A recent study published in Ophthalmology examined the efficacy of monotherapies and combinations of glaucoma medications in reducing intraocular pressure (IOP) and the drug interactions between different categories of medications.
Give me some background.
IOP reduction is the cornerstone of treatment for glaucoma, with a 10% decrease in the risk of progression observed for every 1 mmHg reduction in IOP from baseline.
Previous studies have performed head-to-head comparisons across monotherapies and consistently demonstrated that prostaglandin analogs (PGs) are the most effective medications for lowering IOP.
- But take note: The treatment efficacy of the newly-introduced E-prostanoid receptor agonists (EP2s), rho kinase inhibitors (ROCKIs), and various combination therapies have not yet been evaluated among all available glaucoma treatments.
- Additionally: The synergistic or antagonistic effects of these combination therapies remains unknown.
Now talk about the study.
In this systematic review and meta-analysis, investigators collected randomized controlled trials (RCTs) from Embase and PubMed published up until May 20, 2025, that compared IOP-lowering effects of topical glaucoma monotherapies and combinations in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT).
In total: 166 trials (36,494 participants) were included in the analysis, with the following medications represented in the studies:
- PGs
- Nitric oxide-donating prostaglandin analogs (PGNs)
- EP2s
- Alpha-2 adrenergic agonists (As)
- Beta-adrenergic blockers (Bs)
- Carbonic anhydrase inhibitors (CAIs)
- ROCKIs
- Combinations of these medications
How were study outcomes compared?
A network meta-analysis (NMA) was performed to calculate the weighted mean difference in IOP reduction between treatments.
In addition: Certainty of evidence (COE)—a measure of reporting bias in studies—was evaluated using Confidence in Network Meta-Analysis (CINeMA).
Findings?
PG-based combinations demonstrated the greatest IOP reduction (-7.41 to -5.81 mmHg, low COE), with PG+CAI ranking highest.
Among monotherapies, PGN was most effective (-5.15, 95% confidence interval [CI]: -6.18 to -4.11 mmHg, low COE), followed by:
- PG (-4.75, 95% CI: -5.19 to -4.31 mmHg, high COE)
- EP2 (-3.50, 95% CI: -4.27 to -2.73 mmHg, high COE)
ROCKI (-3.24, 95% CI: -3.85 to -2.63 mmHg, high COE) was comparable to As (-3.36, 95% CI: -3.85 to -2.86 mmHg, high COE) and Bs (-3.29, 95% CI: -3.71 to -2.87 mmHg, high COE).
Anything else?
Non-PG-based dual combinations (-5.10 to -4.82 mmHg, low to high COE) showed efficacy comparable to PG monotherapies, while non-PG-based triple combinations (A+B+C, -7.22, 95% CI: -9.04 to -5.40 mmHg, low COE) showed efficacy similar to the top-ranking PG-based combinations.
Analyses revealed antagonism between PG+B (1.26 mmHg) and PG+ROCKI (0.84 mmHg), while a synergy was observed with PG+CAI (-2.05 mmHg).
Expert opinion?
The study authors speculated that the observed antagonistic interaction between PG and Bs may be attributed to the paradoxical effects of different classes of glaucoma medications on cyclic adenosine monophosphate (cAMP) levels in the ciliary body.
Note: PG and CAI can increase cAMP levels, whereas Bs reduce cAMP production, thereby decreasing aqueous humor production.
- Meaning: The absence of fixed combinations of PG and CAI on the market suggests a significant opportunity for pharmaceutical development.
Limitations?
These included:
- Due to the lack of RCTs in certain categories of medications, certain groups, such as PG+A, PG+CAI, EP2+B, and A+B+C had limited data
- The researchers treated different medications within the same category as a single node to simplify the analyses; however, variations in efficacy existed among medications within the same category
- It was also assumed that drug interactions were consistent within the same class of medications—which is a premise that requires further validation
Take home.
These findings suggest that PG-based combination therapies, especially PG+CAI were the most effective, comparable to non-PG-based triple combinations.
- Further: EP2 outperformed other non-PG treatments, but ranked below PG and PGN.
PG+B and PG+ROCKI demonstrated antagonism, while the synergy of PG+CAI suggested a promising avenue for new combinations.