英国伯明翰大学Philip N. Newsome团队研究了皮下注射索马鲁肽治疗非酒精性脂肪性肝炎的疗效。2020年11月13日，该研究发表在《新英格兰医学杂志》上。

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疾病，但治疗选择有限。尚不清楚胰高血糖素样肽-1受体激动剂索马鲁肽治疗NASH患者的疗效和安全性。

研究组进行了一项为期72周的双盲、2期临床试验，招募经活检证实为NASH且F1、F2或F3期肝纤维化的患者，以3：3：3：1：1：1的比例将患者随机分组，分别接受每日一次0.1、0.2或0.4 mg的索马鲁肽皮下注射，或注射相应剂量的安慰剂。主要终点为NASH缓解且无纤维化恶化。次要终点为纤维化阶段至少改善一期，且NASH未恶化。

研究组共招募了320名患者，其中230名为F2或F3期纤维化，0.1 mg剂量索马鲁肽组有80名患者，0.2 mg剂量组有78名患者，0.4 mg剂量组有82名患者，安慰剂组有80名患者。0.1 mg组中在无纤维化恶化的情况下达到NASH缓解的患者占40％，0.2 mg组为36%，0.4 mg组为59%，均显著高于安慰剂组（17%）。

0.4 mg组中有43％的患者纤维化分期改善，安慰剂组中有33％。0.4 mg组患者的平均体重减轻了13％，安慰剂组减轻了1％。0.4 mg组的恶心、便秘和呕吐的发生率高于安慰剂组。索马鲁肽组中有3例患者（1%）发生恶性肿瘤，显著高于安慰剂组。索马鲁肽组中共有15％的患者罹患肿瘤，包括良性、恶性或未明确，安慰剂组中有8％。

研究结果表明，索马鲁肽治疗NASH患者疾病缓解率显著高于安慰剂，但纤维化分期改善无显著差异。

附：英文原文

Title: A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis | NEJM

Author: 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.

Issue&Volume: 2020-11-13

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.

DOI: 10.1056/NEJMoa2028395

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2028395