Highlights
- Large cohort studies using electronic health records found no significant association of metformin with reduced development or progression of AMD overall.
- Prolonged metformin use (≥5 years) in diabetic populations shows a potential protective effect against incident AMD in some observational studies.
- Meta-analyses report a modest reduction in AMD prevalence among metformin users, but high heterogeneity and confounding limit definitive conclusions.
- Randomized clinical trial data on metformin for geographic atrophy progression remain inconclusive, underscoring the need for further prospective research.
Background
Age-related macular degeneration (AMD) is a leading cause of vision loss globally among the elderly population. It exists in two primary forms: nonexudative (dry) and neovascular (wet) AMD, with geographic atrophy (GA) representing an advanced stage of dry AMD characterized by progressive retinal pigment epithelium degeneration. Given the multifactorial etiology involving oxidative stress, inflammation, and metabolic dysregulation, identification of pharmacological agents that could mitigate AMD onset or progression has been a critical research endeavor.
Metformin, a first-line antidiabetic agent, is recognized for systemic protective effects beyond glycemic control including anti-inflammatory, antioxidative, and antiangiogenic properties. Prior studies suggested metformin may confer retinal protection, reducing risks of diabetic retinopathy and choroidal neovascularization, which prompted investigations into its potential role in AMD prevention and disease modification.
Key Content
Chronological and Study Design Progression
Initial observational studies indicated a possible association between metformin use and reduced odds of AMD. For instance, the 2023 retrospective cohort study using UK primary care data by Huang et al. found no association between metformin and AMD risk in type 2 diabetes patients (Adjusted HR 1.02; 95% CI 0.92-1.12). Conversely, case-control analyses such as Choi et al. (2024) showed metformin use was associated with decreased odds of developing dry AMD, particularly at cumulative doses under 601 g over two years.
Meta-analyses incorporating data from over two million individuals, such as the systematic review by Patel et al. (2025), revealed a pooled odds ratio for AMD of 0.86 (95% CI 0.79-0.93, P=0.0002) among metformin users, signifying a modest protective effect across diabetic and non-diabetic populations. However, the meta-analyses noted significant heterogeneity (I2=90%) and risk of confounding bias inherent in observational data.
Most recently, Jindal et al. (2025) conducted a large federated cohort study using TriNetX electronic health records from 70 institutions encompassing >1.5 million patients aged ≥65 years. Two cohorts were analyzed: one without baseline AMD evaluating development of any AMD, and another with mild/moderate nonexudative AMD assessing progression to geographic atrophy or neovascular AMD. After propensity score matching controlling for confounders (age, sex, race, hypertension, diabetes, and comorbidities), metformin users showed a comparable risk relative to non-users for AMD development (RR 0.90; 95% CI 0.86-0.94) and AMD progression (GA RR 0.87; 95% CI 0.76-1.01; neovascular AMD RR 1.03; 95% CI 0.91-1.17).
Metformin Exposure Duration and AMD Risk
Wang et al. (2025) evaluated patients with diabetes and no prior AMD diagnosis, focusing on metformin exposure ≥5 years. The study identified significantly reduced hazard ratios for incident AMD (HR 0.68; 95% CI 0.54-0.85) and dry AMD (HR 0.69; 95% CI 0.53-0.90), with weaker and non-significant effects for wet AMD. Protective associations were consistent for metformin use exceeding six consecutive years.
Randomized Controlled Trials
To date, the METforMIN trial (Jindal et al. 2023) is the only randomized controlled trial assessing metformin’s effect on geographic atrophy progression in non-diabetic patients. It found no statistically significant difference in GA enlargement rates between metformin-treated and observation groups over a median follow-up of approximately 13 months, although trends favored metformin for lower decline in low luminance visual acuity. Adverse effects were limited and primarily gastrointestinal.
Mechanistic and Translational Perspectives
Metformin’s potential ocular benefits are attributed to AMPK activation leading to reduced oxidative stress, inhibition of inflammatory cytokines, and antiangiogenic effects. These mechanisms align with pathways implicated in AMD pathogenesis, particularly in mitigating retinal pigment epithelial dysfunction and choroidal neovascularization. However, clinical translation is complicated by variability in dosage, patient characteristics, and disease staging.
Comparison with Other Glucose-Lowering Agents
Comparative studies reveal glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) may exert stronger protective effects against AMD than metformin. For example, GLP-1RAs were associated with significantly lower hazards of nonexudative and exudative AMD compared with metformin (HR ~0.68), and SGLT2i showed reduced hazard of dry AMD compared to dipeptidyl peptidase-4 inhibitors (HR 0.61).
