Introduction
Metabolic dysfunction-associated steatohepatitis (MASH) increases the risk of cardiovascular (CV) events and liver fibrosis. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces CV risk associated with overweight and obesity in the absence of diabetes and has a profound effect on weight reduction and MASH resolution. Management of MASH may benefit from a deeper understanding of the mechanistic basis of semaglutide-induced MASH resolution.
Aims & Methods
This study used a multi-omics approach to investigate the effects of semaglutide on the hepatic microenvironment and fibrosis development in the context of semaglutide-induced MASH resolution. GLP-1 receptor expression was assessed using RNA in situ hybridization and immunohistochemistry in human liver tissue and immunohistochemistry in liver tissue from DIO‑NASH and CDA-HFD mice. The effect of semaglutide treatment on liver fibrosis was also assessed using liver transcriptome analysis in both of these mouse models of MASH. Proteomic analyses of 4,979 proteins using the SomaScan Platform were conducted on serum samples from 293 patients with MASH who received semaglutide or placebo in a phase 2b study (NCT02970942), and an independent cohort of 141 patients with MASH and 89 healthy volunteers.
Results
GLP-1 receptor mRNA or protein expression were not detected in human or mouse liver tissue. However, semaglutide improved histological markers of fibrosis and expression of genes involved in collagen turnover in two distinct mouse models of MASH; one that phenocopies the metabolic-associated features of human disease and another that exhibits non-abdominal obesity-induced advanced steatohepatitis and rapid fibrosis. In semaglutide-treated patients with MASH, proteomics identified 72 proteins significantly associated with MASH resolution after 72 weeks of treatment. These 72 proteins were also identified as differentially expressed in patients with MASH who were not treated for MASH, relative to healthy individuals. In semaglutide-treated patients with MASH, the abundance of the 72 proteins was similarly altered; however, semaglutide reverted the altered disease profile to that seen in non-pharmacologically treated healthy individuals. In contrast, changes in the levels of the 72 proteins in patients who received placebo were negligible. Notably, changes in the abundance of 26 of the 72 proteins were significant even after correction for weight loss. Although most of these 26 proteins are associated with metabolic functions, several are implicated in fibrosis-related pathways and CV disease (e.g. ADAMTSL2 and ACY1), and hepatocellular carcinoma (e.g. SERPINC1).
Conclusion
Based on circulating proteomic profiling, semaglutide-induced MASH resolution is associated with changes in multiple pathogenic pathways even after correction for weight loss. Semaglutide appears to re-balance the expression levels of disease-associated proteins in MASH to levels found in healthy individuals.
Disclosure
MJ is an employee of Novo Nordisk A/S. JN is an employee of Novo Nordisk A/S. MSK is an employee of Novo Nordisk A/S. KA is an employee of Novo Nordisk A/S. KMB is an employee of Novo Nordisk A/S. EB served as a consultant or advisory board member for Boehringer Ingelheim, Gilead Sciences, Intercept, Merck, Novo Nordisk, Pfizer, ProSciento. Grants from Gilead Sciences for fatty liver research, Speaker for Gilead Sciences, Intercept, Merck, Novo Nordisk, and Pfizer. KC served as a consultant for Aligos Therapeutics, Arrowhead, AstraZeneca, 89Bio, BMS, Eli Lilly & Co., Merck, Novo Nordisk, Prosciento, Sagimet Biosciences, Siemens, and Terns Pharma. Received research support (University of Florida; Principal Investigator) from Boehringer Ingelheim, Echosens, Inventiva, Labcorp, and Perspectum. EDG is an employee of Novo Nordisk A/S. MG is an employee of Novo Nordisk A/S. LLG is an employee of Novo Nordisk A/S. LMH is an employee of Novo Nordisk A/S. RL is a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals and Viking Therapeutics. His institutions received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sonic Incytes and Terns Pharmaceuticals. Co-founder of LipoNexus Inc. GM is an employee of Novo Nordisk A/S. PNN is a consultant for Novo Nordisk, Boehringer Ingelheim, Gilead, Intercept, Poxel Pharmaceuticals, Bristol Myers Squibb (BMS), Pfizer, Sun Pharma, Madrigal and GSK. He also reports honoraria as a speaker for Novo Nordisk and AiCME; support for attending meetings from for Novo Nordisk; and participation on an advisory board for Novo Nordisk, Boehringer Ingelheim, Gilead, Intercept, Poxel Pharmaceuticals, BMS, Pfizer, Sun Pharma, Madrigal, and GSK. LMN is an employee of Novo Nordisk A/S. MSP is an employee of Novo Nordisk A/S. VR received consulting fees from Novo-Nordisk, Sagimet, Madrigal, Enyo, Poxel, Northsea, Intercept Pharmaceuticals, Prosciento. Research grants (to institution) from Gilead Sciences and Intercept Pharmaceuticals. A-SS is an employee of Novo Nordisk A/S. VWW served as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, and TARGET PharmaSolutions. Has received a research grant from Gilead Sciences. Speaker for Abbott, AbbVie, Gilead Sciences, Novo Nordisk, and Unilab. Co-founder of Illuminatio Medical Technology Limited. Has received travel support from AbbVie and Gilead Sciences. QMA is coordinator of the IMI2 Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) consortium, which is funded by the European Union Horizon 2020 programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). This multi-stakeholder consortium includes industry partners. He reports research grant funding from AstraZeneca, Boehringer Ingelheim, and Intercept; consultancy on behalf of Newcastle University for Alimentiv, Akero, AstraZeneca, Axcella, 89Bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, Genfit, Genentech, Gilead, GlaxoSmithKline, Hanmi, HistoIndex, Intercept, Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGMBio, Novartis, Novo Nordisk, PathAI, Pfizer, Prosciento, Poxel, Resolution Therapeutics, Roche, Ridgeline Therapeutics, RTI, Shionogi, and Terns; speaker fees/honoraria from Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape, and Springer Healthcare; and royalties from Elsevier. LBK is an employee of Novo Nordisk A/S.