Cai Cindy X, Hribar Michelle, Baxter Sally, Goetz Kerry, Swaminathan Swarup S, Flowers Alexis, Brown Eric N, Toy Brian, Xu Benjamin, Chen John, Chen Aiyin, Wang Sophia, Lee Cecilia, Leng Theodore, Ehrlich Joshua R, Barkmeier Andrew, Armbrust Karen R, Boland Michael V, Dorr David, Boyce Danielle, Alshammari Thamir, Swerdel Joel, Suchard Marc A, Schuemie Martijn, Bu Fan, Sena Anthony G, Hripcsak George, Nishimura Akihiko, Nagy Paul, Falconer Thomas, DuVall Scott L, Matheny Michael, Viernes Benjamin, O'Brien William, Zhang Linying, Martin Benjamin, Westlund Erik, Mathioudakis Nestoras, Fan Ruochong, Wilcox Adam, Lai Albert, Stocking Jacqueline C, Takkouche Sahar, Lee Lok Hin, Xie Yangyiran, Humes Izabelle, McCoy David B, Adibuzzaman Mohammad, Areaux Raymond G, Rojas-Carabali William, Brash James, Lee David A, Weiskopf Nicole G, Mawn Louise, Agrawal Rupesh, Morgan-Cooper Hannah, Desai Priya, Ryan Patrick B
Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland.
Biomedical Informatics and Data Science, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
JAMA Ophthalmol. 2025 Apr 1;143(4):304-314. doi: 10.1001/jamaophthalmol.2024.6555.
Semaglutide, a glucagonlike peptide-1 receptor agonist (GLP-1RA), has recently been implicated in cases of nonarteritic anterior ischemic optic neuropathy (NAION), raising safety concerns in the treatment of type 2 diabetes (T2D).
To investigate the potential association between semaglutide and NAION in the Observational Health Data Sciences and Informatics (OHDSI) network.
DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective study across 14 databases (6 administrative claims and 8 electronic health records). Included were adults with T2D taking semaglutide, other GLP-1RA (dulaglutide, exenatide), or non-GLP-1RA medications (empagliflozin, sitagliptin, glipizide) from December 1, 2017, to December 31, 2023. The incidence proportion and rate of NAION were calculated. Association between semaglutide and NAION was assessed using 2 approaches: an active-comparator cohort design comparing new users of semaglutide with those taking other GLP-1RAs and non-GLP-1RA drugs, and a self-controlled case-series (SCCS) analysis to compare individuals' risks during exposure and nonexposure periods for each drug. The cohort design used propensity score-adjusted Cox proportional hazards models to estimate hazard ratios (HRs). The SCCS used conditional Poisson regression models to estimate incidence rate ratios (IRRs). Network-wide HR and IRR estimates were generated using a random-effects meta-analysis model.
GLP-1RA and non-GLP-1RAs.
NAION under 2 alternative definitions based on diagnosis codes: one more inclusive and sensitive, the other more restrictive and specific.
The study included 37.1 million individuals with T2D, including 810 390 new semaglutide users. Of the 43 620 new users of semaglutide in the Optum's deidentified Clinformatics Data Mart Database, 24 473 (56%) were aged 50 to 69 years, and 26 699 (61%) were female. The incidence rate of NAION was 14.5 per 100 000 person-years among semaglutide users. The HR for NAION among new users of semaglutide was not different compared with that of the non-GLP-1RAs using the sensitive NAION definition-empagliflozin (HR, 1.44; 95% CI, 0.78-2.68; P = .12), sitagliptin (HR, 1.30; 95% CI, 0.56-3.01; P = .27), and glipizide (HR, 1.23; 95% CI, 0.66-2.28; P = .25). The risk was higher only compared with patients taking empagliflozin (HR, 2.27; 95% CI, 1.16-4.46; P = .02) using the specific definition. SCCS analysis of semaglutide exposure showed an increased risk of NAION (meta-analysis IRR, 1.32; 95% CI, 1.14-1.54; P < .001).
Results of this study suggest a modest increase in the risk of NAION among individuals with T2D associated with semaglutide use, smaller than that previously reported, and warranting further investigation into the clinical implications of this association.
司美格鲁肽是一种胰高血糖素样肽-1受体激动剂（GLP-1RA），最近有病例显示其与非动脉炎性前部缺血性视神经病变（NAION）有关，这引发了对2型糖尿病（T2D）治疗安全性的担忧。
在观察性健康数据科学与信息学（OHDSI）网络中研究司美格鲁肽与NAION之间的潜在关联。
设计、设置和参与者：这是一项对14个数据库（6个行政索赔数据库和8个电子健康记录数据库）进行的回顾性研究。纳入的是2017年12月1日至2023年12月31日期间服用司美格鲁肽、其他GLP-1RA（度拉鲁肽、艾塞那肽）或非GLP-1RA药物（恩格列净、西他列汀、格列吡嗪）的T2D成人患者。计算了NAION的发病比例和发病率。使用两种方法评估司美格鲁肽与NAION之间的关联：一种是活性对照队列设计，将司美格鲁肽新使用者与服用其他GLP-1RA和非GLP-1RA药物的使用者进行比较；另一种是自我对照病例系列（SCCS）分析，比较个体在每种药物暴露期和非暴露期的风险。队列设计使用倾向评分调整的Cox比例风险模型来估计风险比（HRs）。SCCS使用条件泊松回归模型来估计发病率比（IRRs）。使用随机效应荟萃分析模型生成全网络的HR和IRR估计值。
GLP-1RA和非GLP-1RA药物。
基于诊断代码的两种替代定义下的NAION：一种更具包容性和敏感性，另一种更具限制性和特异性。
该研究纳入了3710万T2D患者，其中包括810390名司美格鲁肽新使用者。在Optum的去识别化临床信息数据集市数据库中，43620名司美格鲁肽新使用者中，24473名（56%）年龄在50至69岁之间，26699名（61%）为女性。司美格鲁肽使用者中NAION的发病率为每10万人年14.5例。使用敏感的NAION定义时，司美格鲁肽新使用者中NAION的HR与非GLP-1RA药物使用者相比无差异——恩格列净（HR，1.44；95%CI，0.78 - 2.68；P = 0.12）、西他列汀（HR，1.30；95%CI，0.56 - 3.01；P = 0.27）和格列吡嗪（HR，1.23；95%CI，0.66 - 2.28；P = 0.25）。仅在使用特异性定义时，与服用恩格列净的患者相比风险更高（HR，2.27；95%CI，1.16 - 4.46；P = 0.02）。司美格鲁肽暴露的SCCS分析显示NAION风险增加（荟萃分析IRR，1.32；95%CI，1.14 - 1.54；P < 0.001）。
本研究结果表明，T2D患者中与使用司美格鲁肽相关的NAION风险有适度增加，比先前报道的要小，有必要进一步研究这种关联的临床意义。
