For older men managing lower urinary tract symptoms with tadalafil — a PDE5 inhibitor increasingly prescribed for benign prostatic hyperplasia — a meaningful ocular trade-off may exist that clinicians and patients have largely overlooked. The finding reframes tadalafil not merely as a cardiovascular and erectile drug but as a medication with plausible long-term effects on intraocular pressure and optic nerve health.

This retrospective cohort study drew on the multinational TriNetX database, enrolling 73,854 propensity-score-matched men aged 40 and older with documented lower urinary tract symptoms between 2012 and 2022. After carefully balancing age, race, comorbidities, renal function, and concomitant medications, tadalafil users showed a 22% elevated hazard of incident glaucoma over five years compared with non-PDE5 inhibitor users (HR 1.22; 95% CI 1.12–1.33). The signal was particularly sharp for ocular hypertension (HR 1.32), primary open-angle glaucoma (HR 1.33), and initiation of glaucoma treatment (HR 1.33). Absolute incidence rates were 3.93% in tadalafil users versus 3.16% in controls — a modest but statistically robust difference. Critically, no elevated risk emerged for low-tension or angle-closure glaucoma subtypes, pointing toward a pressure-mediated rather than purely vascular mechanism.

The proposed biological pathway is coherent: PDE5 inhibition modulates nitric oxide signaling in trabecular meshwork cells, which governs aqueous humor outflow and intraocular pressure. Prior mechanistic work has demonstrated PDE5 receptor expression in ocular tissue, lending biological plausibility. However, this is an observational, retrospective design — causality cannot be established, and residual confounding by unmeasured lifestyle or systemic factors remains possible. The TriNetX database also captures only patients within integrated health networks, potentially introducing selection bias. Still, the dose-response and subtype specificity add credibility. For a drug now routinely prescribed to millions of middle-aged men, even a modest elevation in open-angle glaucoma risk warrants consideration in ophthalmologic screening protocols. This finding is incremental but clinically actionable.