Emerging Role of GLP-1 Receptor Agonists for the Treatment of MASH

Abstract:

Emerging as a major global health concern, metabolic dysfunction-associated steatohepatitis (MASH) is closely linked to obesity, type 2 diabetes, and other metabolic disorders. Advances in metabolic research have positioned glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as a promising therapeutic option for MASH, extending their use beyond diabetes and obesity management. This article examines the potential of GLP-1 RAs in MASH treatment, exploring their mechanisms of action, clinical benefits, developmental challenges, and evaluation strategies in preclinical MASH models.

Introduction:

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 25% of the global population ^[1], and 20-30% of these cases progress to a more severe stage known as MASH^[2]. Primary pathological features include hepatic fat accumulation, inflammation, fibrosis, and ballooning degeneration of hepatocytes. If left untreated, these changes can progress to liver fibrosis, cirrhosis, and ultimately liver failure.

MASH is more commonly found in individuals with obesity, insulin resistance, and metabolic syndrome. Lifestyle changes have led to a surge in the incidence of obesity and type 2 diabetes, correlating to the increasing global prevalence of MASH (Fig.1). Often considered a “silent” disease, MASH frequently presents no noticeable symptoms until substantial liver damage has already occurred, making early detection through regular screenings vital to prevent further progression and complications. Despite extensive investment in MASH drug development, only one medication (resmetirom) has been officially approved for MASH treatment to date. Achieving breakthroughs in MASH therapeutics remains a formidable challenge.

GLP-1 RAs in MASH: Mechanisms of Action

Although primarily used for the management diabetes and obesity, recent research indicates that GLP-1 RAs may also offer benefits to liver health. GLP-1 RAs work by mimicking the actions of the naturally occurring hormone GLP-1. They bind to its receptors, which are primarily located in the pancreas, brain, and gut. This triggers a cascade of beneficial effects such as increased insulin secretion, improved glucose uptake, and a sensation of satiety, making them valuable in managing metabolic disorders like diabetes and obesity.

Fig.1 Prevalence MASH and the key role of GLP-1 RAs in its treatment ^[2]

GLP-1 RAs work to improve liver function by indirectly regulating factors such as insulin and glucose levels in the bloodstream, thus diminishing liver fat accumulation and the associated toxicity from lipid buildup (Fig. 2) ^[2]. When GLP-1 binds to its receptor, it amplifies the insulin signaling pathway, causing increased phosphorylation of insulin receptor substrates and activating the PI3K/Akt pathway, which ultimately results in enhanced glucose uptake, utilization within the liver, and reduced production of glucose (gluconeogenesis). Concurrently, GLP-1 also reduces fat build-up in the liver by activating AMPK, which then inhibits fatty acid synthesis while promoting the breakdown of fatty acids (beta-oxidation), leading to less lipid droplet accumulation in hepatocytes. GLP-1 exerts anti-inflammatory effects by suppressing the NF-κB signaling pathway, which leads to a decrease in the production of pro-inflammatory cytokines like TNF-α and IL-6, thereby mitigating liver inflammation and fibrosis. Additionally, GLP-1 can inhibit apoptosis by activating the PI3K/Akt pathway, promoting the anti-apoptotic protein Bcl-2 and hindering the activity of caspases. This process further slows the progression of liver fibrosis and cirrhosis through reducing cell death ^[3].

Fig.2 Pleiotropic effects of GLP1-RA leading to improvement MASLD/MASH ^[2]

GLP-1RA in MASH Treatment: Clinical Progress 

Several GLP-1RAs and related agents are currently in various phases of clinical development for MASH treatment ^[4]. According to data presented at the AASLD Liver Meeting in November 2024, semaglutide has shown significant efficacy in managing liver inflammation and fibrosis in a phase III clinical trial. Patients taking semaglutide showed considerable improvement compared to those on placebo, potentially positioning semaglutide as a promising option for MASH. At week 72, primary endpoints showed 62.9% of people treated with 2.4 mg semaglutide achieved resolution of steatohepatitis with no worsening of liver fibrosis compared to 34.1% on placebo. In addition, 37.0% of people treated with 2.4 mg semaglutide achieved improvements in liver fibrosis with no worsening of steatohepatitis compared to 22.5% on placebo. Secondary endpoints showed 32.8% of patients treated with 2.4 mg semaglutide achieved both resolution of steatohepatitis with improvements in liver fibrosis (as compared to 16.2% of patients on placebo). Based on these results, semaglutide is expected to be submitted to FDA for MASH in 2025, potentially becoming the first GLP-1 RA officially approved for MASH.

