Proteomic signatures reflect effects of semaglutide treatment for MASH

IF 7.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports Pub Date : 2025-07-22 DOI:10.1016/j.jhepr.2025.101521

Jörn M. Schattenberg , Henning Grønbæk , Iris Kliers , Steen Ladelund , Michelle T. Long , Sune Boris Nygård , Arun J. Sanyal , Melanie J. Davies

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Abstract

Background & Aims

Proteomic technology has emerged as a non-invasive method for grading and staging metabolic dysfunction-associated steatohepatitis (MASH). The aims of this post hoc analysis of the STEP 1 and STEP 2 trials were to assess the distribution of SomaSignal-derived MASH components, evaluate the effect of semaglutide (2.4 mg and 1.0 mg) on these components, and test concordance with biopsy-based MASH histology from the phase IIb Sema-MASH trial.

Methods

Participants with overweight or obesity (STEP 1) and type 2 diabetes (STEP 2), who received once-weekly semaglutide or placebo for 68 weeks and had available biological samples, were included. In addition, participants with biopsy-confirmed MASH from the phase IIb Sema-MASH trial who received once-daily semaglutide or placebo for 72 weeks were included.

Results

SomaSignal-derived steatosis was prevalent in both STEP 1 (43.2%) and STEP 2 (71.7%). At week 68, participants who received semaglutide had significantly lower odds of exhibiting SomaSignal-defined MASH components compared with those on placebo. They were also more likely to have a less severe SomaSignal-derived stage of metabolic dysfunction-associated steatotic liver disease, with odds ratios for semaglutide 2.4 mg of 5.26 (95% CI 3.59–7.72) in STEP 1 and 4.90 (95% CI 2.86–8.40) in STEP 2; both p <0.0001. SomaSignal-derived MASH components correlated with histologic changes, standard liver-related biomarkers, and measures of glycemic control.

Conclusions

These findings suggest that SomaSignal MASH component testing may be useful for evaluating the potential therapeutic effects of semaglutide in patients with MASH and related comorbidities. However, prospective randomized clinical trials are necessary to confirm these results.

Clinical trial registration numbers

STEP 1: NCT03548935; STEP 2: NCT03552757; MASH phase IIb trial: NCT02970942.

Impact and implications

Liver biopsy is the current gold standard for the diagnosis of metabolic dysfunction-associated steatohepatitis (MASH); however, this procedure is invasive and time consuming for patients living with MASH. The use of non-invasive tests to diagnose MASH is becoming increasingly popular and many clinicians see this approach as the diagnostic future. SomaSignal is a proteomics-based model designed to non-invasively test for and validate MASH components as well as detect the prevalence of metabolic dysfunction-associated steatotic liver disease stages, against biopsy results. In the future, SomaSignal MASH components may have an impact on future clinical practice by providing clinicians with an alternative option for non-invasive assessment of treatment effects in the early clinical stages of therapeutic development.

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蛋白质组学特征反映了semaglutide治疗MASH的效果

背景和目的蛋白质组学技术已成为一种非侵入性方法，用于代谢功能障碍相关脂肪性肝炎（MASH）的分级和分期。对第1步和第2步试验进行事后分析的目的是评估somassignal衍生的MASH成分的分布，评估semaglutide （2.4 mg和1.0 mg）对这些成分的影响，并测试与IIb期Sema-MASH试验中基于活检的MASH组织学的一致性。方法纳入超重或肥胖（step1）和2型糖尿病（step2）的参与者，他们每周接受一次西马鲁肽或安慰剂治疗，持续68周，并有可用的生物样本。此外，从IIb期Sema-MASH试验中活检证实的MASH患者接受每日一次的semaglutide或安慰剂治疗72周。结果somassignal衍生的脂肪变性在step1（43.2%）和step2（71.7%）中都很普遍。在第68周，与安慰剂组相比，接受semaglutide的参与者表现出somassignal定义的MASH成分的几率显着降低。他们也更有可能出现较不严重的somasigna衍生的代谢功能障碍相关脂肪变性肝病阶段，semaglutide 2.4 mg的比值比在第1步为5.26 (95% CI 3.59-7.72)，在第2步为4.90 (95% CI 2.86-8.40)；p <0.0001。somassignal衍生的MASH成分与组织学改变、标准肝脏相关生物标志物和血糖控制措施相关。结论somassignal MASH成分检测可用于评估西马鲁肽对MASH及相关合并症患者的潜在治疗效果。然而，需要前瞻性随机临床试验来证实这些结果。临床试验注册号第一步：NCT03548935；第二步：nct03552757；MASH ii期临床试验：NCT02970942。影响和意义银活检是目前诊断代谢功能障碍相关脂肪性肝炎（MASH）的金标准；然而，对于患有MASH的患者来说，该手术是有创的且耗时的。使用非侵入性测试来诊断MASH正变得越来越流行，许多临床医生认为这种方法是诊断的未来。somassignal是一种基于蛋白质组学的模型，设计用于无创检测和验证MASH成分，以及根据活检结果检测代谢功能障碍相关脂肪变性肝病分期的患病率。在未来，somassignal MASH组件可能会对未来的临床实践产生影响，为临床医生提供一种在治疗发展的早期临床阶段对治疗效果进行非侵入性评估的替代选择。

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来源期刊

JHEP Reports GASTROENTEROLOGY & HEPATOLOGY-

CiteScore

12.40

自引率

2.40%

发文量

161

审稿时长

36 days

期刊介绍： JHEP Reports is an open access journal that is affiliated with the European Association for the Study of the Liver (EASL). It serves as a companion journal to the highly respected Journal of Hepatology. The primary objective of JHEP Reports is to publish original papers and reviews that contribute to the advancement of knowledge in the field of liver diseases. The journal covers a wide range of topics, including basic, translational, and clinical research. It also focuses on global issues in hepatology, with particular emphasis on areas such as clinical trials, novel diagnostics, precision medicine and therapeutics, cancer research, cellular and molecular studies, artificial intelligence, microbiome research, epidemiology, and cutting-edge technologies. In summary, JHEP Reports is dedicated to promoting scientific discoveries and innovations in liver diseases through the publication of high-quality research papers and reviews covering various aspects of hepatology.