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

Abstract

Importance: 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.

Objective: 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.

Interventions: Participants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo.

Main outcomes and measures: Prevalence of AMD in the treatment arms.

Results: 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 [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 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.

Figure 1.. Distribution of Age-Related Macular Degeneration Severity in the 3 Study Arms

There was no significant difference in age-related macular degeneration presence or severity between intensive lifestyle (ILS), metformin, and placebo arms.

Figure 2.. Association Between DPP Baseline Characteristics and Diabetes Prevention Program Outcomes Study Retinal Imaging Visit Characteristics With Prevalence of Age-Related Macular Degeneration

SI conversion factors: To convert glucose to millimoles per liter, multiply by 0.0555; hemoglobin to proportion of total hemoglobin, multiply by 0.01. Forest plot of logistic regression adjusting for demographic information and treatment. Log (odds ratio [OR]) vs reference category or per sample SD change for continuous measures. ACE indicates angiotensin-converting enzyme; BMI, body mass index, DPP, Diabetes Prevention Program; HbA_1c, hemoglobin A1_c.