{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T19:58:50Z","timestamp":1790366330903,"version":"4.1.0"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eye"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background\/objectives<\/jats:title>\n                    <jats:p>To evaluate the association between phosphodiesterase type 5 inhibitor (PDE5I) use and incident diabetic retinopathy (DR) among men with erectile dysfunction (ED) and type 2 diabetes (T2D).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Subjects\/methods<\/jats:title>\n                    <jats:p>Male patients aged \u226550 years with ED and T2D were identified from the TriNetX global electronic health record network. Patients receiving PDE5I were compared with non-users. After 1:1 propensity score matching for demographic, systemic, laboratory and treatment-related variables, 1823 patients were included in each cohort. Follow-up extended for up to seven years. Outcomes were identified using ICD-10 and procedural codes and analysed using Kaplan-Meier survival analysis and Cox proportional hazards models. Ophthalmologic follow-up was evaluated as a negative-control outcome to assess surveillance bias.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      During follow-up, PDE5I use was associated with a lower incidence of DR overall (hazard ratio [HR] 0.83, 95% confidence interval [CI] [0.71, 0.96];\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0139; adjusted\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.0626) and proliferative diabetic retinopathy (PDR; HR 0.35, 95% CI [0.21, 0.59];\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001; adjusted\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0009). After correction for multiple comparisons, only the association with PDR remained statistically significant (adjusted\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0009). No significant differences were observed for diabetic macular oedema, intravitreal injections, or laser photocoagulation. Rates of ophthalmologic follow-up were comparable between groups (HR 0.93, 95% CI [0.84, 1.02];\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.1072).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In men aged \u226550 years with ED and T2D, PDE5I use was associated with a lower observed incidence of PDR, while a nominal association with overall DR was also observed. These findings identify an association between PDE5I use and DR outcomes that warrants further evaluation in prospective studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s41433-026-04893-4","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T06:41:46Z","timestamp":1790318506000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phosphodiesterase 5 inhibitor use and incident diabetic retinopathy in men with erectile dysfunction and type 2 diabetes: a propensity-matched cohort study"],"prefix":"10.1038","author":[{"given":"Natan","family":"Lishinsky-Fischer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elad","family":"Eilon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sima","family":"Gharra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0043-4354","authenticated-orcid":false,"given":"Jaime","family":"Levy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"4893_CR1","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/S0140-6736(09)62124-3","volume":"376","author":"N Cheung","year":"2010","unstructured":"Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010;376:124\u201336.","journal-title":"Lancet"},{"key":"4893_CR2","doi-asserted-by":"publisher","first-page":"1580","DOI":"10.1016\/j.ophtha.2021.04.027","volume":"128","author":"ZL Teo","year":"2021","unstructured":"Teo ZL, Tham YC, Yu M, Chee ML, Rim TH, Cheung N, et al. Global prevalence of diabetic retinopathy and projection of burden through 2045: systematic review and meta-analysis. Ophthalmology. 2021;128:1580\u201391.","journal-title":"Ophthalmology"},{"key":"4893_CR3","doi-asserted-by":"publisher","first-page":"1816","DOI":"10.3390\/ijms19061816","volume":"19","author":"W Wang","year":"2018","unstructured":"Wang W, Lo ACY. Diabetic retinopathy: pathophysiology and treatments. Int J Mol Sci. 2018;19:1816.","journal-title":"Int J Mol Sci"},{"key":"4893_CR4","doi-asserted-by":"crossref","unstructured":"Gericke A, Buonfiglio F. Physiological and pathophysiological relevance of nitric oxide synthases (NOS) in retinal blood vessels. Front Biosci. 