Association of Metformin With the Development of Age-Related Macular Degeneration

Abstract

ImportanceAge-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.ObjectiveTo investigate the association between metformin use and age-related macular degeneration (AMD).Design, Setting, and ParticipantsThe 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.InterventionsParticipants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo.Main Outcomes and MeasuresPrevalence of AMD in the treatment arms.ResultsOf 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 [9] 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 RelevanceThese 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 Degeneration in the Diabetes Prevention Program Outcomes Study

“…Additional limitations include a lack of actual measurement of data for possible confounding factors, such as family history, relevant genetic information, pertinent medication history that might be associated with macular abnormalities, or cardiovascular factors. We wonder if these numerous limitations weaken the confidence of the authors’ conclusion that their investigation of metformin use does not affect the prevalence of AMD in this population.…”

“…More than half of all participants had diabetes at the time of the AMD evaluation based on fundus photographs and spectral-domain ocular coherence tomography images. The authors conclude that the risk for AMD was not less among patients who were taking metformin, had intensive lifestyle interventions, or taking placebo.…”

“…One limitation of this investigation was that the participants did not undergo a previous ophthalmological study. The authors considered that the prevalence of AMD before starting the study was the same between the groups; however, we cannot know that for certain. It is possible that an unknown number of these patients had undiagnosed AMD prior to randomization?…”

“…To the Editor We read with interest the article “Association of Metformin With the Development of Age-Related Macular Degeneration” by Domalpally et al The association between metformin use and the development of age-related macular degeneration (AMD) was evaluated in the Diabetes Prevention Program trial participants approximately 16 years after the trial completion. More than half of all participants had diabetes at the time of the AMD evaluation based on fundus photographs and spectral-domain ocular coherence tomography images.…”

Association of Metformin With the Development of Age-related Macular Degeneration in the Diabetes Prevention Program Outcomes Study—Reply

“…In Reply We thank Asensio-Sánchez for sharing his thoughts and appreciate the opportunity to respond to the comments. Asensio-Sánchez has accurately interpreted that this is the first time in the Diabetes Prevention Program Outcomes Study that age-related macular degeneration (AMD) assessment was performed; therefore, one cannot hypothesize on the prevalence or stage of AMD before the images were acquired . The prevalence reported is for the current visit and does not account for previous time points.…”