Metformin and retinal diseases in preclinical and clinical studies: Insights and review of literature

Abstract

Metformin is one of the most prescribed drugs in the world giving potential health benefits beyond that of type 2 diabetes (T2DM). Emerging evidence suggests that it may have protective effects for retinal/posterior segment diseases including diabetic retinopathy (DR), age-related macular degeneration (AMD), inherited retinal degeneration such as retinitis pigmentosa (RP), primary open angle glaucoma (POAG), retinal vein occlusion (RVO), and uveitis. Metformin exerts potent anti-inflammatory, antiangiogenic, and antioxidative effects on the retina in response to pathologic stressors. In this review, we highlight the broad mechanism of action of metformin through key preclinical studies on animal models and cell lines used to simulate human retinal disease. We then explore the sparse but promising retrospective clinical data on metformin’s potential protective role in DR, AMD, POAG, and uveitis. Prospective clinical data is needed to clarify metformin’s role in management of posterior segment disorders. However, given metformin’s proven broad biochemical effects, favorable safety profile, relatively low cost, and promising data to date, it may represent a new therapeutic preventive and strategy for retinal diseases.

The Risk of Age-Related Macular Degeneration Is Reduced in Type 2 Diabetes Patients Who Use Metformin

“…Fourth, the findings provide good rationale and references for the conduction of clinical trials to verify the beneficial effects of metformin on AMD. A phase 2 clinical trial is being conducted to investigate metformin’s effect on AMD [ 57 , 58 ] and a recent study suggested that the effect of anti-VEGF in the treatment of diabetic macular edema could be enhanced by metformin [ 59 ]. Some bio-nanotechnologies are being developed to improve the delivery of metformin and probucol as potential antioxidants to block the formation of reactive oxygen species for the treatment of chemotherapy-induced hearing loss [ 60 ] or age-related hearing loss [ 61 ].…”

Association of metformin use with risk of newly onset neovascular age-related macular degeneration development

“…Metformin has been shown on a cellular level to regulate lipid metabolism, inhibit vascular endothelial growth factor and inflammation, mediate oxidative stress, and prevent retinal cell death. [4][5][6]20 Additionally, in a recent study by our group, we queried a large bioinformatics database of genes associated with AMD, wet AMD, dry AMD, intermediate AMD, and geographic atrophy to identify potential drug candidates that may have interactions with AMD-related genes. This study found that of the 77,146 drugs queried, metformin was the 1st potential drug candidate for wet AMD-related genes, 13th for dry AMD-related genes, and 21st for all AMD-related genes.…”

“…21 Therefore, it may have promise as a drug candidate for the prevention of AMD and nAMD, especially as it is an food and drug administration (FDA)-approved treatment for Type 2 diabetes and has few side effects. 20 In addition, it has been used safely without causing hypoglycemia and offers a similarly favorable safety profile in the treatment of other conditions, including polycystic ovarian syndrome, prediabetes, and obesity, and is being studied in others, including cardiovascular disease, malignancy, and age-related dementia. 22 Although a positive association between diabetes and AMD is documented in the literature, [23][24][25] the association between DR and AMD has been inconsistently demonstrated.…”

Role of Oxidative Stress in Ocular Diseases: A Balancing Act

“…The secondary effects of metformin have been attributed to the activation of the metabolic regulator AMP-activated protein kinase and the potent antioxidant enzyme peroxiredoxin-2 [ 454 ]. Metformin has been proposed as a treatment for ocular conditions associated with mitochondrial dysfunction [ 455 , 456 , 457 ]. Retrospective studies have shown a modest trend of a reduced risk of AMD in subjects taking metformin, though confounding factors such as the presence of cardiovascular disease and diabetes have likely contributed to conflicting findings [ 458 ].…”