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 the drug interactions among different categories of medications.

Clinical relevance: The treatment efficacy of the newly-introduced E-prostanoid receptor agonists(EP2), rho kinase inhibitors(ROCKI), and various combination therapies, has not been evaluated among all available glaucoma treatments. The synergistic or antagonistic effects of these combination therapies remain unknown.

Methods: Embase and PubMed were searched until 5/20/2025 for randomized controlled trials comparing IOP-lowering effects of topical glaucoma monotherapies and combinations in patients with primary open angle glaucoma or ocular hypertension. The medications evaluated included F-prostanoid receptor agonists prostaglandin analogs(PG), nitric oxide-donating prostaglandin analogs(PGN), EP2, alpha-2 adrenergic agonists(A), beta-adrenergic blockers(B), carbonic anhydrase inhibitors(C), ROCKI, and their combinations. A network meta-analysis(NMA) was performed using contrast-based frequentist random-effects models to calculate the weighted mean difference in IOP reduction among treatments. Efficacy rankings were determined using P-scores. The risk of bias was assessed with RoB2, and the certainty of evidence(COE) was evaluated using Confidence in Network Meta-Analysis(CINeMA). Component NMA(cNMA) was employed to explore interactions between different medications. The study was registered with PROSPERO (CRD42024573926).

Results: A total of 166 trials (36,494 participants) were included. PG-based combinations demonstrated the greatest IOP reduction (-7.41∼-5.81 mmHg,low COE), with PG+C ranking highest. Among monotherapies, PGN was most effective (-5.15[-6.18∼-4.11] mmHg,low COE), followed by PG (-4.75[-5.19∼-4.31] mmHg,high COE) and EP2 (-3.50[-4.27∼-2.73]mmHg,high COE). ROCKI (-3.24[-3.85∼-2.63]mmHg,high COE) was comparable to A (-3.36[-3.85∼-2.86] mmHg,high COE) and B (-3.29[-3.71∼-2.87]mmHg,high COE). Non-PG-based dual combinations (-5.10∼-4.82 mmHg,low to high COE) showed efficacy comparable to PG monotherapies, while non-PG-based triple combinations (A+B+C, -7.22[-9.04∼-5.40]mmHg,low COE) showed efficacy similar to the top-ranking PG-based combinations. cNMA revealed antagonism between PG+B(1.26mmHg) and PG+ROCKI(0.84mmHg), while a synergy was observed with PG+C(-2.05mmHg). Seventy-two percent of mixed comparisons had moderate to high COE, whereas all indirect comparisons had low to very low COE.

Conclusion: PG-based combinations, especially PG+C, were the most effective, comparable to non-PG-based triple combinations. EP2 outperformed other non-PG treatments but ranked below PG and PGN. PG+B and PG+ROCKI showed antagonism, whereas the synergy of PG+C suggested a promising avenue for new combinations.