Tadalafil use tied to modest rise in glaucoma risk among men treated for urinary symptoms

Men who took tadalafil for lower urinary tract symptoms (LUTS) had a 22% higher risk of developing glaucoma than matched peers who did not use a phosphodiesterase type 5 inhibitor (PDE5i), according to a multinational retrospective cohort study published in the British Journal of Ophthalmology.¹ The increase was seen largely in primary open-angle glaucoma (POAG) and ocular hypertension, and the authors say the findings support closer ophthalmic monitoring in men on long-term tadalafil therapy who carry other glaucoma risk factors.

Study design

Tadalafil is a long-acting PDE5 inhibitor that was FDA-approved for erectile dysfunction in 2003 and 2011 for the treatment of signs and symptoms of benign prostatic hyperplasia (BPH), both alone and in men who also have erectile dysfunction.³ Its mechanism—inhibiting the breakdown of cyclic guanosine monophosphate (cGMP) to relax smooth muscle—improves urinary flow in men with BPH-related LUTS, a use now supported by more than a decade of clinical data.²

To examine whether that same mechanism might carry ocular consequences, investigators led by Yun Hsia and colleagues used the TriNetX federated health research network to identify men aged 40 years and older with a history of LUTS between 2012 and 2022.¹ Men with a prior diagnosis of glaucoma were excluded. Tadalafil users were then propensity-score matched 1:1 with men who had LUTS but did not use any PDE5i, balancing the 2 groups on age, race, comorbidities, renal function, and concomitant medications. The final matched cohort included 36,927 tadalafil users and 36,927 non-users, followed for up to 5 years.

Key findings

Over the follow-up period, tadalafil use was associated with a significantly higher risk of any glaucoma diagnosis (hazard ratio [HR], 1.22; 95% CI, 1.12-1.33). Five-year cumulative incidence was 3.93% in tadalafil users versus 3.16% in non-users (P <.001).¹

When the authors broke the outcome down by subtype, the association was concentrated in two categories:

• POAG: HR, 1.33 (95% CI, 1.05-1.67)
• Ocular hypertension: HR, 1.32 (95% CI, 1.06-1.65)

No significant association emerged for normal-tension glaucoma or primary angle-closure glaucoma. Tadalafil users were also more likely to be started on glaucoma therapy during follow-up (HR, 1.33; 95% CI, 1.20-1.47), a proxy the authors used to capture clinically actionable disease rather than coding alone.

The elevated risk held up across several sensitivity analyses, including lag times of 1, 3, and 6 months built in to reduce the chance that early diagnoses reflected pre-existing, undetected disease rather than a true drug effect. The association was also consistent across subgroups, including men older than 50 years, White patients, and patients with varying comorbidity burdens.

Biological plausibility

The finding is not without mechanistic grounding. PDE5 inhibitors act on the nitric oxide (NO)-cGMP signaling pathway, which is increasingly recognized as a regulator of intraocular pressure (IOP): NO stimulates guanylate cyclase to generate cGMP, which relaxes trabecular meshwork cells and widens the intercellular spaces that govern conventional aqueous outflow through the trabecular meshwork and Schlemm canal.⁵ That same pathway is the target of newer NO-donating and guanylate cyclase-directed glaucoma therapeutics, underscoring how sensitive outflow physiology is to changes in cGMP signaling.⁵ Whether chronic, sustained PDE5 inhibition could paradoxically disrupt this balance, alter ocular blood flow, or interact with other risk factors to raise IOP over time is not established by this study, and the authors did not report IOP data directly.

The PDE5i class already carries a distinct ophthalmic safety signal that clinicians should keep separate from these new glaucoma findings: nonarteritic anterior ischemic optic neuropathy (NAION), a sudden, typically painless optic nerve event unrelated to IOP, is a recognized if uncommon adverse effect associated with PDE5 inhibitor use, most often reported with short-term, on-demand dosing for erectile dysfunction.⁴ A systematic review and meta-analysis, along with case-series data summarized by the American Academy of Ophthalmology, have reinforced that signal, particularly in patients with vasculopathic risk factors such as diabetes, and some authors have advised discontinuing the drug after a first NAION event in one eye to protect the fellow eye.⁶,⁷ The new glaucoma findings are mechanistically and clinically distinct from NAION but add to a broader picture of PDE5 inhibitors as a drug class with measurable, if modest, effects on ocular physiology.

