一项安慰剂对照试验评估皮下司美格鲁肽在非酒精性脂肪性肝炎中的疗效。

A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis.

机构信息

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.).

出版信息

N Engl J Med. 2021 Mar 25;384(12):1113-1124. doi: 10.1056/NEJMoa2028395. Epub 2020 Nov 13.

DOI:10.1056/NEJMoa2028395

PMID:33185364

Abstract

BACKGROUND

Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known.

METHODS

We conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients.

RESULTS

In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P = 0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4-mg group than in the placebo group (nausea, 42% vs. 11%; constipation, 22% vs. 12%; and vomiting, 15% vs. 2%). Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group; no pattern of occurrence in specific organs was observed.

CONCLUSIONS

This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.).

摘要

背景

非酒精性脂肪性肝炎（NASH）是一种常见疾病，与发病率和死亡率的增加有关，但治疗选择有限。胰高血糖素样肽-1 受体激动剂司美格鲁肽在 NASH 患者中的疗效和安全性尚不清楚。

方法

我们进行了一项 72 周、双盲的 2 期临床试验，纳入了经活检证实患有 NASH 和 F1、F2 或 F3 期肝纤维化的患者。患者按 3:3:3:1:1:1 的比例随机接受每日一次皮下注射司美格鲁肽 0.1、0.2 或 0.4mg 或相应的安慰剂。主要终点是 NASH 缓解且纤维化无恶化。确认的次要终点是至少改善一个纤维化阶段且 NASH 无恶化。这些终点的分析仅在纤维化分期为 F2 或 F3 的患者中进行；其他分析在所有患者中进行。

结果

共有 320 名（其中 230 名纤维化分期为 F2 或 F3）患者被随机分配接受司美格鲁肽 0.1mg（80 名）、0.2mg（78 名）或 0.4mg（82 名）或安慰剂（80 名）治疗。NASH 缓解且纤维化无恶化的患者比例在 0.1mg 组为 40%，0.2mg 组为 36%，0.4mg 组为 59%，安慰剂组为 17%（司美格鲁肽 0.4mg 与安慰剂相比，P<0.001）。0.4mg 组有 43%的患者纤维化分期改善，安慰剂组有 33%（P=0.48）。0.4mg 组的平均体重减轻 13%，安慰剂组为 1%。0.4mg 组恶心、便秘和呕吐的发生率高于安慰剂组（恶心，42%比 11%；便秘，22%比 12%；呕吐，15%比 2%）。接受司美格鲁肽治疗的 3 名患者（1%）和接受安慰剂的患者中均报告了恶性肿瘤。总体而言，司美格鲁肽组有 15%的患者（1%）和安慰剂组 8%的患者（8%）报告了肿瘤（良性、恶性或未指明）；未观察到特定器官发生的模式。