Metformin as a Neuroprotective Therapy for Glaucoma - A Randomized Controlled Trial

Glaucoma, a chronic degenerative disease of the optic nerve, is the leading cause of irreversible blindness worldwide. Although lowering the intraocular pressure (IOP) has been shown to be effective to slow optic nerve degeneration, a significant portion of glaucoma patients continue to develop progressive loss in vision despite adequate control of IOP. Development of neuroprotective therapy to prevent optic nerve degeneration by mechanisms other than IOP- lowering is critical to reduce the burden of glaucoma blindness. With 76 million glaucoma patients in 2020 worldwide, the need to investigate neuroprotection for glaucoma is pressing. While metformin is a widely adopted oral hypoglycemic medication for treatment of type 2 diabetes mellitus (DM), increasing evidence from clinical studies has shown that metformin can decrease the risk of many age-related diseases including neurodegenerative diseases. In a retrospective study of 150,016 patients with DM, those taking metformin at >1500mg/day had a 25% reduced risk of development of open-angle glaucoma than those who took no metformin. Metformin has a high safety profile. We aim to investigate whether metformin can be repurposed to a neuroprotective therapy for glaucoma patients in a randomized controlled trial. We propose to conduct a 24-month, double-blind, placebo-controlled, parallel group, multi- center trial, randomizing 240 primary open angle glaucoma patients who have progressive retinal nerve fiber layer ganglion cell inner plexiform layer (RNFL-GCIPL) thinning in at least one eye, as determined by wide-field optical coherence tomography Trend-based Progression Analysis, to receive metformin 1500mg/day or placebo. All patients will be followed up at 2- month intervals for IOP, RNFL-GCIPL thickness, and visual field (VF) measurements. The objectives are to compare (1) the rates of change of average RNFL-GCIPL thickness (primary outcome measure), and (2) the rates of change of VF mean deviation (MD) (secondary outcome measure) between treatment groups. We hypothesize that patients treated with metformin have a slower rate of RNFL-GCIPL thinning, and a slower rate of VF MD decline compared with those treated with placebo at similar levels of IOP over the 24-month follow-up. The proposed study has the potential to mark a paradigm shift in the management of glaucoma patients by demonstrating that neuroprotection is attainable with metformin, which will alleviate the increasing burden of glaucoma blindness in China and other Asian countries where glaucoma patients with normal levels of IOP are prevalent. Furthermore, it will inform and impact the study design in future neuroprotection trials which can expedite the development of neuroprotective therapy for glaucoma.

To investigate whether metformin has a neuroprotective effect in patients with primary open-angle glaucoma by comparing the rates of change of average retinal nerve fiber layer ganglion cell inner plexiform layer (RNFL-GCIPL) thickness (primary outcome measure) between patients randomized to receive metformin versus those randomized to receive placebo. To identify the risk factors associated with progressive RNFL-GCIPL thinning and progressive decline in visual field mean deviation in patients with glaucoma.

This study takes 24 months. Participants will have 12 visits within 24 months. All of the investigations will be carried out at Grantham Hospital and Hong Kong Eye Hospital. Patients will be randomly assigned in a 1:1 ratio to receive, twice daily, oral metformin 750mg (i.e. 1500mg/day) or identical-appearing oral placebo. The investigators and patients will be blinded to the treatment assignment. Participants will be followed up at 2-month intervals for 24 months.

The rates of RNFL-GCIPL thinning between the metformin-treated group and the placebotreated group will be compared using a linear mixed model after adjusting for clustering between fellow eyes and covariates (i.e.signal strength, baseline RNFL-GCIPL thickness, IOP during follow-up, age, and axial length).The average RNFL-GCIPL thickness of an eye in each visit (i.e. the dependent variable in the linear mixed model) is obtained from taking the

The rates of change of VF MD will be compared between treatment groups with linear mixed models as described; differences in time from baseline to the event of progressive RNFLGCIPL thinning (by TPA) and VF progression (by EMGT criteria) between treatment groups will be compared with Cox proportional hazards models using shared-frailty to adjust for correlation between fellow eyes. Missing data (e.g. lost to follow-up) will be imputed using multiple imputation by chained equations.

Inclusion Criteria: age ≥18 years; best corrected VA ≥20/40; IOP ≤24mmHg at the screening and baseline visits; and progressive RNFL-GCIPL thinning by TPA over the past 3 years in at least one eye (described in lines 202-215). Exclusion Criteria: patients with DM, kidney or liver diseases, pathological myopia, cognitive impairment (e.g. Alzheimer's disease), or diseases that may cause visual field loss or optic disc abnormalities other 169 than glaucoma; inability to perform reliable visual field; and suboptimal quality of OCT images (described in lines 198-200). Both eyes of a patient will be included in the analysis if both eyes are eligible for inclusion.