phosphodiesterase 5 inhibition: the old, the new and the perspective in human health. Frontiers in Endocrinology, 15. https://doi.org/10.3389/fendo.2024.1461642
  22. Seidu, S., Cebrián, A., Kunutsor, S. K., & Khunti, K. (2022). Erectile dysfunction, phosphodiesterase-5 inhibitor use and risk of cardiovascular disease and mortality in people with diabetes. Primary Care Diabetes, 16(5), 601–613. https://doi.org/10.1016/j.pcd.2022.09.004
  23. Soulaidopoulos, S., Terentes-Printzios, D., Ioakeimidis, N., Tsioufis, K. P., & Vlachopoulos, C. (2024). Long-term effects of phosphodiesterase-5 inhibitors on cardiovascular outcomes and death. European Heart Journal Cardiovascular Pharmacotherapy, 10(5), 403–412. https://doi.org/10.1093/ehjcvp/pvae029
  24. Stamatiou, K., Perletti, G., Magri, V., & Trinchieri, A. (2024). The Role of 5-Phosphodiesterase Inhibitors (PDE-5I) in Current Benign Prostatic Hyperplasia Treatment. Medicina (Kaunas), 60(11). https://doi.org/10.3390/medicina60111736
  25. Swiecicka, A. (2023). The efficacy of PDE5 inhibitors in diabetic patients. Andrology, 11(2), 245–256. https://doi.org/10.1111/andr.13328
  26. Tian, Y., Yang, S., & Gao, S. (2020). Advances, Perspectives and Potential Engineering Strategies of Light-Gated Phosphodiesterases for Optogenetic Applications. International Journal of Molecular Sciences, 21(20). https://doi.org/10.3390/ijms21207544
  27. Vestergaard, N., Søgaard, P., Torp-Pedersen, C., & Aasbjerg, K. (2017). Relationship between treatment of erectile dysfunction and future risk of cardiovascular disease. European Journal of Preventive Cardiology, 24(14), 1498–1505. https://doi.org/10.1177/2047487317718082
  28. Xanthopoulos, A., Magouliotis, D. E., Tryposkiadis, K., Zotos, P. A., Spiliopoulos, K., & Athanasiou, T. (2022). Post-Implant Phosphodiesterase-5 Inhibitors in Patients with Left Ventricular Assist Device. Journal of Clinical Medicine, 11(20). https://doi.org/10.3390/jcm11205988
  29. Zahir, M., Samzadeh, M., Poopak, A., Khoshdel, A. R., & Armin, A. (2023). Sildenafil Vs. Tadalafil for The Treatment of Benign Prostatic Hyperplasia. Urology Journal, 20(4), 255–260. https://doi.org/10.22037/uj.v20i.7593
  30. Zhu, Z., Tang, W., Qiu, X., Xin, X., & Zhang, J. (2024). Advances in targeting Phosphodiesterase 1: From mechanisms to potential therapeutics. European Journal of Medicinal Chemistry, 263, 115967. https://doi.org/10.1016/j.ejmech.2023.115967

Issue

Downloads

PDF

Statistic

Abstract Views
: 47 times
PDF
: 86 times

Downloads

Download data is not yet available.