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.