2024;29:190.","DOI":"10.31083\/j.fbl2905190"},{"key":"4893_CR5","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1146\/annurev-pharmtox-040122-034745","volume":"63","author":"A Samidurai","year":"2023","unstructured":"Samidurai A, Xi L, Das A, Kukreja RC. Beyond erectile dysfunction: cGMP-specific phosphodiesterase 5 inhibitors for other clinical disorders. Annu Rev Pharm Toxicol. 2023;63:585\u2013615.","journal-title":"Annu Rev Pharm Toxicol"},{"key":"4893_CR6","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1038\/sj.eye.6702908","volume":"22","author":"C Foresta","year":"2008","unstructured":"Foresta C, Caretta N, Zuccarello D, Poletti A, Biagioli A, Caretti L, et al. Expression of the PDE5 enzyme on human retinal tissue: New aspects of PDE5 inhibitors' ocular side effects. Eye. 2008;22:144\u20139.","journal-title":"Eye"},{"key":"4893_CR7","doi-asserted-by":"publisher","DOI":"10.1186\/s40942-020-00241-0","volume":"6","author":"NFS Da Cruz","year":"2020","unstructured":"Da Cruz NFS, Polizelli MU, Cezar LM, Cardoso EB, Penha F, Farah ME, et al. Effects of phosphodiesterase type 5 inhibitors on choroid and ocular vasculature: a literature review. Int J Retin Vitreous. 2020;6:38.","journal-title":"Int J Retin Vitreous"},{"key":"4893_CR8","doi-asserted-by":"publisher","first-page":"176","DOI":"10.2164\/jandrol.111.013367","volume":"33","author":"L Deyoung","year":"2012","unstructured":"Deyoung L, Chung E, Kovac JR, Romano W, Brock GB. Daily use of sildenafil improves endothelial function in men with type 2 diabetes. J Androl. 2012;33:176\u201380.","journal-title":"J Androl"},{"key":"4893_CR9","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1007\/s11010-023-04793-1","volume":"479","author":"R AlRuwaili","year":"2024","unstructured":"AlRuwaili R, Al-Kuraishy HM, Alruwaili M, Khalifa AK, Alexiou A, Papadakis M, et al. The potential therapeutic effect of phosphodiesterase 5 inhibitors in acute ischemic stroke (AIS). Mol Cell Biochem. 2024;479:1267\u201378.","journal-title":"Mol Cell Biochem"},{"key":"4893_CR10","doi-asserted-by":"publisher","first-page":"8075","DOI":"10.1523\/JNEUROSCI.0864-09.2009","volume":"29","author":"D Puzzo","year":"2009","unstructured":"Puzzo D, Staniszewski A, Deng SX, Privitera L, Leznik E, Liu S, et al. Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-\u03b2 load in an Alzheimer\u2019s disease mouse model. J Neurosci. 2009;29:8075\u201386.","journal-title":"J Neurosci"},{"key":"4893_CR11","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1001\/jamaophthalmol.2022.0663","volume":"140","author":"M Etminan","year":"2022","unstructured":"Etminan M, Sodhi M, Mikelberg FS, Maberley D. Risk of ocular adverse events associated with use of phosphodiesterase 5 inhibitors in men in the US. JAMA Ophthalmol. 2022;140:480\u20134.","journal-title":"JAMA Ophthalmol"},{"key":"4893_CR12","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1111\/andr.13328","volume":"11","author":"A \u015awiecicka","year":"2023","unstructured":"\u015awiecicka A. The efficacy of PDE5 inhibitors in diabetic patients. Andrology. 2023;11:245\u201356.","journal-title":"Andrology"},{"key":"4893_CR13","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1111\/dme.13403","volume":"34","author":"Y Kouidrat","year":"2017","unstructured":"Kouidrat Y, Pizzol D, Cosco T, Thompson T, Carnaghi M, Bertoldo A, et al. High prevalence of erectile dysfunction in diabetes: a systematic review and meta-analysis of 145 studies. Diabet Med. 2017;34:1185\u201392.","journal-title":"Diabet Med"},{"key":"4893_CR14","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/bs.vh.2021.11.006","volume":"118","author":"L Taoro-Gonz\u00e1lez","year":"2022","unstructured":"Taoro-Gonz\u00e1lez L, Cabrera-Pastor A, Sancho-Alonso M, Felipo V. Intracellular and extracellular cyclic GMP in the brain and the hippocampus. Vitam Horm. 2022;118:247\u201388.","journal-title":"Vitam Horm"},{"key":"4893_CR15","doi-asserted-by":"publisher","first-page":"2011","DOI":"10.1161\/ATVBAHA.115.306133","volume":"35","author":"C Krawutschke","year":"2015","unstructured":"Krawutschke C, Koesling D, Russwurm M. Cyclic GMP in vascular relaxation: export is of similar importance as degradation. Arterioscler Thromb Vasc Biol. 2015;35:2011\u20139.","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"4893_CR16","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/j.amjmed.2012.08.015","volume":"126","author":"BG