Hartman Mark L, Loomba Rohit, Lawitz Eric J, Vuppalanchi Raj, Boursier Jérôme, Bugianesi Elisabetta, Yoneda Masato, Tang Yuanyuan, Brouwers Bram, Bunck Mathijs C, Haupt Axel, Sanyal Arun J
Eli Lilly and Company, Indianapolis, Indiana, United States.
MASLD Research Center, Division of Gastroenterology and Hepatology, University of California San Diego, San Diego, California, United States.
JHEP Rep. 2025 Jun 6;7(8):101472. doi: 10.1016/j.jhepr.2025.101472. eCollection 2025 Aug.
BACKGROUND & AIMS: In the SYNERGY-NASH trial for metabolic dysfunction-associated steatohepatitis (MASH) with stage 2 or 3 fibrosis, tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, effectively resolved MASH without worsening fibrosis in up to 73% of patients. We explored the extent of histological improvements across clinically relevant subgroups in this trial.
Participants (n = 190) were randomly assigned 1:1:1:1 to receive once-weekly subcutaneous tirzepatide (5, 10, or 15 mg) or placebo for 52 weeks. We analyzed 155 participants who completed the study on treatment with evaluable end-of-treatment biopsies. subgroups (n = 34) were defined by demographics, histology, serum, and imaging biomarkers using the median of baseline values for continuous variables. Risk differences (RDs) placebo (95% CI) were calculated using a logistic regression model.
Compared with placebo, tirzepatide was consistently associated with improved MASH resolution without worsening fibrosis across subgroups defined by sex, age, ethnicity, BMI, type 2 diabetes status, histological disease activity, fibrosis stage, serum aminotransferases, serum biomarkers of fibrosis and MASH, and imaging assessments of liver fat, fibroinflammation, and stiffness. For tirzepatide 5, 10 and 15 mg, RDs were statistically significant (0.05) for 74%, 97%, and 100% of the subgroups, respectively. While most RDs for fibrosis improvement without worsening of MASH favored tirzepatide, statistical significance was not reached in 59-79% of subgroups due to limited sample sizes. Significant fibrosis improvement (0.05) was observed with tirzepatide 5 and 15 mg among participants with stage 3 fibrosis.
These analyses suggest that tirzepatide was consistently associated with improved MASH resolution without worsening of fibrosis across subgroups defined by demographics, histology, and biomarkers, compared with placebo.
In participants with metabolic dysfunction-associated steatohepatitis (MASH), tirzepatide demonstrated superiority to placebo for resolution of MASH without worsening of fibrosis, but the extent of MASH resolution across clinically relevant subgroups was not reported. In these analyses, we show that tirzepatide was consistently associated with improved MASH resolution without worsening of fibrosis across subgroups defined by demographics, histology, serum biomarkers, and imaging tests. These data support further investigation of tirzepatide in larger studies of participants with MASH including representation from diverse populations.
在针对伴有2期或3期纤维化的代谢功能障碍相关脂肪性肝炎（MASH）的SYNERGY-NASH试验中，葡萄糖依赖性促胰岛素多肽和胰高血糖素样肽-1受体激动剂替尔泊肽可有效缓解MASH，且在高达73%的患者中未使纤维化恶化。我们在该试验中探讨了临床相关亚组中组织学改善的程度。
将190名参与者按1:1:1:1随机分配，分别接受每周一次皮下注射替尔泊肽（5、10或15毫克）或安慰剂，为期52周。我们分析了155名完成研究并接受可评估的治疗结束时活检的参与者。连续变量以基线值的中位数为依据，通过人口统计学、组织学、血清和影像学生物标志物定义亚组（n = 34）。使用逻辑回归模型计算风险差异（RDs）及与安慰剂相比的95%置信区间（CI）。
与安慰剂相比，在按性别、年龄、种族、体重指数、2型糖尿病状态、组织学疾病活动度、纤维化阶段、血清转氨酶、纤维化和MASH的血清生物标志物以及肝脏脂肪、纤维炎症和硬度的影像评估所定义的亚组中，替尔泊肽始终与MASH缓解改善相关且未使纤维化恶化。对于5毫克、10毫克和15毫克的替尔泊肽，分别有74%、97%和100%的亚组的RDs具有统计学意义（P<0.05）。虽然大多数在不恶化MASH的情况下改善纤维化的RDs有利于替尔泊肽，但由于样本量有限，59 - 79%的亚组未达到统计学意义。在3期纤维化参与者中，5毫克和15毫克的替尔泊肽观察到显著的纤维化改善（P<0.05）。
这些分析表明，与安慰剂相比，替尔泊肽在由人口统计学、组织学定义的亚组中始终与MASH缓解改善相关且未使纤维化恶化。
在代谢功能障碍相关脂肪性肝炎（MASH）参与者中，替尔泊肽在缓解MASH且不使纤维化恶化方面优于安慰剂，但未报告临床相关亚组中MASH缓解的程度。在这些分析中，我们表明替尔泊肽在由人口统计学、组织学、血清生物标志物和影像检查定义的亚组中始终与MASH缓解改善相关且未使纤维化恶化。这些数据支持在更大规模的MASH参与者研究中进一步研究替尔泊肽，包括来自不同人群的代表。
