Association of Metformin Use With Age-Related Macular Degeneration

Abstract

IMPORTANCE Age-related macular degeneration (AMD), the leading cause of irreversible blindness in older adults, appears to have no effective preventive measures. The common antidiabetic drug metformin has been shown to have protective outcomes in multiple age-associated diseases and may have the potential to protect against the development of AMD.OBJECTIVE To determine whether metformin use is associated with reduced odds of developing AMD. DESIGN, SETTING, AND PARTICIPANTSThis case-control study of patients from a nationwide health insurance claims database included a population-based sample of patients. Those aged 55 years and older with newly diagnosed AMD from January 2008 to December 2017 were defined as cases and matched with control participants. Data analyses were completed from June 2019 to February 2020.EXPOSURES Dosage of metformin and exposure to other prescribed medications, as identified from outpatient drug claims. MAIN OUTCOMES AND MEASURES Risk of developing AMD.RESULTS A total of 312 404 affected individuals were included (181 817 women [58.2%]). After matching, 312 376 control participants were included (172 459 women [55.2%]; age range, 55 to 107 years). The case group had a slightly higher percentage of participants with diabetes (81 262 participants [26.0%]) compared with the control group (79 497 participants [25.5%]). Metformin use was associated with reduced odds of developing AMD (odds ratio [OR], 0.94 [95% CI, 0.92-0.96]). This association was dose dependent, with low to moderate doses of metformin showing the greatest potential benefit (dosages over 2 years: 1-270 g, OR, 0.91 [95% CI, 0.88-0.94]; 271-600 g, OR, 0.90 [95% CI, 0.87-0.93]; 601-1080 g, OR, 0.95 [95% CI, 0.92-0.98]). Doses of more than 1080 g of metformin over 2 years did not have reduced odds of developing AMD. Both the reduction in odds ratio and the dose-dependent response were preserved in a cohort consisting only of patients with diabetes. Metformin use was associated with a decreased OR of AMD in patients with diabetes without coexisting diabetic retinopathy (OR, 0.93 [95% CI, 0.91-0.95]) but was a risk factor in patients with diabetic retinopathy (OR, 1.07 [95% CI,).CONCLUSION AND RELEVANCE In this study, metformin use was associated with reduced odds of developing AMD. This association was dose dependent, with the greatest benefit at low to moderate doses. When looking only at patients with diabetes, we saw a preservation of the dose-dependent decrease in the odds of patients developing AMD. Metformin does not appear to be protective in patients with diabetes and coexisting diabetic retinopathy. This study suggests that metformin may be useful as a preventive therapy for AMD and provides the basis for potential prospective clinical trials.

Long-Term Oral Treatment with Non-Hypoglycemic Dose of Glibenclamide Reduces Diabetic Retinopathy Damage in the Goto-KakizakiRat Model

“…Our study also indicates that glibenclamide, particularly if formulated for ocular delivery, could be used for other degenerative retinal diseases associated with oxidative stress, inflammation and inflammasome activation, such as age-related macular degeneration (AMD). Recently, metformin was found to potentially reduce the incidence of AMD in large, retrospective studies [51] that need to be interpreted with caution [52]. Taking into account the fact that no treatment is currently available to prevent or delay retinal degeneration, the effects of old and known drugs with a known safety profile could be evaluated in treated patients that are affected by retinal diseases that induce rapid retinal cell death, such as retinal detachment [53].…”

Metformin, A Potential Role in Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis

“…The overall OR of any AMD from metformin use was 0.80 with 95% CI 0.54-1.05. In a sensitivity analysis, the OR remained stable and the upper limit of the confidence interval remained close to 1.0, affecting the statistical significance (removing study by Blitzer et al [34]: OR 0.75, 95% CI 0.52-0.97, P \ 0.001, I 2 = 87.1%; Stewart et al [33]: OR 0.82, 95% CI 0.53-1.12, P \ 0.001, I 2 = 99.1%; Brown et al [32]: OR 0.82, 95% CI 0.54-1.11, P \ 0.001, I 2 = 99.1%; Chen et al [35]: OR 0.87, 95% CI 0.70-1.05, P = 0.002, I 2 = 79.7%; Lee et al [36]: 0.72, 95% CI 0.44-1.01, P \ 0.001, I 2 = 99.1%).…”

“…The third study in the USA [34] used data of 624,780 patient records (312,404 AMD and 312,376 non-AMD) of people aged 55 years and older who had eye examinations at least two times during the previous 12 months from IBM MarketScan Commercial and Medicare Supplemental Databases from January 2008 to December 2017. In multivariable logistic regression analysis, the use of metformin was reported to slightly lower the odds of having any AMD in a whole study population (OR 0.94; 95% CI 0.92-0.96, P \ 0.001) and in a subgroup of people with diabetes (OR 0.95; 95% CI 0.93-0.97, P \ 0.001).…”

“…1 PRISMA flowchart of study selection process We identified that there are no published prospective studies that have investigated metformin in AMD. Only two studies in the metaanalysis presented the association of metformin and AMD in people with and without diabetes [32,34] and one study in people with diabetes or cardiovascular disease [36]. A phase 2 randomized clinical trial study began in 2016 to investigate the effects of metformin on the progression of geographic atrophy and drusen in AMD in patients without diabetes initiated by University of California; no data or results have been reported (ClinicalTrials.gov Identifier NCT02684578).…”

“…We performed a meta-analysis for the association of metformin and any AMD in people with diabetes. We could not generalize the results in people without diabetes, as only two studies reported data in this group [32,34]. We analysed 'any AMD' since all studies included all AMD, not only atrophic and neovascular AMD, but also unspecified form of macular degeneration (Supplementary Material B).…”