Protective Role of Metformin in Glaucoma: Prospective Cohort Study, Meta-Analysis, and Drug-Target Mendelian Randomization.

PURPOSE: Preclinical studies suggested that metformin use may protect against glaucoma through multiple mechanisms, while observational studies reported mixed results. To clarify this association, we conducted a prospective cohort study, a meta-analysis, and a drug-target Mendelian randomization (MR) analysis.

DESIGN

A prospective cohort study, meta-analysis, and drug-target MR analysis.

PARTICIPANTS

The cohort analysis included 24 206 UK Biobank participants with diabetes who were free of glaucoma at baseline.

METHODS

In the UK Biobank, we examined the association between metformin use and incident glaucoma using multivariable Cox regression. A random-effect meta-analysis was performed to synthesize existing evidence on the association between metformin and glaucoma from human studies. For drug-target MR, genetic variants close to 5 metformin targets genes were weighted by their genetic association with glycated hemoglobin A1c (HbA1c) to proxy their therapeutic effects. The genome-wide association study summary data for primary open-angle glaucoma (POAG) was sourced from the International Glaucoma Genetics Consortium, including only individuals of European ancestry. The drug-target MR analysis was performed using the generalized least squares-inverse variance weighted model.

MAIN OUTCOME MEASURES: Incident glaucoma in UK Biobank, pooled effect estimates from meta-analysis, and MR-derived causal estimates for metformin's effect on POAG.

RESULTS

During a mean follow-up of 12.1 ± 2.8 years, 841 glaucoma cases occurred, with an incident rate of 2.87 per 1000 person-years. Metformin use was associated with a 19% lower glaucoma risk (hazard ratio, 0.81; 95% confidence interval [CI], 0.67-0.97; P = 0.019) in individuals of European ancestry, independent of glycemic control, intraocular pressure, diabetes duration, and other confounders. Random-effect meta-analysis of cohort studies showed a consistent protective effect (pooled risk ratio, 0.81; 95% CI, 0.72-0.93; P = 0.002) of metformin on glaucoma incidence among subjects with diabetes. Genetically proxied effects of 5 metformin targets, scaled to per standard deviation reduction of HbA1c level, were associated with 34% lower glaucoma risk (odds ratio, 0.66; 95% CI, 0.46-0.94; P = 0.022).

CONCLUSIONS

Convergent evidence from cohort, meta-analytic, and genetic analyses supports a possible protective association between metformin use and glaucoma among patients with diabetes. These findings support the need for randomized clinical trials to evaluate metformin's potential as a preventive glaucoma therapy in individuals with diabetes.

FINANCIAL DISCLOSURES: The authors have no proprietary or commercial interest in any materials discussed in this article.