Background

Patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis are at high risk of liver-related and all-cause morbidity and mortality. We investigated the efficacy and safety of the glucagon-like peptide-1 analogue semaglutide in patients with NASH and compensated cirrhosis.

Methods

This double-blind, placebo-controlled phase 2 trial enrolled patients from 38 centres in Europe and the USA. Adults with biopsy-confirmed NASH-related cirrhosis and body-mass index (BMI) of 27 kg/m² or more were randomly assigned (2:1) to receive either once-weekly subcutaneous semaglutide 2·4 mg or visually matching placebo. Patients were randomly allocated via an interactive web response system, stratified by presence or absence of type 2 diabetes. Patients, investigators, and those assessing outcomes were masked to treatment assignment. The primary endpoint was the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH after 48 weeks, assessed by biopsy in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is closed and completed, and registered with ClinicalTrials.gov, number NCT03987451.

Findings

71 patients were enrolled between June 18, 2019, and April 22, 2021; 49 (69%) patients were female and 22 (31%) were male. Patients had a mean age of 59·5 years (SD 8·0) and mean BMI of 34·9 kg/m² (SD 5·9); 53 (75%) patients had diabetes. 47 patients were randomly assigned to the semaglutide group and 24 to the placebo group. After 48 weeks, there was no statistically significant difference between the two groups in the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH (five [11%] of 47 patients in the semaglutide group vs seven [29%] of 24 in the placebo group; odds ratio 0·28 [95% CI 0·06–1·24; p=0·087). There was also no significant difference between groups in the proportion of patients who achieved NASH resolution (p=0·29). Similar proportions of patients in each group reported adverse events (42 [89%] patients in the semaglutide group vs 19 [79%] in the placebo group) and serious adverse events (six [13%] vs two [8%]). The most common adverse events were nausea (21 [45%] vs four [17%]), diarrhoea (nine [19%] vs two [8%]), and vomiting (eight [17%] vs none). Hepatic and renal function remained stable. There were no decompensating events or deaths.

Interpretation

In patients with NASH and compensated cirrhosis, semaglutide did not significantly improve fibrosis or achievement of NASH resolution versus placebo. No new safety concerns were raised.

Funding

Novo Nordisk A/S.

中文翻译：

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Semaglutide 2·4 mg 每周一次治疗非酒精性脂肪性肝炎相关肝硬化患者：一项随机、安慰剂对照的 2 期试验

背景

非酒精性脂肪性肝炎 (NASH) 相关肝硬化患者发生肝脏相关和全因发病率和死亡率的风险很高。我们调查了胰高血糖素样肽 1 类似物 semaglutide 在 NASH 和代偿性肝硬化患者中的疗效和安全性。

方法

这项双盲、安慰剂对照的 2 期试验招募了来自欧洲和美国 38 个中心的患者。经活检证实患有 NASH 相关肝硬化且体重指数 (BMI) 为 27 kg/m ^{2的成年人}或更多人被随机分配 (2:1) 接受每周一次皮下注射 semaglutide 2·4 mg 或外观匹配的安慰剂。患者通过交互式网络响应系统随机分配，根据是否存在 2 型糖尿病进行分层。患者、研究人员和评估结果的人员对治疗分配设盲。主要终点是在意向治疗人群中通过活组织检查评估 48 周后肝纤维化改善一个或多个阶段而 NASH 没有恶化的患者比例。在接受至少一剂研究药物的所有患者中评估安全性。该试验已结束并完成，并在ClinicalTrials.gov注册，编号NCT03987451。

发现

2019年6月18日至2021年4月22日期间招募了71名患者；49 名 (69%) 患者为女性，22 名 (31%) 患者为男性。患者的平均年龄为 59·5 岁 (SD 8·0)，平均 BMI 为 34·9 kg/m ² (SD 5·9)；53 名 (75%) 患者患有糖尿病。47 名患者被随机分配到索马鲁肽组，24 名患者被随机分配到安慰剂组。48 周后，两组间肝纤维化改善一级或以上且 NASH 未恶化的患者比例无统计学显着差异（semaglutide 组 47 名患者中有 5 名 [11%] vs.安慰剂组 24 人中有七人 [29%]；比值比 0·28 [95% CI 0·06–1·24；p=0·087）。在实现 NASH 解决的患者比例方面，各组之间也没有显着差异 (p=0·29)。每组中报告不良事件的患者比例相似（semaglutide 组 42 例 [89%] vs安慰剂组 19 例 [79%]）和严重不良事件（6 例 [13%] vs 2 例 [8%]）。最常见的不良事件是恶心（21 [45%] vs 4 [17%]）、腹泻（9 [19%] vs 2 [8%]）和呕吐（8 [17%] vs无）。肝肾功能保持稳定。没有失代偿事件或死亡。

解释

在患有 NASH 和代偿性肝硬化的患者中，与安慰剂相比，semaglutide 没有显着改善纤维化或 NASH 消退的实现。没有提出新的安全问题。

资金

诺和诺德 A/S。