Lin Huan-Tang, Tsai Yung-Fong, Liao Pei-Lun, Wei James Cheng-Chung
Department of Anesthesiology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
College of Medicine, Chang Gung University, Taoyuan, Taiwan.
JAMA Netw Open. 2025 Jul 1;8(7):e2521016. doi: 10.1001/jamanetworkopen.2025.21016.
Glucagon-like peptide 1 receptor agonists (GLP-1RAs), such as semaglutide and tirzepatide, provide cardiometabolic benefits to patients with type 2 diabetes and obesity, but their potential benefits in mitigating neurodegenerative and cerebrovascular diseases remain unclear.
To evaluate the association of semaglutide and tirzepatide with the incidence of dementia, Parkinson disease, ischemic stroke, intracerebral hemorrhage, and all-cause mortality compared with other antidiabetic drugs in adults with type 2 diabetes and obesity.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study analyzed electronic health record-based data from the TriNetX US network (December 1, 2017, to June 30, 2024) in adults aged 40 years or older with type 2 diabetes and obesity initiating semaglutide, tirzepatide, or other antidiabetic drugs, excluding those with prior neurodegenerative or cerebrovascular diseases. Propensity score matching was used to balance the baseline characteristics.
Patients treated with antidiabetic drugs were categorized as GLP-1RA (semaglutide or tirzepatide) or other antidiabetic drug (biguanides, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, thiazolidinediones, and α-glucosidase inhibitors) users.
The primary outcomes were the incidence of neurodegenerative diseases (dementia, Parkinson disease, and mild cognitive impairment) and cerebrovascular (stroke and intracerebral hemorrhage) diseases, while the secondary outcome was all-cause mortality. Cox proportional hazard models were used to estimate hazard ratios (HRs) with 95% CIs.
A total of 60 860 adults with type 2 diabetes and obesity were included, with 30 430 each in the GLP-1RA group (mean [SD] age, 57.9 [9.9] years; 50.2% female) and the other antidiabetic drug group (mean [SD] age, 58.0 [10.8] years; 51.4% female) after propensity score matching. During a 7-year follow-up, GLP-1RA users had a lower risk of dementia (HR, 0.63; 95% CI, 0.50-0.81), stroke (HR, 0.81; 95% CI, 0.70-0.93), and all-cause mortality (HR, 0.70; 95% CI, 0.63-0.78), with no significant differences in the risk of Parkinson disease or intracerebral hemorrhage. Subgroup analyses revealed greater benefits in patients aged 60 years or older, women, and patients with a body mass index of 30 to 40.
In this cohort study, the use of GLP-1RAs semaglutide and tirzepatide was associated with a lower risk of dementia, stroke, and all-cause mortality in adults with type 2 diabetes and obesity. These findings suggest potential neuroprotective and cerebrovascular benefits of GLP-1RAs beyond glycemic control, warranting further trials to confirm these outcomes.
胰高血糖素样肽1受体激动剂（GLP-1RAs），如司美格鲁肽和替尔泊肽，可为2型糖尿病和肥胖患者带来心脏代谢方面的益处，但其在减轻神经退行性疾病和脑血管疾病方面的潜在益处仍不明确。
评估与其他抗糖尿病药物相比，司美格鲁肽和替尔泊肽与2型糖尿病和肥胖成人患者患痴呆症、帕金森病、缺血性中风、脑出血及全因死亡率的关联。
设计、设置和参与者：这项回顾性队列研究分析了TriNetX美国网络（2017年12月1日至2024年6月30日）中基于电子健康记录的数据，研究对象为40岁及以上开始使用司美格鲁肽、替尔泊肽或其他抗糖尿病药物的2型糖尿病和肥胖成人患者，排除既往有神经退行性或脑血管疾病的患者。采用倾向评分匹配法平衡基线特征。
接受抗糖尿病药物治疗的患者被分为GLP-1RA（司美格鲁肽或替尔泊肽）使用者或其他抗糖尿病药物（双胍类、磺脲类、二肽基肽酶4抑制剂、钠-葡萄糖协同转运蛋白2抑制剂、噻唑烷二酮类和α-葡萄糖苷酶抑制剂）使用者。
主要结局为神经退行性疾病（痴呆症、帕金森病和轻度认知障碍）和脑血管疾病（中风和脑出血）的发病率，次要结局为全因死亡率。采用Cox比例风险模型估计风险比（HRs）及95%置信区间（CIs）。
共纳入60860例2型糖尿病和肥胖成人患者，倾向评分匹配后，GLP-1RA组和其他抗糖尿病药物组各有30430例（GLP-1RA组平均[标准差]年龄为57.9[9.9]岁，女性占50.2%；其他抗糖尿病药物组平均[标准差]年龄为58.0[10.8]岁，女性占51.4%）。在7年的随访期间，GLP-1RA使用者患痴呆症（HR = 0.63；95%CI，0.50 - 0.81）、中风（HR = 0.81；95%CI，0.70 - 0.93）和全因死亡率（HR = 0.70；95%CI，0.63 - 0.78）的风险较低，帕金森病或脑出血风险无显著差异。亚组分析显示，60岁及以上患者、女性以及体重指数为30至40的患者获益更大。
在这项队列研究中，使用GLP-1RAs司美格鲁肽和替尔泊肽与2型糖尿病和肥胖成人患者患痴呆症、中风和全因死亡率的风险较低相关。这些发现表明GLP-1RAs除血糖控制外可能具有神经保护和脑血管益处，值得进一步试验以证实这些结果。
