A study aimed to clarify metformin’s potential role in mitigating the increased glaucoma risk in patients with diabetes.A study conducted by researchers from Singapore demonstrates a protective effect of metformin against glaucoma in patients with diabetes.
“Our study is among the first to triangulate evidence from a prospective cohort analysis, a meta-analysis, and a drug-target Mendelian randomization (MR) analysis, suggesting an association between metformin use and lower glaucoma risk,” said the investigators, led by Dr Can Can Xue from the Singapore Eye Research Institute.
Prospective study
This included 24,206 participants (mean age 59.9 years, 59 percent men, 52 percent on metformin) from the UK Biobank who had diabetes without glaucoma or glaucoma suspect at baseline. Of these, 5,972 had intraocular pressure (IOP) measurement. A total of 841 patients developed glaucoma over a mean follow-up of 12.1 years.
After multivariate adjustments, metformin use was associated with a lower risk of incident glaucoma in all participants (hazard ratio [HR], 0.81; p=0.018). [Ophthalmol Sci 2026;6:101074]
This association was also evident in the sensitivity analyses evaluating participants with complete IOP measurement (n=4,699) in the unadjusted model (HR, 0.76; p=0.040) and across all adjusted models (HRs, 0.40–0.66; p≤0.001 for all).
Meta-analysis
In four cohort studies, metformin was significantly associated with a reduced risk of glaucoma (relative risk [RR], 0.81; p=0.002), with no significant heterogeneity (I2=0 percent; p=0.520). “[Of note, our] study contributed substantially to the pooled estimates (57.3 percent). The association was not significant (RR, 0.83; p=0.102) after excluding it,” said Xue and colleagues.
Metformin showed a nonsignificant trend toward reduced glaucoma risk in three cross-sectional studies (odds ratio [OR], 0.31; p=0.054) with substantial heterogeneity (I2=87.8 percent; p<0.001), as well as in the pooled analysis (OR, 0.65; p=0.071).
Drug-target MR analysis
This analysis included participants with matching variants in the primary open-angle glaucoma (POAG; n=55) or IOP (n=53) genome-wide association study summary data.
Genetically proxied effects of five metformin targets, scaled to a 1-standard deviation reduction of HbA1c level, were associated with a lower risk of POAG (OR, 0.66; p=0.022).
“Drug-target MR … focuses on genetic variants located within or near the protein-coding gene of interest to proxy the effect of modifying a specific drug target,” the researchers explained. However, as this only proxied the effects of five known metformin targets, the overall effects of metformin were not captured. This analysis also did not account for tissue-specific drug accessibility, dosage, or treatment duration, they added.
IOP-lowering can only go so far
The researchers noted that teasing out the potential protective effect of metformin from the underlying disease risk is quite a challenge. “This complexity is further compounded by using other antidiabetic medications, which may have their own effects on glaucoma risk.”
Several potential mechanisms for metformin’s protective effect against glaucoma include retinal ganglion cell preservation, trabecular meshwork protection, or IOP reduction, among others. [Exp Eye Res 2022;217:108979; Elife 2023;12:e81198; J Glaucoma 2024;33:387-393] However, IOP lowering may only slow the progression of, and rarely stops, vision loss, highlighting the need for adjuvant or IOP-independent therapies. [Am J Ophthalmol 2013;156:724-730; Lancet 2023;402:1788-1801]
Metformin’s protective effect may also stem from its glycaemic-control properties, given the shared pathophysiology of diabetes and glaucoma, and the observed dose–response relationship between high blood glucose level and glaucoma risk. [J Glaucoma 2024;33:387-393; Ophthalmology 2015;122:72-78]
“By integrating multiple approaches, our study aimed to clarify metformin’s potential role in mitigating the increased glaucoma risk in patients with diabetes, with implications for future clinical trials, drug development, and treatment strategies,” the researchers said.
They called for more trials to confirm their results, inform potential metformin use to mitigate increased glaucoma risk in patients with diabetes, and determine whether the lower glaucoma risk implies a higher risk with alternative antidiabetic therapies or underlying metabolic differences between groups.