Metformin, A Potential Role in Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis

Abstract

Background Currently, no generally approved medical treatment can delay the onset of age-related macular degeneration (AMD) or slow the progression of degenerative changes. Repurposing drugs with beneficial effects on AMD pathophysiology offers a route to new treatments which is faster, cost-effective, and safer for patients. Recent studies indicate a potential role for metformin in delaying AMD development and progression. In this context, we conducted a systematic review and meta-analysis to look for beneficial associations between metformin and AMD. Methods We systematically searched Medline and Embase (via Ovid), Web of Science, and ClinicalTrials.gov databases for clinical studies in humans that examined the associations between metformin treatment and AMD published from inception to February 2021. We calculated pooled odds ratio (OR) with 95% confidence interval (CI) considering a random effect model in the meta-analysis. Results Five retrospective studies met the inclusion criteria. There are no prospective studies that have reported the effect of metformin in AMD. The meta-analysis showed that people taking metformin were less likely to have AMD although statistical significance was not met (pooled adjusted OR = 0.80, 95% CI 0.54–1.05, I 2 = 98.8%). Subgroup analysis of the association between metformin and early and late AMD could not be performed since the data was not available from the included studies. Conclusions Analysis of retrospective data suggests a signal that metformin may be associated with decreased risk of any AMD. It should be interpreted with caution because of the failure to meet statistical significance, the small number of studies, and the limitation of routine record data. However prospective studies are warranted in generalizable populations without diabetes, of varied ethnicities, and AMD stages. Clinical trials are needed to determine if metformin has efficacy in treating early and late-stage AMD. Supplementary Information The online version contains supplementary material available at 10.1007/s40123-021-00344-3.

Long-Term Oral Treatment with Non-Hypoglycemic Dose of Glibenclamide Reduces Diabetic Retinopathy Damage in the Goto-KakizakiRat Model

“…Our study also indicates that glibenclamide, particularly if formulated for ocular delivery, could be used for other degenerative retinal diseases associated with oxidative stress, inflammation and inflammasome activation, such as age-related macular degeneration (AMD). Recently, metformin was found to potentially reduce the incidence of AMD in large, retrospective studies [51] that need to be interpreted with caution [52]. Taking into account the fact that no treatment is currently available to prevent or delay retinal degeneration, the effects of old and known drugs with a known safety profile could be evaluated in treated patients that are affected by retinal diseases that induce rapid retinal cell death, such as retinal detachment [53].…”

Association of lipid-lowering drugs and antidiabetic drugs with age-related macular degeneration: a meta-analysis in Europeans

“…Subsequently, a recent meta-analysis on retrospective data suggested a trend of reduced risk for AMD in patients using metformin without reaching statistical significance, underscoring the scarcity of data and highlighting the need for further prospective studies. [64] Suggested mechanisms include different pathways of biological aging. Metformin is considered to have anti-oxidative and anti-inflammatory properties and to reduce oxidative stress within the RPE, which is an important part of AMD pathophysiology.…”

“…Metformin is considered to have anti-oxidative and anti-inflammatory properties and to reduce oxidative stress within the RPE, which is an important part of AMD pathophysiology. [21,64] Rodent models indicated an influence on the adenosine triphosphate (ATP) levels, restoring cellular energy homeostasis [65] and an increased autophagy needed for the clearance of dysfunctional cell components. [64,66] Previous results, however, are not easily transferable to the general population, given that the included patients suffered from diabetes, which may interfere with AMD pathogenesis.…”

“…[21,64] Rodent models indicated an influence on the adenosine triphosphate (ATP) levels, restoring cellular energy homeostasis [65] and an increased autophagy needed for the clearance of dysfunctional cell components. [64,66] Previous results, however, are not easily transferable to the general population, given that the included patients suffered from diabetes, which may interfere with AMD pathogenesis. A clinical trial investigating the safety and efficacy of metformin use to decrease GA progression in nondiabetic patients with dry AMD is being conducted at the moment (METforMIN, ClinicalTrials.gov: NCT02684578).…”

Using Advanced Bioinformatics Tools to Identify Novel Therapeutic Candidates for Age-Related Macular Degeneration

“…Recent investigations by our team and others support these findings by demonstrating that metformin is associated with decreased risk of developing AMD after adjusting for age, gender, and comorbidities. 30 , 67 – 69 Metformin is the most commonly used drug for type II diabetes that has been shown to have versatile protective properties for other aging-related conditions such as cardiovascular diseases, dementia, and some carcinomas. 70 – 72 Connection between AMD and diabetes has been proposed through a unifying mechanism in inflammation and breakdown of the blood-brain barrier 73 ; therefore it is hypothesized that antidiabetic drugs like metformin may have a preventive and therapeutic role in AMD.…”