New research suggests that metformin use doesn’t have a protective effect against AMD. Photo: Carolyn Majcher, OD. Click image to enlarge.

Various retrospective studies have suggested that metformin, a drug often prescribed to treat patients with type 2 diabetes, could potentially have a protective effect against the development or progression of age-related macular degeneration (AMD). However, evidence from a new study reports this may not be the case. The researchers analyzed participants with over 20 years of follow-up data involved in the Diabetes Prevention Program Outcomes Study. In their paper on the findings published recently in JAMA Ophthalmology, they concluded that neither long-term metformin use nor lifestyle changes initiated for diabetes prevention seemed to be associated with a risk of any form of AMD.¹

The longitudinal Diabetes Prevention Program Outcomes Study included 2,776 participants at high risk of developing type 2 diabetes, 1,592 of whom had retinal imaging available and were included in this analysis. Participants were randomly distributed between three treatment arms: lifestyle (32.3%), metformin (34.5%) and placebo (33.2%). Lifestyle intervention focused on achieving at least 150 minutes of physical activity weekly and at least a 7% body weight loss. Participants in the metformin group received 850mg of the drug twice daily with standard diet and exercise recommendations Those in the placebo arm received placebo pills twice daily with standard diet and exercise recommendations. Baseline characteristics were similar across the groups.

The researchers found that there was no significant difference in AMD prevalence between the three groups (29.6% in the lifestyle arm, 30.2% in the metformin arm and 30.7% in the placebo arm). There was also no difference between groups in the distribution of early, intermediate and advanced AMD.

The mean duration of metformin use was comparable among participants with and without AMD (8.0 vs. 8.5 years on average). The researchers noted in their paper that “in the multivariate models, history of smoking was associated with increased risks of AMD (odds ratio: 1.3).”¹

The authors of a commentary on the study’s findings, which was also published recently in JAMA Ophthalmology, pointed out several advantages of the study’s design.² “Some of the previous observational metformin-AMD studies included patients without diabetes (and, hence, a near-zero chance of receiving metformin),” the commentary authors wrote. “This introduced a potential source of confounding bias due to the systematic differences between exposure groups (i.e., between patients with and without a history of metformin use).” They suggested in their paper that given the advantages of this particular study, which include a well-characterized cohort and standardized grading of retinal images, “healthcare practitioners and researchers are likely to note with interest the lack of an association detected between metformin and AMD.”²

The researchers concluded that there was no association between metformin use and the presence or severity of AMD, nor between metformin use duration and AMD presence or severity. Surprisingly, implementing health-promoting lifestyle changes (physical activity and weight loss) also did not seem to affect the risk of any form of AMD in this study.

“Until randomized data are available, the Diabetes Prevention Program Outcomes Study provides strong evidence that does not support the use of metformin in the treatment of any stage of AMD,” the study authors concluded in their paper.¹

1. Domalpally A, Whittier SA, Pan Q, et al. Association of metformin with the development of age-related macular degeneration. JAMA Ophthalmol. December 22, 2022. [Epub ahead of print]. 2. McGuinness MB, Abbott CJ. Choosing analysis methods to match estimands when investigating interventions for macular disease. JAMA Ophthalmol. December 22, 2022. [Epub ahead of print].