For the millions of middle-aged and older men managing benign prostatic hyperplasia with tadalafil, a widely prescribed PDE5 inhibitor, a significant ophthalmological question has gone largely unanswered — until now. Whether a drug known to alter vascular tone and ocular perfusion pressure could quietly accelerate glaucoma onset is not a trivial concern, particularly given glaucoma's status as the leading cause of irreversible blindness worldwide.
This multinational retrospective cohort study, drawing on the TriNetX database, enrolled over 73,000 men aged 40 and older — 36,927 tadalafil users matched 1:1 with non-PDE5 inhibitor controls using propensity score matching across age, race, comorbidities, renal function, and concomitant medications. Over a five-year follow-up, tadalafil use was associated with a 22% higher overall glaucoma risk (HR 1.22; 95% CI 1.12–1.33). More specifically, risks for ocular hypertension and primary open-angle glaucoma each rose by approximately 33%, and initiation of glaucoma treatment increased by 33% as well. Five-year cumulative incidence diverged meaningfully: 3.93% in tadalafil users versus 3.16% in controls. No elevated risk emerged for low-tension or primary angle-closure subtypes, suggesting a mechanism tied to elevated rather than reduced intraocular pressure dynamics.
The proposed biological rationale involves PDE5 inhibition increasing nitric oxide–mediated vasodilation in the trabecular meshwork and ciliary body, potentially impairing aqueous humor drainage. This mechanism is biologically plausible but remains unconfirmed in prospective human studies. The study's retrospective design means residual confounding cannot be excluded — men on tadalafil may have more healthcare encounters, increasing detection rates for subclinical glaucoma. The absolute risk difference, while statistically robust, is modest (roughly 0.8 percentage points over five years), and causality cannot be established from this design alone. Nevertheless, the consistency of results across subgroups and multiple washout windows strengthens confidence. This finding warrants ophthalmologists and prescribing urologists alike to consider baseline and periodic intraocular pressure monitoring in long-term tadalafil users.