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期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2401943

摘要内容如下：

背景

代谢功能障碍相关性脂肪性肝炎（MASH）是一种与肝脏相关并发症和死亡相关的进行性肝脏疾病。葡萄糖依赖性促胰岛素多肽和胰高血糖素样肽-1受体激动剂Tirzepatide在MASH和中度或重度纤维化患者中的疗效和安全性尚不清楚。

方法

我们进行了一项2期、剂量探索、多中心、双盲、随机、安慰剂对照试验，参与者为经活检证实的MASH和F2或F3期（中度或重度）纤维化患者。参与者被随机分配接受每周一次的皮下注射Tirzepatide（5 mg、10 mg或15 mg）或安慰剂，持续52周。主要终点是在52周时MASH消退而无纤维化恶化。关键的次要终点是至少一个纤维化阶段的改善（减少），而MASH没有恶化。

结果

在接受随机分组的190名参与者中，157名在第52周时有可以评估的肝活检结果，并在假设他们将遵循安慰剂组的结果模式的情况下估算缺失值。在安慰剂组中，符合MASH消退而纤维化未恶化标准的参与者百分比为10%，在5-mg tirzepatide组中为44%（与安慰剂相比，差异为34个百分点；95%可信区间[CI]，17-50），10-mg tirzepatide组为56%（差异，46个百分点；95%可信区间（CI）为29-62），而15-mg Tirzepatide组为62%（差异为53个百分点；95%CI，37至69）（所有三项比较P<0.001）。至少一个纤维化阶段得到改善而MASH没有恶化的参与者的百分比在安慰剂组中为30%，在5-mg tirzepatide组中为55%（与安慰剂相比，差异为25个百分点；95%CI，5-46），10-mg Tirzepatide组为51%（差异，22个百分点；95%CI，1至42），而15-mg Tirzepatide组为51%（差异，21个百分点；95%置信区间，1至42）。Tirzepatide组最常见的不良事件是胃肠道事件，大多数为轻度或中度。

结论

在这项涉及MASH和中度或重度纤维化参与者的2期试验中，在MASH消退而纤维化不恶化方面，使用Tirzepatide治疗52周比安慰剂更有效。需要更大规模和更长时间的试验来进一步评估Tirzepatide治疗MASH的疗效和安全性。（由礼来公司资助；Synergy-Nash ClinicalTrials.gov编号，NCT04166773。）

英文原文如下：

Abstracts

BACKGROUND  Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.

METHODS  We conducted a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial involving participants with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis. Participants were randomly assigned to receive once-weekly subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 52 weeks. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.

RESULTS  Among 190 participants who had undergone randomization, 157 had liver-biopsy results at week 52 that could be evaluated, with missing values imputed under the assumption that they would follow the pattern of results in the placebo group. The percentage of participants who met the criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% confidence interval [CI], 17 to 50), 56% in the 10-mg tirzepatide group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg tirzepatide group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage of participants who had an improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg tirzepatide group (difference vs. placebo, 25 percentage points; 95% CI, 5 to 46), 51% in the 10-mg tirzepatide group (difference, 22 percentage points; 95% CI, 1 to 42), and 51% in the 15-mg tirzepatide group (difference, 21 percentage points; 95% CI, 1 to 42). The most common adverse events in the tirzepatide groups were gastrointestinal events, and most were mild or moderate in severity.

CONCLUSIONS  In this phase 2 trial involving participants with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to resolution of MASH without worsening of fibrosis. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. (Funded by Eli Lilly; SYNERGY-NASH ClinicalTrials.gov number, NCT04166773.).

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