Schwartz","year":"2013","unstructured":"Schwartz BG, Jackson G, Stecher VJ, Campoli-Richards DM, Kloner RA. Phosphodiesterase type 5 inhibitors improve endothelial function and may benefit cardiovascular conditions. Am J Med. 2013;126:192\u20139.","journal-title":"Am J Med"},{"key":"4893_CR17","doi-asserted-by":"publisher","first-page":"3633","DOI":"10.2174\/1381612826666200403172736","volume":"26","author":"J Blanco-Rivero","year":"2020","unstructured":"Blanco-Rivero J, Xavier FE. Therapeutic potential of phosphodiesterase inhibitors for endothelial dysfunction- related diseases. Curr Pharm Des. 2020;26:3633\u201351.","journal-title":"Curr Pharm Des"},{"key":"4893_CR18","doi-asserted-by":"publisher","first-page":"R103","DOI":"10.1530\/EJE-14-0700","volume":"172","author":"D Santi","year":"2015","unstructured":"Santi D, Giannetta E, Isidori AM, Vitale C, Aversa A, Simoni M. Therapy of endocrine disease. Effects of chronic use of phosphodiesterase inhibitors on endothelial markers in type 2 diabetes mellitus: a meta-analysis. Eur J Endocrinol. 2015;172:R103\u201314.","journal-title":"Eur J Endocrinol"},{"key":"4893_CR19","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/S0014-2999(99)00242-3","volume":"374","author":"MC Koss","year":"1999","unstructured":"Koss MC. Functional role of nitric oxide in the regulation of ocular blood flow. Eur J Pharmacol. 1999;374:161\u201374.","journal-title":"Eur J Pharmacol"},{"key":"4893_CR20","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1167\/iovs.07-1208","volume":"49","author":"Z Yuan","year":"2008","unstructured":"Yuan Z, Hein TW, Rosa RH, Kuo L. Sildenafil (viagra) evokes retinal arteriolar dilation: dual pathways via NOS activation and phosphodiesterase inhibition. Investig Ophthalmol Vis Sci. 2008;49:720\u20135.","journal-title":"Investig Ophthalmol Vis Sci"},{"key":"4893_CR21","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1038\/s41433-020-01377-x","volume":"35","author":"AM Joussen","year":"2021","unstructured":"Joussen AM, Ricci F, Paris LP, Korn C, Quezada-Ruiz C, Zarbin M. Angiopoietin\/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data. Eye. 2021;35:1305\u201316.","journal-title":"Eye"},{"key":"4893_CR22","volume":"2019","author":"M Whitehead","year":"2019","unstructured":"Whitehead M, Osborne A, Widdowson PS, Yu-Wai-Man P, Martin KR. Angiopoietins in diabetic retinopathy: current understanding and therapeutic potential. J Diab Res. 2019;2019:5140521.","journal-title":"J Diab Res"},{"key":"4893_CR23","doi-asserted-by":"publisher","first-page":"e0126580","DOI":"10.1371\/journal.pone.0126580","volume":"10","author":"MA Venneri","year":"2015","unstructured":"Venneri MA, Giannetta E, Panio G, De Gaetano R, Gianfrilli D, Pofi R, et al. Chronic inhibition of PDE5 limits pro-inflammatory monocyte-macrophage polarization in streptozotocin-induced diabetic mice. PLoS One. 2015;10:e0126580.","journal-title":"PLoS One"},{"key":"4893_CR24","doi-asserted-by":"publisher","first-page":"2623","DOI":"10.1210\/jc.2018-02525","volume":"104","author":"MA Venneri","year":"2019","unstructured":"Venneri MA, Barbagallo F, Fiore D, De Gaetano R, Giannetta E, Sbardella E, et al. PDE5 inhibition stimulates Tie2-expressing monocytes and angiopoietin-1, restoring angiogenic homeostasis in diabetes. J Clin Endocrinol Metab. 2019;104:2623\u201336.","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Eye"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41433-026-04893-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41433-026-04893-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41433-026-04893-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T19:02:34Z","timestamp":1790362954000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41433-026-04893-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":24,"alternative-id":["4893"],"URL":"https:\/\/doi.org\/10.1038\/s41433-026-04893-4","relation":{},"ISSN":["0950-222X","1476-5454"],"issn-type":[{"value":"0950-222X","type":"print"},{"value":"1476-5454","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]},"assertion":[{"value":"2 June 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 August 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 September 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 September 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}