既往有证据提示,GLP-1受体激动剂暴露可降低痴呆和阿尔兹海默病风险。《柳叶刀》(The Lancet)发表两项3期、随机、安慰剂对照试验(evoke和evoke+),旨在探究口服司美格鲁肽在早期阿尔兹海默病患者中的有效性和安全性。两项试验共纳入约3800名55-85岁轻度阿尔兹海默病患者,每日口服最多14mg司美格鲁肽或安慰剂。两年后,两组疾病进展无显著差异;四分之一的参与者延长治疗一年,结果仍无差异。在近200名患者的脑脊液亚组中,司美格鲁肽组相关生物标志物水平显著降低,但未转化为疾病进展的减缓。识别文中二维码或点击文末“阅读原文”,查阅原文。《柳叶刀》(The Lancet)发表的3期随机对照试验发现,对于轻度阿尔兹海默病患者而言,口服司美格鲁肽(一种GLP-1口服药)在延缓疾病进展方面无效。针对2型糖尿病和/或肥胖患者开展的早期阶段研究,包括动物实验、观察性研究以及临床试验,均提示GLP-1类药物可能延缓全因痴呆或阿尔兹海默病的进展。EVOKE和EVOKE+试验是首批在早期阿尔兹海默病患者中探究这一可能性的大型3期试验。两项试验共纳入约3800名年龄在55-85岁之间、确诊为阿尔兹海默病且为轻度症状的患者,参与者每日接受最多14mg口服司美格鲁肽或安慰剂。两年后,服用司美格鲁肽的参与者与服用安慰剂的参与者在疾病进展方面无显著差异。四分之一的参与者完成了额外一年的试验,两组间疾病进展仍无差异。在近200名参与者组成的脑脊液样本亚组中,司美格鲁肽组阿尔兹海默病相关生物标志物的脑脊液含量显著降低,但这并未成功转化为对疾病进展的减缓。口服司美格鲁肽14mg(灵活剂量)在早期症状性阿尔兹海默病中的有效性和安全性:两项3期、随机、安慰剂对照试验(evoke和evoke+)背景针对2型糖尿病和/或肥胖患者的各类动物实验、临床研究、真实世界研究证据均提示,GLP-1受体激动剂暴露可降低痴呆和阿尔兹海默病风险。evoke和evoke+试验旨在探究口服司美格鲁肽在早期阿尔兹海默病患者中的有效性和安全性。方法evoke和evoke+是两项多中心、随机、双盲、安慰剂对照的3期试验,共在40个国家的566个中心开展。两项试验旨在针对年龄在55-85岁间,具有轻度认知障碍或轻度痴呆的淀粉样蛋白阳性阿尔茨海默病患者,评估每日口服一次司美格鲁肽(最多14mg)的有效性和安全性。在evoke+试验中,还纳入了存在明显小血管病变的参与者。在两项试验中,参与者被1:1随机分配至每日一次司美格鲁肽14mg(灵活剂量)组或安慰剂组,试验最长持续156周。所有接受随机分配的参与者均进行主要终点指标评估,主要终点是临床痴呆评定量表-评分总和(CDR-SB)从基线至第104周的变化。安全性评估在接受随机分配且接受至少一次给药的参与者中进行。这两项研究已在ClinicalTrials.gov官网上注册,注册编号分别为NCT04777396和NCT04777409。由于临床结果阴性,目前两项试验均已终止。结果2021年5月18日至2023年9月8日期间,共筛选9981名参与者,其中符合条件的3808名接受随机分配。evoke试验共纳入1855名参与者(司美格鲁肽组n=928,安慰剂组n=927),evoke+试验纳入1953名参与者(司美格鲁肽组n=976,安慰剂组n=977)。参与者平均年龄为72.2岁(标准差7.1),基线CDR-SB评分均值为3.7分(标准差1.6)。在evoke+试验中,54名(2.8%)参与者存在小血管病变。在基线至第104周CDR-SB评分的均值变化方面,evoke和evoke+试验中司美格鲁肽组的变化分别为2.3分(标准误0.1)和2.2分(0.1),安慰剂组的变化则分别为2.3分(0.1)和2.1分(0.1)(均值变化的估计差异:evoke试验为-0.08,95% CI:−0.35至0.20,p=0.57;evoke+试验为0.10,95% CI:-0.17至0.38,p=0.46)。在接受司美格鲁肽治疗的1896名参与者中,1729名(91.2%)报告了治疗期间的不良事件;在接受安慰剂治疗的1902名受试者中,1613名(84.8%)报告了治疗期间的不良事件。经研究者认定,有5例死亡与治疗相关,其中司美格鲁肽组1例,安慰剂组4例。图2 从基线到第104周,evoke(A)和evoke+(B)的CDR-SB评分变化图3 从基线到第104周,evoke(A)和evoke+(B)的ADCS-ADL-MCI评分变化解读对于早期阿尔兹海默病患者而言,口服司美格鲁肽在延缓临床进展方面未显示出有效性。司美格鲁肽对于早期阿尔茨哈默病患者的安全性和耐受性与针对其他适应症的研究结果一致。ENDFundingNovo Nordisk.Declaration of interestsJLC has provided consultation to Acadia, Actinogen, Acumen, AlphaCognition, ALZpath, Aprinoia, AriBio, Artery, Biogen, Biohaven, BioVie, Bio X Cel, Bristol-Myers Squib, Cassava, Cerecin, Diadem, Eisai, GAP Foundation, GemVax, Janssen, Jocasta, Karuna, Lighthouse, Lilly, Lundbeck, LSP/eqt, Merck, NervGen, New Amsterdam, Novo Nordisk, Oligomerix, OptoCeutics, Ono, Otsuka, Oxford Brain Diagnostics, Prothena, ReMYND, Roche, Sage Therapeutics, Signant Health, Simcere, Sinaptica, Suven, TrueBinding, Vaxxinity, and Wren pharmaceutical, assessment, and investment companies. He is supported by National Institute of General Medical Sciences grant P20GM109025, National Institute on Aging (NIA) grant R35AG71476, NIA grant R25 AG083721-01, Alzheimer's Disease Drug Discovery Foundation, Ted and Maria Quirk Endowment, and Joy Chambers-Grundy Endowment. AA has, in the last 10 years, served as a consultant or received honoraria or support for consulting; participating in independent data safety monitoring boards; providing educational lectures, programmes, and materials; and serving on advisory boards for AbbVie, Acadia, Allergan, Alzheimer's Disease International, the Alzheimer's Association, AriBio, Axovant, Axsome, AZTherapies, Biogen, Eisai, Grifols, Harvard Medical School Graduate Continuing Education, JOMDD, Johnson & Johnson, Life Molecular Imaging/Lantheus, Lundbeck, Merck, Michael J Fox Foundation, Novo Nordisk, ONO, Otsuka, Prothena, Qynapse, Roche/Genentech, Sunovion, Suven, Synexus, and Vaxxinity. He receives book royalties from Oxford University Press for a medical book on dementia. He receives institutional research grant or contract funding from the NIA/National Institutes of Health (NIH; 