Metformin protects retinal ganglion cells in a preclinical model of retinal ischemia/reperfusion injury and stabilizes visual field in diabetic patients with glaucoma.

Metformin, a first-line treatment for type 2 diabetes, has gained attention as a promising neuroprotective agent due to its pleiotropic effects - including anti-inflammatory, anti-apoptotic, and autophagy-enhancing properties. Here we provide both preclinical and clinical evidence demonstrating the neuroprotective effects of metformin in the context of retinal ganglion cell (RGC) degeneration, a hallmark of glaucoma, a leading cause of irreversible blindness for which no direct RGC-neuroprotective therapies are currently available. In a mouse model of retinal ischemia/reperfusion injury systemic administration of metformin significantly prevented RGC loss and preserved retinal structure. Enhanced phosphorylation of AMP-activated protein kinase (AMPK) was observed, along with increased autophagosome formation and upregulation of key mitophagy markers - including LC3II, optineurin, and Parkin - indicating improved mitochondrial quality control mechanisms. Proteomic analysis revealed that metformin modulated several proteins implicated in mitochondrial respiratory function, ubiquitination, and intracellular trafficking, suggesting broader effects on retinal cellular homeostasis. Complementing our preclinical observations, a retrospective clinical study in diabetic patients with glaucoma showed that individuals treated with metformin maintained stable visual field (VF) parameters over a six-month period, whereas those treated with insulin exhibited significant VF deterioration. These findings position metformin as a promising intraocular pressure (IOP)-independent neurotherapeutic for slowing or preventing glaucomatous neurodegeneration.