Metformin Shows No Significant Effect on Age-Related Macular Degeneration Risk

Age-related macular degeneration is a leading cause of vision loss in older adults, and identifying modifiable risk factors or protective pharmacological agents remains a high priority. Metformin, the most widely prescribed oral diabetes medication, has shown anti-inflammatory and anti-aging properties and has been associated with reduced risk of certain cancers, cardiovascular disease, and retinal conditions such as diabetic retinopathy and choroidal neovascularization. Prior smaller observational studies suggested metformin might also protect against AMD, prompting this large-scale investigation.

This cohort study leveraged TriNetX, a federated EHR platform aggregating deidentified data from 70 US health institutions, covering records from January 2013 to June 2025. Two separate cohorts were constructed: Cohort 1 included adults aged 65 or older without AMD at baseline — 297,008 metformin-exposed and 1,269,644 unexposed — to assess incident AMD development. Cohort 2 included adults with early or intermediate non-exudative AMD — 12,843 exposed and 77,279 unexposed — to evaluate progression to geographic atrophy or neovascular AMD. Participants were required to meet inclusion criteria at least 6 months before the outcome of interest, and those with prior outcomes were excluded. Propensity score matching balanced groups on age, sex, race, hypertension, diabetes, and other systemic comorbidities.

After matching, participants prescribed metformin showed a risk ratio of 0.90 (95% CI, 0.86–0.94) for developing any AMD compared to unexposed participants. However, given the authors' pre-specified threshold that CIs crossing 0.90–1.10 were considered non-significant, this result was interpreted as not clinically meaningful. At 5 years, the RR was 0.94 (95% CI, 0.90–0.99) and at 10 years, 0.91 (95% CI, 0.87–0.94) — both within or at the boundary of non-significance. For AMD progression, the RR for geographic atrophy was 0.87 (95% CI, 0.76–1.01) and for neovascular AMD was 1.03 (95% CI, 0.91–1.17), neither reaching statistical significance.

These findings stand in contrast to some prior studies that reported protective associations, though those studies were often smaller, lacked rigorous confounder control, or were conducted in diabetic-only populations. The authors acknowledge that dosage, duration, and cumulative exposure to metformin were not assessed — variables that could reveal a dose-response relationship missed in this analysis. Additionally, the EHR-based design carries inherent limitations including coding variability, detection bias (metformin users may receive more medical monitoring including eye exams), and inability to confirm medication adherence.

For clinicians and longevity-focused practitioners, this study provides important reassurance that prescribing metformin for its approved indications does not appear to harm retinal health, but it also tempers enthusiasm for using metformin as a preventive AMD therapy. Prospective clinical trials examining specific dosing regimens and longer follow-up periods are needed before any AMD-specific recommendations can be made.