Metformin’s potential impact on AMD prevention

Bios Mr. Moir is a fourth-year medical student at the University of Chicago Pritzker School of Medicine.  Dr. Gonnah is a second-year surgical vitreoretinal fellow in the department of ophthalmology and visual science at the University of Chicago.  Dr. Yehia is a first-year surgical vitreoretinal fellow in the department of ophthalmology and visual science at the University of Chicago.  Dr. Skondra is an associate professor specializing in vitreoretinal disease and surgery in the department of ophthalmology and visual science at the University of Chicago.  DISCLOSURES: Mr. Moir, Dr. Gonnah and Dr. Yehia have no relevant disclosures. Dr. Skondra disclosed relationships with Biogen, Allergan/AbbVie, Focuscope, LaGrippe Research, Keywest Health, Lumina and Trinity Life Sciences.

Intravitreal anti-VEGF agents have revolutionized the treatment of wet age-related macular degeneration, but treatment options for the dry form have remained scarce.¹ Retina specialists have been largely restricted to recommending AREDS2 vitamins and minerals to prevent progression to advanced AMD along with recommending pertinent lifestyle interventions, such as smoking cessation.²

This year, the Food and Drug Administration approved two treatments for treatment of dry AMD: intravitreal pegcetacoplan (Syfovre, Apellis Pharmaceuticals), which was shown to mildly slow the progression of geographic atrophy;³ and, more recently, avacincaptad pegol (Izervay, Iveric Bio/Astellas), which demonstrated a statistically significant reduction in GA progression.⁴ 

However, no medication is known to prevent disease progression regardless of staging. This is a notable shortcoming, considering that the dry AMD accounts for approximately 90 percent of all AMD cases and can slowly progress to GA, which causes permanent central vision loss. 

Furthermore, wet AMD accounts for 80 to 90 percent of all blindness related to AMD. However, treatments with recurrent injections may present uncomfortable burdens to patients, and few if any interventions exist to prevent or delay conversion to wet AMD.⁵ 

Hence, an ideal medication would prevent the onset of AMD entirely or prevent its progression to advanced and debilitating stages of disease, all while offering safety and ease of use to patients. That has inspired some researchers to evaluate the potential of using metformin for management of AMD. 

Metformin’s expanding use

Metformin is a first-line oral medication for treating type 2 diabetes. In recent years, its off-label use has expanded for treating polycystic ovarian syndrome, gestational diabetes and prediabetes, and for managing the metabolic effects from antipsychotic medications.⁶ Part of this growing therapeutic range is attributable to its benign side-effect profile. Metformin isn’t associated with a risk of hypoglycemia and is generally well-tolerated.⁶ 

Also emerging is evidence of metformin’s potential geroprotective properties. Metformin may have an anti-aging effect through its interactions with age-related cellular pathways, and its use has been shown to decrease mortality from dementia, cancer and cardiovascular disease.⁷ 

Metformin’s beneficial anti-aging associations, expanding therapeutic use and safety profile have inspired researchers to explore its possible connections with AMD.

Possible mechanism for metformin in AMD

While the pathogenesis of AMD is multifactorial and isn’t completely characterized, complement, angiogenic, oxidative stress, lipid, extracellular matrix and inflammatory pathways all contribute.⁸ Metformin may interact with these pathways to modulate prevention or delay the progression of AMD through several plausible mechanisms. 

Metformin acts through activation of AMP-activated protein kinase (AMPK), which is responsible for inhibition of glucose production in hepatocytes.⁹ AMPK downregulates mammalian target of rapamycin (mTOR), a kinase that plays a key role in aging, and inhibition of mTOR can extend the lifespan of mammalian model organisms.¹⁰ 

Through AMPK-dependent and independent pathways, metformin also reduces levels of reactive oxygen species and pro-inflammatory cytokines while enhancing autophagy and delaying stem cell aging.¹¹ These findings help to explain metformin’s purported anti-aging properties. 

Within retinal tissue, metformin exhibits antiangiogenic and anti-inflammatory properties,¹² protects against oxidative stress¹³ and augments autophagy-mediated removal of damaged RPE cells.¹⁴ 

Given the considerable overlap between the pathways on which metformin acts and the pathways responsible for the development of AMD, researchers have turned their attention to observational studies to determine whether metformin may protect against AMD.

Implications of the available evidence 

Retina specialists should understand how metformin’s effects differ in nondiabetes patients. Three points warrant this additional analysis:

• Prior studies have either exclusively included patients with diabetes or a combination of patients with and without diabetes, making it difficult to parse the effect of metformin from the effect of diabetes on AMD risk. 
• Metformin can be taken safely by patients who don’t have diabetes. 
• As Andrea Blitzer, MD, and colleagues at the University of Chicago demonstrated, metformin wasn’t protective in patients with diabetic retinopathy, which is generally associated with more severe diabetes.¹⁵ 

With these points in mind, it’s possible that metformin may have the greatest benefit in patients who don’t have diabetes.

Inconsistencies in observational studies

Data behind metformin dosing is still unclear and has been described inconsistently in observational studies. Some studies have described a protective effect with metformin that’s enhanced with greater dosing.^16,17 Others have reported an optimal effect at lower doses.^15,18 This point requires further investigation as well.

Lastly, only one study has reported the impact of metformin separately on dry and wet AMD.¹⁹ Metformin may modulate disease activity differently in these two forms due to unique aspects of their pathogenesis. 

It’s crucial to understand if metformin protects against GA, considering its severe and irreversible visual burdens, and if metformin protects against the rapidly progressive wet AMD—both shortcomings in the current literature. An ongoing phase II clinical trial of metformin in nondiabetes patients with GA will shed light on its ability to prevent progression of this debilitating and advanced form of AMD.²⁰ 

Bottom line

While it’s too early to discern whether metformin will ultimately have a role in the management of AMD, results from multiple observational studies across North America, Europe and Asia are encouraging. 

In conjunction with a plausible mechanism that preclinical studies have uncovered, sufficient evidence from observational studies has amassed to warrant testing of metformin in prospective clinical trials. We should eagerly await the results of these trials as they could have the potential to further revolutionize treatment of this debilitating disease. RS

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^{2. No authors listed. The Age-Related Eye Disease Study 2 (AREDS2) Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: The Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309:2005-2015.} 

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^{4. Iveric Bio receives U.S. FDA approval for Izervay (avacincaptad pegol intravitreal solution), a new treatment for geographic atrophy [press release]. Tokyo; Astellas Pharma; August 5, 2023. Available at: https://www.astellas.com/en/news/28281. Accessed September 6, 2023.}

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