阿尔茨海默氏症的突破：流行的糖尿病药物与更低的风险有关

诸平

Fig. 1 Researchers have discovered that semaglutide, a diabetes and weight-loss medication sold under the brand names Wegovy and Ozempic, might significantly reduce the risk of Alzheimer’s in type 2 diabetes patients.

Fig. 2 Rong Xu. Credit: Case Western Reserve University

据美国凯斯西储大学（Case Western Reserve University, Cleveland, Ohio, USA）2024年10月27日提供的消息，阿尔茨海默氏症的突破：流行的糖尿病药物索马鲁肽与更低的风险有关（Alzheimer’s Breakthrough: Popular Diabetes Drug Ozempic Linked to Much Lower Risk）。

塞马格鲁肽（Semaglutide）是一种用于治疗2型糖尿病（type 2 diabetes简称T2D）的荷尔蒙药物，通过模拟人体胰岛素的作用来降低血糖。但是，它也可以降低2型糖尿病(T2D)患者患阿尔茨海默氏症风险，研究表明，与其他糖尿病药物相比，塞马格鲁肽具有显著的保护作用。相关研究结果于2024年10月24日已经在《阿尔茨海默症与痴呆症》（Alzheimer’s & Dementia）杂志网站在线发表——William Wang, QuangQiu Wang, Xin Qi, Mark Gurney, George Perry, Nora D. Volkow, Pamela B. Davis, David C. Kaelber, Rong Xu. Associations of semaglutide with first-time diagnosis of Alzheimer’s disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US. Alzheimer’s & Dementia, 24 October 2024. DOI: 10.1002/alz.14313. First published: 24 October 2024. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.14313

参与此项研究的有来自美国凯斯西储大学医学院（Case Western Reserve University School of Medicine, Cleveland, Ohio, USA）、美国德克萨斯大学圣安东尼奥分校(The University of Texas at San Antonio, San Antonio, Texas, USA)、美国国立卫生研究院国家药物滥用研究所（National Institute on Drug Abuse, National Institutes of Health, Maryland, USA）、美国都市卫生系统临床信息学研究与教育中心(Center for Clinical Informatics Research and Education, The MetroHealth System, Ohio, USA)的研究人员。

凯斯西储大学医学院等机构的研究人员发现，与其他7种抗糖尿病药物相比，塞马格鲁肽（semaglutide）可以降低2型糖尿病（T2D）患者患阿尔茨海默病（Alzheimer ' s disease）的风险。塞马格鲁肽是一种常用的糖尿病和减肥药物。

阿尔茨海默氏症是一种进化性的大脑疾病，逐渐损害记忆和认知能力。根据阿尔茨海默氏症协会（Alzheimer’s Association）的数据，目前有近700万65岁及以上的美国人患有这种疾病，每年导致的死亡人数超过乳腺癌和前列腺癌死亡人数之合。

研究结果及影响（Study Findings and Implications）

发表于阿尔茨海默氏症协会杂志《阿尔茨海默病与痴呆症》（Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association）的研究表明，服用塞马格鲁肽的T2D患者患阿尔茨海默氏症的风险显著降低。这种效果在不同的亚组中一致观察到，包括肥胖状况、性别和年龄的差异。

塞马格鲁肽（Semaglutide）作用于胰高血糖素样肽受体{glucagon-like peptide receptor, GLP-1R}，抑制饥饿感，调节T2D血糖，也是糖尿病减肥药Wegovy和Ozempic的活性成分。

由生物医学信息学教授徐蓉（Rong Xu音译）领导的研究小组，分析了近100万美国T2D患者3年的电子记录。研究人员使用了一种模拟随机临床试验的统计方法。

他们发现，与服用其他7种抗糖尿病药物——包括其他类型的GLP - 1R靶向药物（GLP-1R-targeting medications）——的患者相比，服用塞马格鲁肽的患者患阿尔茨海默病的风险明显降低。

根据美国疾病控制与预防中心（CDC）的数据，每年约有12万美国人死于阿尔茨海默病，该疾病被列为美国第七大死因。

徐蓉说，这项新的研究为其对阿尔茨海默病的影响提供了现实世界的证据，尽管临床前研究表明，塞马格鲁肽可能会预防神经变性和神经炎症。徐蓉同时也是凯斯西储大学医学院药物发现人工智能中心（medical school’s Center for AI in Drug Discovery, Case Western Reserve University）的主任，也是凯斯西储大学医学院凯斯癌症综合中心癌症基因组学表观基因组学项目（Cancer Genomics Epigenomics Program at the Case Cancer Comprehensive Center, School of Medicine, Case Western Reserve University）的成员。

思考与未来研究（Considerations and Future Research）

她说，尽管他们的发现可能支持了塞马格鲁肽可以预防阿尔茨海默病的观点，但这项研究的局限性限制了研究人员得出确切的因果结论。

“我们的研究结果表明，需要通过随机临床试验进一步研究塞马格鲁肽的使用，以便测试替代药物作为这种使人衰弱的疾病的潜在治疗方法，”徐蓉说。

本研究得到了美国国立卫生研究院下属的美国国家老龄化研究所{National Institute on Aging(NIA) AG057557 AG061388 AG062272 AG076649/AG/NIA NIH HHS/United States; R01 AG076051/AG/NIA NIH HHS/United States; RF1 AG074346/AG/NIA NIH HHS/United States; R01 AG065240/AG/NIA NIH HHS/United States}和美国国家促进转化科学中心{National Center for Advancing Translational Sciences (NCATS) TR004528/TR/NCATS NIH HHS/United States}的支持或资助。

上述介绍，仅供参考。欲了解更多信息，敬请注意浏览原文或者相关报道。

Abstract

Introduction: Emerging preclinical evidence suggests that semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA) for type 2 diabetes mellitus (T2DM) and obesity, protects against neurodegeneration and neuroinflammation. However, real-world evidence for its ability to protect against Alzheimer's disease (AD) is lacking.

Methods: We conducted emulation target trials based on a nationwide database of electronic health records (EHRs) of 116 million US patients. Seven target trials were emulated among 1,094,761 eligible patients with T2DM who had no prior AD diagnosis by comparing semaglutide with seven other antidiabetic medications. First-ever diagnosis of AD occurred within a 3-year follow-up period and was examined using Cox proportional hazards and Kaplan-Meier survival analyses.

Results: Semaglutide was associated with significantly reduced risk for first-time AD diagnosis, most strongly compared with insulin (hazard ratio [HR], 0.33 [95% CI: 0.21 to 0.51]) and most weakly compared with other GLP-1RAs (HR, 0.59 [95% CI: 0.37 to 0.95]). Similar results were seen across obesity status, gender, and age groups.

Discussion: These findings support further studies to assess semaglutide's potential in preventing AD.

Highlights: Semaglutide was associated with 40% to 70% reduced risks of first-time AD diagnosis in T2DM patients compared to other antidiabetic medications, including other GLP-1RAs. Semaglutide was associated with significantly lower AD-related medication prescriptions. Similar reductions were seen across obesity status, gender, and age groups. Our findings provide real-world evidence supporting the potential clinical benefits of semaglutide in mitigating AD initiation and development in patients with T2DM. These findings support further clinical trials to assess semaglutide's potential in delaying or preventing AD.