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皮下注射索马鲁肽治疗非酒精性脂肪性肝炎的安慰剂对照试验
A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis


Philip N. Newsome ... 其他 • 2021.03.25
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• 非酒精性脂肪性肝炎的病因、发病机制和治疗 • 治疗非酒精性脂肪性肝炎的试验性药物 • pegbelfermin治疗非酒精性脂肪性肝炎

索马鲁肽:GLP-1RA治疗非酒精性脂肪性肝炎的又一颗新星

 

施漪雯,范建高*

上海交通大学医学院附属新华医院消化内科

*通讯作者

 

非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)与肥胖和代谢功能障碍密切相关,鉴于目前尚无疗效确切的针对NAFLD患者肝脏炎症损伤和纤维化的药物,研究者也把目光投向了胰岛素增敏剂等降血糖药物。其中胰高血糖素样肽-1受体激动剂(GLP-1RA)和钠-葡萄糖协同转运蛋白2(SGLT-2)抑制剂是目前最被看好的老药新用于NAFLD的治疗。研究发现GLP-1受体也存在于肝细胞中,体内研究显示了其抗炎、改善胰岛素抵抗和减轻脂毒性的潜力1。利拉鲁肽作为GLP-1RA的代表2,早在2017年就获得了美国肝病学会(American Association for the Study of Liver Diseases,AASLD)NAFLD指南的关注。但考虑到利拉鲁肽2期临床试验的样本量小,证据不够充分,AASLD指南认为使用GLP-1RA治疗NAFLD的严重型非酒精性脂肪性肝炎(nonalcoholic steatosis,NASH)为时尚早3

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摘要


背景

非酒精性脂肪性肝炎(NASH)是与发病率和死亡率增加相关的常见病,但目前的治疗方案有限。胰高血糖素样肽-1受体激动剂索马鲁肽对NASH患者的疗效和安全性尚不明确。

 

方法

我们在活检确诊NASH合并F1、F2或F3期肝纤维化的患者中开展了一项为期72周的双盲、2期试验。我们以3∶3∶3∶1∶1∶1的比例将患者随机分组,几组分别接受0.1 mg、0.2 mg或0.4 mg索马鲁肽或相应安慰剂每日一次皮下注射。主要终点是NASH消退且纤维化未恶化。确证性次要终点是纤维化改善至少1个分期且NASH未恶化。对这些终点的分析仅在F2或F3期纤维化患者中进行;其他分析在全部患者中进行。

 

结果

共计320例患者(其中230例患F2或F3期纤维化)被随机分配接受0.1 mg(80例患者)、0.2 mg(78例患者)或0.4 mg(82例患者)索马鲁肽或者接受安慰剂(80例患者)治疗。在0.1 mg组、0.2 mg组、0.4 mg组和安慰剂组中,NASH消退且纤维化未恶化的患者百分比分别为40%、36%、59%和17%(索马鲁肽0.4 mg vs.安慰剂的P<0.001)。0.4 mg组43%和安慰剂组33%患者的纤维化分期改善(P=0.48)。在0.4 mg组和安慰剂组中,平均体重减轻百分比分别为13%和1%。在0.4 mg组中,恶心、便秘和呕吐的发生率高于安慰剂组(恶心,42% vs. 11%;便秘,22% vs. 12%;呕吐,15% vs. 2%)。据报告索马鲁肽组3例患者(1%)和安慰剂组0例患者发生了恶性肿瘤。据报告,索马鲁肽组15%的患者和安慰剂组8%的患者发生了肿瘤(良性、恶性或未特指);未观察到特定器官发生肿瘤的模式。

 

结论

在NASH患者中开展的此项2期试验表明,与安慰剂相比,索马鲁肽使显著较高比例的患者达到NASH消退。然而,本试验表明,在纤维化分期改善的患者百分比方面,无显著组间差异(由诺和诺德公司资助,在ClinicalTrials.gov注册号为NCT02970942)。





作者信息

Philip N. Newsome, M.B., Ch.B., Ph.D., Kristine Buchholtz, M.D., Ph.D., Kenneth Cusi, M.D., Martin Linder, M.Sc., Takeshi Okanoue, M.D., Ph.D., Vlad Ratziu, M.D., Ph.D., Arun J. Sanyal, M.D., Anne-Sophie Sejling, M.D., Ph.D., and Stephen A. Harrison, M.D. for the NN9931-4296 Investigators*
From the National Institute for Health Research Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, and the Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham (P.N.N.), and the Radcliffe Department of Medicine, University of Oxford, Oxford (S.A.H.) — all in the United Kingdom; Novo Nordisk, Søborg, Denmark (K.B., M.L., A.-S.S.); the Division of Endocrinology, Diabetes, and Metabolism, University of Florida, Gainesville (K.C.); the Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan (T.O.); the Institute of Cardiometabolism and Nutrition, Sorbonne Université, Hôpital Pitié–Salpêtrière, Assistance Publique–Hôpitaux de Paris, INSERM Unité Mixte de Recherche Scientifique 1138 Centre de Recherche des Cordeliers, Paris (V.R.); and the Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University School of Medicine, Richmond (A.J.S.). Address reprint requests to Dr. Newsome at the Centre for Liver and Gastrointestinal Research, 5th Flr., Institute of Biomedical Research, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom, or at p.n.newsome@bham.ac.uk. *A complete list of the investigators in this trial is provided in the Supplementary Appendix, available at NEJM.org.

 

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