Metformin and AMD: New Studies Yield Conflicting Evidence

Three new studies examining whether the diabetes drug metformin affects the risk of age-related macular degeneration (AMD) have returned conflicting results, with one cohort study finding no association and two others suggesting reduced odds of specific AMD forms.

A cohort study published in JAMA Ophthalmology pooled data from the Singapore Epidemiology of Eye Diseases (SEED) study and the UK Biobank, finding no association between metformin use and AMD risk in patients with diabetes. In SEED, 2,869 participants with diabetes were analyzed; the adjusted odds ratio for prevalent AMD in metformin users versus patients taking other non-metformin diabetes drugs was 0.99, and for incident AMD it was 1.07. In the UK Biobank, metformin users initially showed a higher crude incidence of AMD than people taking no antidiabetic medication (3.6% vs. 2.7%), but after adjustment the association lost statistical significance (hazard ratio: 1.13). The researchers concluded that they found no association between metformin use and AMD in patients with diabetes “when triangulating findings from a multiethnic Asian population cohort and the UK Biobank with comprehensive covariate adjustment.” They cautioned, “Given the observational nature of this evidence, causal approaches would be needed to clarify whether a causal effect exists.”

In contrast, a study published online Jan. 30 in Ophthalmology Retina found that metformin use was associated with reduced adjusted odds of new-onset neovascular AMD (nAMD). The case-control analysis included 22,205 cases with new-onset ICD coding of nAMD and 22,126 matched controls without AMD identified between 2008 and 2017. Any metformin use was associated with an adjusted odds ratio of 0.84 for new-onset nAMD, with the largest magnitude in the mid-dose range (271 to 600 g; adjusted odds ratio, 0.73). Among patients with diabetes, the associations persisted (adjusted odds ratios 0.83, 0.72, and 0.85 for any metformin use, 271 to 600 g, and >1,080 g, respectively). Reduced odds were seen in patients with diabetes without retinopathy (adjusted odds ratio, 0.79), but the association was absent in those with retinopathy. The authors wrote that “metformin’s widespread availability and low-risk side-effect profile may make it a promising addition for preventing or managing nAMD.”

A third study, published in BMJ Open Ophthalmology, reported that metformin use was associated with a lower incidence of intermediate AMD over five years among patients with type 2 diabetes. The population-based study used data from the Individualized Screening for Diabetic Retinopathy (ISDR) study in Liverpool, UK, and graded AMD directly from color fundus photographs using a modified Age-Related Eye Disease Study system. Among 2,089 patients with gradable images at five-year follow-up, 836 were prescribed metformin at baseline and during follow-up, while 1,253 were not. After adjusting for confounders such as age, sex, diabetic retinopathy status, glycemic control, and diabetes duration, metformin use was associated with a 37% lower incidence of intermediate AMD over five years. However, metformin was not associated with reduced incidence of early AMD or with progression from early or intermediate AMD to late AMD, and the number of patients who developed late AMD was relatively small, which limited the ability to detect meaningful differences in advanced disease outcomes.

The researchers across these studies emphasized that the findings remain observational and cannot establish causality. The BMJ Open Ophthalmology study noted that multiple meta-analyses have reported modest associations between metformin exposure and reduced odds of AMD, but most prior studies relied on administrative data sources prone to misclassification—particularly for intermediate AMD, which may be asymptomatic and inconsistently documented in routine care. The authors of that study concluded that the findings support prospective clinical trials evaluating metformin as a potential intervention to reduce AMD progression prior to vision-threatening disease.