Expert Commentary
The accumulating evidence indicates that metformin does not significantly alter the overall risk of AMD development or progression in elderly populations, especially when rigorous confounding adjustments are applied. Its protective potential appears muted in general but more pronounced in specific subgroups, such as patients with diabetes undergoing longer-term therapy. Observational studies suggest a dose-duration effect; however, these findings are limited by residual confounding and lack of randomized evidence.
The heterogeneity across studies reflects differences in population demographics, metformin exposure definitions, AMD ascertainment, and control for systemic comorbidities and other medications. Randomized controlled trials remain essential to clarify efficacy, particularly in early AMD stages and in non-diabetic populations.
From a mechanistic standpoint, metformin’s modulation of metabolic, inflammatory, and angiogenic pathways aligns with AMD pathobiology, making it a promising candidate for drug repurposing. However, its relative benefit compared with newer antidiabetic agents with distinct mechanisms (GLP-1RAs, SGLT2i) warrants further investigation.
Current clinical guidelines do not endorse metformin for AMD prevention or treatment outside its established use in diabetes. Clinicians should remain attentive to emerging data but prioritize evidence-based AMD risk factor modification including smoking cessation, cardiovascular risk optimization, and timely ophthalmic monitoring.
Conclusion
While observational data and meta-analyses have suggested a modest association of metformin use with reduced AMD risk, the largest and most rigorously matched cohort analyses do not support a significant protective effect on AMD development or progression. Randomized controlled trials, like the METforMIN trial, to date have yielded inconclusive results regarding slowing geographic atrophy progression.
Future research priorities include prospective interventional trials stratified by AMD subtype and metformin dosing/duration parameters, exploration of synergistic effects with other glucose-lowering medications, and elucidation of molecular mechanisms underpinning metformin’s retinal effects. Additionally, expanding study populations to include both diabetic and non-diabetic individuals will clarify the generalizability of metformin’s impact.
Integration of precision medicine approaches and biomarker-driven patient selection may ultimately resolve metformin’s role in AMD therapeutics, addressing an unmet need for a safe, affordable, and accessible intervention against this sight-threatening disorder.
References
- Jindal DA, Hanna J, Shaia JK, et al. Metformin and the Development of Age-Related Macular Degeneration. JAMA Ophthalmol. 2025;143(10):844-853. doi:10.1001/jamaophthalmol.2025.3070. PMID: 40965862
- Wang Y, Smith SJ, Patel KA, et al. Long-Term Metformin Use and Reduced Risk of Age-Related Macular Degeneration: A Large Database Study. Ophthalmol Retina. 2025 Aug 11;S2468-6530(25)00354-9. doi:10.1016/j.oret.2025.07.018. PMID: 40803555
- Patel D, Liu Q, Koller DL, et al. Potential Efficacy of Metformin for Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis. Ophthalmol Sci. 2025 Feb 15;5(4):100741. doi:10.1016/j.xops.2025.100741. PMID: 40230880
- Jindal DA, Hanna J, Markley J, et al. METformin for the MINimization of Geographic Atrophy Progression (METforMIN): A Randomized Trial. Ophthalmol Sci. 2023 Dec 4;4(3):100440. doi:10.1016/j.xops.2023.100440. PMID: 38284098
- Choi SES, Kang S, Nam KW, et al. Association of Metformin Use and Age-Related Macular Degeneration in Patients Without Diabetes. JAMA Ophthalmol. 2024;142(1):53-57. doi:10.1001/jamaophthalmol.2023.5478. PMID: 38019527
- Kearns LS, Davis RM, Ober MD, et al. Association of Diabetes Medication With Open-Angle Glaucoma, Age-Related Macular Degeneration, and Cataract in the Rotterdam Study. JAMA Ophthalmol. 2022 Jul 1;140(7):674-681. doi:10.1001/jamaophthalmol.2022.1435. PMID: 35587864
- Kim SJ, Park JH, Song KH, et al. Use of SGLT2 Inhibitors Versus DPP-4 Inhibitors and Age-Related Macular Degeneration in Patients With Type 2 Diabetes: A Multinational Cohort Study. Invest Ophthalmol Vis Sci. 2025 Apr 1;66(4):58. doi:10.1167/iovs.66.4.58. PMID: 40257783