1P30AG072980, U24AG057437, 1P30AG072980, R01AG070883, R01AG086363, U01AG082350, U24AG057437), Arizona Department of Health Services (CTR040636), Foundation for the NIH, Washington University in St. Louis, Michael J. Fox Foundation, and Gates Ventures. His institution receives or has received funding for clinical trial grants, contracts, and projects from government, consortia, foundations, and companies, for which he serves or has served as a contracted site principal investigator. He has received or receives honoraria from Novo Nordisk for consulting activities, including for service on the evoke(+) program Steering Committee. MS has served on the Scientific Advisory Board for Medication and as a consultant for Eisai, Avenir, vTv, Biogen, Bio X Cel, F. Hoffman LaRoche, Merck, Novo Nordisk, Novartis, Otsuka, Genentech, and BioVie. She is a member of the Alzheimer Association Medical and Scientific Advisory Group and Chair of the data safety monitoring board for the Phase II Trial to Evaluate Safety and Efficacy of GM-CSF/Sargramostim in Alzheimer's Disease (SESAD; sponsor: University of Colorado). HZ reports a relationship with AbbVie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merck Sharp & Dohme, Merry Life, NervGen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, ReMYND, Roche, Samumed, ScandiBio Therapeutics AB, Siemens Healthineers, Triplet Therapeutics, and Wave that includes consulting or advisory services. He reports a relationship with AlzeCure, BioArctic, Biogen, Cellectricon, Fujirebio, LabCorp, Lilly, Novo Nordisk, Oy Medix Biochemica AB, Roche, and WebMD that includes speaking and lecture fees. He reports a relationship with Brain Biomarker Solutions in Gothenburg AB that includes equity or stocks. FKK, PJ, RMA, and CAW are employees and minor shareholders of Novo Nordisk. TL was an employee and minor shareholder of Novo Nordisk at the time of the analysis. PS is a full-time employee of EQT Life Sciences (formerly LSP) and Professor Emeritus at Amsterdam UMC. He is co-Chair of the Steering Committee for the phase 3 trials evoke and evoke+ with Novo Nordisk. HHF reports a consulting service agreement with Novo Nordisk for serving on the evoke + Steering Committee with funds including travel support for its meetings paid to UC San Diego. He receives no financial support for the present manuscript. Other disclosures include his receiving grants for UC San Diego from Allyx Therapeutics and Vivoryon Therapeutics (Probiodrug). He holds service agreements through UC San Diego for consulting with Biosplice Therapeutics, Arrowhead Pharmaceuticals, Axon Neuroscience, and LuMind Foundation. He provides service as a member of data and safety monitoring boards for Janssen Research & Development and Roche/Genentech and is a Scientific Advisory Board Chair for the Tau Consortium Rainwater Charitable Foundation through a UC San Diego service agreement. He has received travel support from Royal Society of Canada, Translating Research for Elder Care (TREC), Association for Frontotemporal Dementia (AFTD), Rainwater Charitable Foundation, Banner Health, Invictus, Summeet, and Novo Nordisk. He receives philanthropic support for Alzheimer's disease therapeutic research through the Epstein Family Alzheimer's Research Collaboration as well as personal funds for Detecting and Treating Dementia (Serial Number 12/3- 2691 US Patent Number PCT/US2007/07008, Washington DC, US Patent and Trademark Office).题图 Copyright: Israel Sebastian via Getty Images中文翻译仅供参考,所有内容以英文原文为准。DOI: 10.1016/S0140-6736(26)00459-9相关阅读推荐阅读柳叶刀 | 除了减重,司美格鲁肽还可带来心血管益处柳叶刀-初级保健 | GLP-1药物应用于肥胖治疗和减重,面临哪些初级保健挑战?柳叶刀-精神病学 | 司美格鲁肽在服用氯氮平的精神分裂症患者中减重效果明显点击阅读原文,查阅论文原文关注柳叶刀服务号,探索更多科研服务!#柳叶刀 #口服司美格鲁肽不能减缓阿尔兹海默病进展