Jindal Darren A, Hanna Jovana, Shaia Jacqueline K, Markle Jonathan, Rachitskaya Aleksandra, Kaelber David C, Singh Rishi P, Talcott Katherine E
Case Western Reserve University School of Medicine, Cleveland, Ohio.
College of Medicine, Northeast Ohio Medical University, Rootstown.
JAMA Ophthalmol. 2025 Sep 18. doi: 10.1001/jamaophthalmol.2025.3070.
Metformin has demonstrated protective effects in systemic diseases, including cancer, cardiovascular disease, and retinal diseases, such as diabetic retinopathy and choroidal neovascularization. Literature suggests metformin may reduce the risk of age-related macular degeneration (AMD), but a consensus has not been reached.
To evaluate the association of metformin with the development of any AMD and progression to geographic atrophy and neovascular AMD using a large electronic health record (EHR) platform.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study had 2 exposed cohorts of participants aged 65 years or older who were prescribed metformin: one without AMD to assess development of any AMD and the other with mild or moderate nonexudative AMD to evaluate AMD progression to geographic atrophy or neovascular AMD. Corresponding nonexposed cohorts consisted of participants not prescribed metformin. Participants were required to meet inclusion criteria at least 6 months before the outcome of interest occurred. Those who had outcomes of interest before meeting inclusion criteria were excluded from analysis. This cohort study used a federated health research platform aggregating deidentified EHR data from 70 institutions (TriNetX). Data were collected from January 2013 to June 2025 and analyzed from September 2024 to June 2025.
Participants prescribed metformin.
Propensity score matching controlled for confounders, such as age, sex, race, hypertension, diabetes, and other systemic conditions. Risk ratios (RRs) with 95% CIs were calculated to compare outcomes at 5 years, 10 years, and any time after meeting criteria. Any confidence intervals that crossed 0.90 to 1.10 were considered statistically not significant. Comparisons between exposed and unexposed groups were repeated requiring a diagnosis of cataract.
Before propensity score matching, cohort 1 (no AMD) included 297 008 participants exposed to metformin (mean [SD] age, 74.9 [7.0] years; 157 584 [53.1%] female) and 1 269 644 participants unexposed to metformin (mean [SD] age, 76.8 [7.9] years; 738 640 [58.2%] female). Before propensity score matching in cohort 2 (early or intermediate nonexudative AMD), there were 12 843 participants exposed to metformin (mean [SD] age, 79.5 [7.2] years; 7107 [55.3%] female) and 77 279 participants unexposed to metformin (mean [SD] age, 81.6 [7.2] years; 48 491 [62.7%] female). After propensity score matching, participants prescribed metformin had comparable risk of developing any AMD relative to those not prescribed metformin (RR, 0.90; 95% CI, 0.86-0.94). When stratified by time, the risk remained similar at 5 years (RR, 0.94; 95% CI, 0.90-0.99) and 10 years (RR, 0.91; 95% CI, 0.87-0.94). Similarly, participants prescribed vs not prescribed metformin had a comparable risk of AMD progression over these time spans (RR for geographic atrophy, 0.87; 95% CI, 0.76-1.01; RR for neovascular AMD, 1.03; 95% CI, 0.91-1.17).
This study suggests that, overall, metformin is not associated with significant development or progression of AMD. Further studies and prospective analyses are necessary to evaluate whether dosage and longevity of metformin use are associated with AMD development or progression.
二甲双胍已在包括癌症、心血管疾病以及视网膜疾病（如糖尿病性视网膜病变和脉络膜新生血管形成）等全身性疾病中显示出保护作用。文献表明二甲双胍可能会降低年龄相关性黄斑变性（AMD）的风险，但尚未达成共识。
使用大型电子健康记录（EHR）平台评估二甲双胍与任何类型AMD的发生以及进展为地图状萎缩和新生血管性AMD之间的关联。
设计、设置和参与者：这项队列研究有2个暴露队列，参与者为65岁及以上且被开具二甲双胍处方的人群：一个队列无AMD，以评估任何类型AMD的发生情况；另一个队列患有轻度或中度非渗出性AMD，以评估AMD进展为地图状萎缩或新生血管性AMD的情况。相应的非暴露队列由未被开具二甲双胍处方的参与者组成。参与者在感兴趣的结局发生前至少6个月需符合纳入标准。在符合纳入标准之前出现感兴趣结局的参与者被排除在分析之外。这项队列研究使用了一个联合健康研究平台，该平台汇总了来自70个机构（TriNetX）的去识别化EHR数据。数据收集时间为2013年1月至2025年6月，分析时间为2024年9月至2025年6月。
被开具二甲双胍处方的参与者。
倾向评分匹配用于控制混杂因素，如年龄、性别、种族、高血压、糖尿病和其他全身性疾病。计算5年、10年以及符合标准后的任何时间的风险比（RR）及其95%置信区间（CI），以比较结局。任何跨越0.90至1.10的置信区间被认为在统计学上无显著差异。在需要诊断白内障的情况下，重复暴露组与未暴露组之间的比较。
在倾向评分匹配之前，队列1（无AMD）包括297008名暴露于二甲双胍的参与者（平均[标准差]年龄，74.9[7.0]岁；157584[53.1%]为女性）和1269644名未暴露于二甲双胍的参与者（平均[标准差]年龄，76.8[7.9]岁；738640[58.2%]为女性）。在队列2（早期或中期非渗出性AMD）倾向评分匹配之前，有12843名暴露于二甲双胍的参与者（平均[标准差]年龄，79.5[7.2]岁；7107[55.3%]为女性）和77279名未暴露于二甲双胍的参与者（平均[标准差]年龄，81.6[7.2]岁；48491[62.7%]为女性）。倾向评分匹配后，被开具二甲双胍处方的参与者与未被开具二甲双胍处方的参与者相比，发生任何类型AMD的风险相当（RR，0.90；95%CI，0.86 - 0.94）。按时间分层时，5年时风险仍相似（RR，0.94；95%CI，0.90 - 0.99），10年时风险也相似（RR，0.91；95%CI，0.87 - 0.94）。同样，在这些时间段内，被开具与未被开具二甲双胍处方的参与者发生AMD进展的风险相当（地图状萎缩的RR，0.87；95%CI，0.76 - 1.01；新生血管性AMD的RR，1.03；95%CI，0.91 - 1.17）。
本研究表明，总体而言，二甲双胍与AMD的显著发生或进展无关。需要进一步的研究和前瞻性分析来评估二甲双胍的使用剂量和时长是否与AMD的发生或进展相关。
