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Association of Metformin With the Development of Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is a leading cause of blindness with no treatment available for early stages. Retrospective studies have shown an association between metformin and reduced risk of AMD.
To investigate the association between metformin use and age-related macular degeneration (AMD).
DESIGN, SETTING, AND PARTICIPANTS
The Diabetes Prevention Program Outcomes Study is a cross-sectional follow-up phase of a large multicenter randomized clinical trial, Diabetes Prevention Program (1996-2001), to investigate the association of treatment with metformin or an intensive lifestyle modification vs placebo with preventing the onset of type 2 diabetes in a population at high risk for developing diabetes. Participants with retinal imaging at a follow-up visit 16 years posttrial (2017-2019) were included. Analysis took place between October 2019 and May 2022.
Participants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo.
MAIN OUTCOMES AND MEASURES
Prevalence of AMD in the treatment arms.
Of 1592 participants, 514 (32.3%) were in the lifestyle arm, 549 (34.5%) were in the metformin arm, and 529 (33.2%) were in the placebo arm. All 3 arms were balanced for baseline characteristics including age (mean [SD] age at randomization, 49  years), sex (1128 [71%] male), race and ethnicity (784 [49%] White), smoking habits, body mass index, and education level. AMD was identified in 479 participants (30.1%); 229 (14.4%) had early AMD, 218 (13.7%) had intermediate AMD, and 32 (2.0%) had advanced AMD. There was no significant difference in the presence of AMD between the 3 groups: 152 (29.6%) in the lifestyle arm, 165 (30.2%) in the metformin arm, and 162 (30.7%) in the placebo arm. There was also no difference in the distribution of early, intermediate, and advanced AMD between the intervention groups. Mean duration of metformin use was similar for those with and without AMD (mean [SD], 8.0 [9.3] vs 8.5 [9.3] years; P = .69). In the multivariate models, history of smoking was associated with increased risks of AMD (odds ratio, 1.30; 95% CI, 1.05-1.61; P = .02).
CONCLUSIONS AND RELEVANCE
These data suggest neither metformin nor lifestyle changes initiated for diabetes prevention were associated with the risk of any AMD, with similar results for AMD severity. Duration of metformin use was also not associated with AMD. This analysis does not address the association of metformin with incidence or progression of AMD.
Association of Metformin With the Development of Age-Related Macular DegenerationJAMA Ophthalmol 2022 Dec 22;[EPub Ahead of Print], A Domalpally, SA Whittier, Q Pan, DM Dabelea, CH Darwin, WC Knowler, CG Lee, JA Luchsinger, NH White, EY Chew
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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The authors present a thoughtful and well-designed follow-up study of the Diabetes Prevention Program. They randomly allocated this large subset of patients to three treatment arms (metformin, lifestyle modification, and placebo arms) to identify those at the 16-year follow-up visit with a diagnosis of age-related macular degeneration (AMD) based on fundus photographs and spectral-domain ocular coherence tomography images.
The results demonstrated that there were no significant differences in the prevalence of AMD among the treatment arms. Additionally, smoking is the only risk factor associated with an increased risk of AMD, and the presence of diabetes was not associated with an increased AMD prevalence — an association that has been presented in prior studies with conflicting results.
One of the major limitations of this study, which the authors addressed in their discussion, was that participants in all three treatment arms were permitted to take out-of-study metformin. Although data were collected from the participants regarding their use of in-study and out-of-study metformin, we believe that this is a serious limitation, as metformin use may have differed slightly among the three arms, especially in the lifestyle modification and placebo arms, in which the patients were assumed to be metformin-free for the purposes of this analysis. Additionally, participants were not required to undergo an eye examination prior to the start of the study. The authors assumed that the prevalence of AMD prior to study initiation does not differ between the groups; however, we do not know if this is the case. It is possible that a disproportionate number of these patients had an undiagnosed AMD prior to randomization in each arm, which would undoubtedly affect the results. Our prior study, which the authors cited in their paper, showed statistically significant results suggesting that low-to-moderate metformin use was associated with a decreased risk of AMD development. We acknowledge that this study was well-designed; however, we believe that, owing to the limitations discussed, it does not provide definitive evidence that metformin use does not affect the prevalence of AMD in this population.