本文由小咖机器人翻译整理

期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2401755

摘要内容如下：

背景

胰高血糖素受体和胰高血糖素样肽-1（GLP-1）受体的双重激动作用可能比单独的GLP-1受体激动作用更有效地治疗代谢功能障碍相关性脂肪性肝炎（MASH）。Survodutide（胰高血糖素受体和GLP-1受体的双重激动剂）对MASH和肝纤维化患者的疗效和安全性尚不清楚。

方法

在这项为期48周的2期试验中，我们以1:1:1:1的比例将活检证实为MASH和纤维化F1至F3期的成人随机分配接受每周一次的Survodutide皮下注射（剂量为2.4、4.8或6.0 mg）或安慰剂。该试验分为两个阶段:24周的快速剂量递增阶段和24周的维持阶段。主要终点是MASH的组织学改善（减少），无纤维化恶化。次要终点包括肝脏脂肪含量减少至少30%，活检评估纤维化改善（减少）至少一个阶段。

结果

共有293名随机分配的参与者接受了至少一剂Survodutide或安慰剂。Survodutide 2.4 mg组47%的受试者、4.8 mg组62%的受试者和6.0 mg组43%的受试者的MASH改善且无纤维化恶化，而安慰剂组为14%（二次剂量反应曲线作为最佳拟合模型，P<0.001）。Survodutide 2.4 mg组中63%的参与者、4.8 mg组中67%的参与者、6.0 mg组中57%的参与者和安慰剂组中14%的参与者的肝脏脂肪含量至少降低了30%。至少一个阶段的纤维化改善分别为34%、36%、34%和22%。与安慰剂相比，Survodutide更常见的不良事件包括恶心（66%对23%）、腹泻（49%对23%）和呕吐（41%对4%）；Survodutide组和安慰剂组的严重不良事件发生率分别为8%和7%。

结论

Survodutide在改善MASH而不恶化纤维化方面优于安慰剂，值得在3期试验中进一步研究。（由勃林格殷格翰公司资助；1404-0043 ClinicalTrials.gov编号，NCT04771273；Eudract编号，2020-002723-11.）

英文原文如下：

Abstracts

BACKGROUND  Dual agonism of glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor may be more effective than GLP-1 receptor agonism alone for treating metabolic dysfunction-associated steatohepatitis (MASH). The efficacy and safety of survodutide (a dual agonist of glucagon receptor and GLP-1 receptor) in persons with MASH and liver fibrosis are unclear.

METHODS  In this 48-week, phase 2 trial, we randomly assigned adults with biopsy-confirmed MASH and fibrosis stage F1 through F3 in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of survodutide at a dose of 2.4, 4.8, or 6.0 mg or placebo. The trial had two phases: a 24-week rapid-dose-escalation phase, followed by a 24-week maintenance phase. The primary end point was histologic improvement (reduction) in MASH with no worsening of fibrosis. Secondary end points included a decrease in liver fat content by at least 30% and biopsy-assessed improvement (reduction) in fibrosis by at least one stage.

RESULTS  A total of 293 randomly assigned participants received at least one dose of survodutide or placebo. Improvement in MASH with no worsening of fibrosis occurred in 47% of the participants in the survodutide 2.4-mg group, 62% of those in the 4.8-mg group, and 43% of those in the 6.0-mg group, as compared with 14% of those in the placebo group (P<0.001 for the quadratic dose-response curve as best-fitting model). A decrease in liver fat content by at least 30% occurred in 63% of the participants in the survodutide 2.4-mg group, 67% of those in the 4.8-mg group, 57% of those in the 6.0-mg group, and 14% of those in the placebo group; improvement in fibrosis by at least one stage occurred in 34%, 36%, 34%, and 22%, respectively. Adverse events that were more frequent with survodutide than with placebo included nausea (66% vs. 23%), diarrhea (49% vs. 23%), and vomiting (41% vs. 4%); serious adverse events occurred in 8% with survodutide and 7% with placebo.

CONCLUSIONS  Survodutide was superior to placebo with respect to improvement in MASH without worsening of fibrosis, warranting further investigation in phase 3 trials. (Funded by Boehringer Ingelheim; 1404-0043 ClinicalTrials.gov number, NCT04771273; EudraCT number, 2020-002723-11.).

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