Clinical implications

For ophthalmologists, the practical takeaway is awareness rather than alarm. An HR of roughly 1.2 to 1.3 translates into a 5-year absolute risk difference of well under 1 percentage point, and the study's retrospective, claims-based design cannot rule out residual confounding—men prescribed tadalafil for LUTS may differ from non-users in ways not fully captured by the matched variables, including how frequently they see any physician and therefore how likely they are to have incidental glaucoma findings recorded. The authors themselves frame the results as supporting consideration of ophthalmic monitoring rather than a change to prescribing practice.¹

For clinicians managing men on chronic tadalafil for LUTS, particularly those older than 50 years or with other POAG risk factors (family history, elevated baseline IOP, thinner central corneas, or high myopia), the findings are a reasonable prompt to confirm patients are keeping up with routine comprehensive eye examinations, in keeping with existing age- and risk-based screening intervals recommended by the American Academy of Ophthalmology.⁸ Urologists and primary care clinicians prescribing tadalafil for LUTS may also want to ask patients about their eye care history and glaucoma risk factors before or during treatment, and to loop in an ophthalmologist when those risk factors are present.

Limitations

The authors note several limitations inherent to the TriNetX design: reliance on diagnostic and prescription codes rather than validated IOP or optic nerve imaging data, potential misclassification of glaucoma subtype, lack of information on tadalafil dose or adherence, and the possibility that more frequent healthcare contact among tadalafil users increased detection of incidental glaucoma. Because the cohort was restricted to men prescribed tadalafil specifically for LUTS, the results may not generalize to men using PDE5 inhibitors on demand for erectile dysfunction at lower cumulative exposure.

References

1. Hsia Y, Tsai CY, Hung SC, et al. Risk of glaucoma among patients using tadalafil for lower urinary tract symptoms: a multinational cohort study. Br J Ophthalmol. Published online August 4, 2026. doi:10.1136/bjo-2026-329957

2. Yokoyama O, Igawa Y, Takeda M, Yamaguchi T, Murakami M, Viktrup L. Tadalafil for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a review of clinical data in Asian men and an update on the mechanism of action. Ther Adv Urol. 2015. doi:10.1177/1756287215589238

3. Cialis for once daily use now FDA-approved to treat men with signs and symptoms of benign prostatic hyperplasia (BPH) and men with both erectile dysfunction (ED) and signs and symptoms of BPH. News release. Eli Lilly and Company; 2011. Accessed August 24, 2026. https://investor.lilly.com/news-releases/news-release-details/cialisr-once-daily-use-now-fda-approved-treat-men-signs-and

4. Tadalafil. In: StatPearls. StatPearls Publishing; updated 2024. Accessed August 24, 2026. https://www.ncbi.nlm.nih.gov/books/NBK603743/

5. Wareham LK, Buys ES, Sappington RM. The nitric oxide-guanylate cyclase pathway and glaucoma. Nitric Oxide. 2018;77:75-87. doi:10.1016/j.niox.2018.04.010

6. Penedones A, Alves C, Batel Marques F. Risk of nonarteritic ischaemic optic neuropathy with phosphodiesterase type 5 inhibitors: a systematic review and meta-analysis. Acta Ophthalmol. 2020. doi:10.1111/aos.14253

7. American Academy of Ophthalmology. Additional evidence contraindicating PDE5 inhibitors [after unilateral NAION]. Editors' Choice. Accessed August 24, 2026. https://www.aao.org/education/editors-choice/additional-evidence-contraindicating-pde5-inhibito

8. American Academy of Ophthalmology Glaucoma Preferred Practice Pattern Panel. Primary Open-Angle Glaucoma Preferred Practice Pattern. Ophthalmology. 2025. Accessed August 24, 2026. https://www.aao.org/education/preferred-practice-pattern/primary-open-angle-glaucoma-ppp