Efficacy and Drug Interactions of Glaucoma Medications: A Systematic Review and Component Network Meta-analysis.

Topic: To investigate the efficacy of monotherapies and combinations of glaucoma medications in reducing intraocular pressure (IOP) and drug interactions.

Clinical Relevance: The relative treatment efficacy and interaction of the newly introduced E-prostanoid receptor 2 (EP2) agonists, rho-kinase inhibitors (ROCKIs), and various combination therapies remain unknown.

Methods: Embase and PubMed were searched through May 20, 2025, for randomized controlled trials comparing IOP-lowering effects of topical glaucoma medications in patients with primary open-angle glaucoma or ocular hypertension. The medications evaluated included prostaglandin F2α analogs (PGFAs), nitric oxide-donating prostaglandin analogs (NO-PGA), EP2 agonists, unoprostone, α-adrenergic agonists (AAAs), β-adrenergic blockers (BABs), carbonic anhydrase inhibitors (CAIs), ROCKIs, and their combinations. A network meta-analysis (NMA) using contrast-based frequentist random-effects models calculated the weighted mean difference in IOP reduction, with rankings determined using P scores. The risk of bias was assessed with Cochrane Risk of Bias Tool, and the certainty of evidence (COE) was evaluated using confidence in network meta-analysis. Component NMA explored interactions between different medications. The study was registered with the International Prospective Register of Systematic Reviews (identifier, CRD42024573926).

Results: Among 166 trials (36 494 participants), PGFA-based combinations demonstrated the greatest IOP reduction (range, -7.41 to -5.81 mmHg; COE: low), with PGFAs plus CAIs ranking highest. Among monotherapies, NO-PGA was most effective (-5.15 [95% confidence interval: -6.18 to -4.11 mmHg]; COE: low), followed by PGFA (-4.75 [-5.19 to -4.31]; high) and EP2 agonist (-3.50 [-4.27 to -2.73]; high). ROCKIs (-3.24 [-3.85 to -2.63]; high) were comparable with AAA (-3.36 [-3.85 to -2.86]; high) and BAB (-3.29 [-3.71 to -2.87]; high). Non-PGFA-based dual combinations (range, -5.10 to -4.82 mmHg; low to high) were comparable to PGFA, whereas non-PGFA-based triple combinations (AAA plus BAB plus CAI, -7.22 [-9.04 to -5.40]; low) were similar to the top-ranking PGFA-based combinations. Component NMA revealed antagonism between PGFA plus BAB (1.26 mmHg) and PGFA plus ROCKI (0.84), whereas synergy was observed with PGFA plus CAI (-2.05).

Discussion: Non-PGFA-based triple combinations and PGFA-based combinations, especially PGFA plus CAI, were the most effective. E-prostanoid receptor 2 agonists outperformed other non-PGFA treatments but ranked below PGFA and NO-PGA. Prostaglandin F2α analog plus BAB or ROCKI showed antagonism, whereas the synergy of PGFA plus CAI suggested a promising avenue for new combinations.

Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.