NAFLD Research Center, Division of Gastroenterology and Epidemiology, University of California at San Diego, La Jolla, CA, USA.
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
Lancet Gastroenterol Hepatol. 2023 Jun;8(6):511-522. doi: 10.1016/S2468-1253(23)00068-7. Epub 2023 Mar 16.
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.
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/m 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.
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/m (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.
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.
Novo Nordisk A/S.
非酒精性脂肪性肝炎（NASH）相关肝硬化患者存在较高的肝脏相关和全因发病率及死亡率。我们研究了胰高血糖素样肽-1 类似物司美格鲁肽在 NASH 合并代偿性肝硬化患者中的疗效和安全性。
这是一项在欧洲和美国 38 个中心进行的双盲、安慰剂对照的 2 期临床试验。纳入了经活检证实为 NASH 相关肝硬化且体重指数（BMI）≥27 kg/m2 的成年人，将其随机（2:1）分配接受每周一次皮下注射司美格鲁肽 2.4 mg 或视觉匹配的安慰剂。通过交互式网络应答系统，按是否存在 2 型糖尿病进行分层，对患者进行随机分组。患者、研究者和评估结局的人员对治疗分配均设盲。主要终点是在 48 周时，通过肝活检评估的纤维化改善 1 级或以上且 NASH 无恶化的患者比例，在意向治疗人群中评估。在至少接受一剂研究药物的所有患者中评估安全性。该试验已关闭并完成，在 ClinicalTrials.gov 注册，编号为 NCT03987451。
2019 年 6 月 18 日至 2021 年 4 月 22 日期间共纳入 71 例患者；49 例（69%）为女性，22 例（31%）为男性。患者的平均年龄为 59.5 岁（标准差 8.0），平均 BMI 为 34.9 kg/m2（标准差 5.9）；53 例（75%）患有糖尿病。47 例患者被随机分配至司美格鲁肽组，24 例患者被随机分配至安慰剂组。48 周后，两组中纤维化改善 1 级或以上且 NASH 无恶化的患者比例无统计学差异（司美格鲁肽组 5 例[11%]，安慰剂组 7 例[29%]；比值比 0.28[95%CI 0.06-1.24；p=0.087]）。两组中达到 NASH 缓解的患者比例也无显著差异（p=0.29）。每组均有相似比例的患者报告不良事件（司美格鲁肽组 42 例[89%]，安慰剂组 19 例[79%]）和严重不良事件（司美格鲁肽组 6 例[13%]，安慰剂组 2 例[8%]）。最常见的不良事件为恶心（司美格鲁肽组 21 例[45%]，安慰剂组 4 例[17%]）、腹泻（司美格鲁肽组 9 例[19%]，安慰剂组 2 例[8%]）和呕吐（司美格鲁肽组 8 例[17%]，安慰剂组无）。肝肾功能保持稳定。未发生失代偿事件或死亡。
在 NASH 合并代偿性肝硬化患者中，与安慰剂相比，司美格鲁肽并未显著改善纤维化或实现 NASH 缓解。未发现新的安全性问题。
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