Tirzepatide, a dual GIP/GLP-1 receptor co-agonist, also demonstrated significant efficacy in a phase II trial for MASH ^[6]. A 52-week treatment with tirzepatide (5mg, 10mg, or 15 mg) led to a significant MASH resolution without worsening liver fibrosis compared to placebo (Fig.3). However, larger and longer-term studies are still needed to comprehensively evaluate its impact on key liver issues and fully assess its safety profile.

Fig.3 Proportion of patients achieving MASH resolution without worsening of fibrosis with tirzepatide ^[6]

While GLP-1 RAs are proving effective in treating MASH, their lack of direct action on liver tissue could limit their effectiveness in patients with advanced liver fibrosis or cirrhosis. Therefore, the combined use of GLP-1 RAs with therapies targeting intrahepatic pathways, such as thyroid hormone receptor β (THR-β) agonists, fibroblast growth factor-21 (FGF21) analogues, and peroxisome proliferator-activated receptor (PPAR) agonists, presents a promising approach for MASH treatment.

Case Study: Efficacy of Semaglutide and Tirzepatide in Mouse and Rat MASH Models

WuXi Biology’s in vivo pharmacology team assessed the efficacy of semaglutide and tirzepatide in mouse and rat MASH models. The mouse MASH model was established using a high-fat diet combined with carbon tetrachloride (CCl₄) induction, and efficacy tests were conducted with both semaglutide and tirzepatide (Fig.4). Considering the potential appetite-reducing effects of GLP-1 RAs, diet-restricted control groups were included for both drugs, ensuring consistent food intake between treatment and control groups, thereby minimizing any dietary bias.

Hepatic histopathology (Fig.4-A, B) showed that both semaglutide and tirzepatide significantly reduced the non-alcoholic fatty liver disease activity score (NAS) by decreasing steatosis and cell ballooning, compared to the non-restricted diet model group. However, neither drug affected liver fibrosis in these groups. In contrast, both semaglutide and tirzepatide treated groups showed a significant reduction in liver fibrosis compared to their respective diet-restricted controls.

Consistent with these pathological findings, both semaglutide and tirzepatide significantly lowered liver triglycerides (TG) and total cholesterol (TC) (Fig.4-C, D). Both drugs also led to significant reductions in liver enzymes and blood lipid levels, with varying effects on serum TG and TC in the diet-restricted groups (Fig.4-E, F, G, H). These results indicate that GLP-1 RAs exert anti-MASH effects through mechanisms independent of diet. Further investigation of these mechanisms will be explored through transcriptomic analyses.

Fig.4 Efficacy evaluation of semaglutide and tirzepatide in HFD+CCl₄-Induced MASH Mouse Models

A. Liver Tissue Pathology NAS (H&E Staining Score); B. Liver Fibrosis (Picrosirius Red, PSR); C. Liver Triglycerides (TGs) D. Total Cholesterol (TC); E-H. Serum Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), TG, TC. Dietary Restriction (DR） ***p＜0.001, **p＜0.01, *p＜0.05（Source: WuXi AppTec Internal Data）

Additionally, the efficacy of semaglutide in a rat MASH model induced by a choline-deficient high-fat diet (CDHFD) was evaluated. Semaglutide significantly reduced both the NAS score and liver fibrosis area (Fig.5-A, B). Given the fibrosis severity in this model, it is speculated that alleviation of liver fibrosis may lead to increased TG and TC levels (Fig.5-C, D). Biochemical analysis further revealed that semaglutide significantly lowered AST, TG, and TC, although with a slight increase in serum ALT levels (Fig.5-E, F, G, H). Collectively, these data suggest that semaglutide exhibits anti-MASH efficacy in the CDHFD-induced rat model.

Overall, these results demonstrate that GLP-1 RAs may exert their therapeutic effects through multiple mechanisms in MASH treatment. The observed variations in efficacy across different models underscore the need for comprehensive evaluations using various animal models to fully reveal the efficacy of GLP1-RA drugs and elucidate their mechanisms of action.

Fig.5 Efficacy Assessment of Semaglutide in the CDHFD-Induced MASH Rat Models.     

Liver Tissue Pathology NAS (H&E Staining Score); B. Liver Fibrosis Percentage based on PSR Staining; C. Liver TG; D. Liver TC; E-H. Serum ALT, AST, TG, TC ***p < 0.001, **p < 0.01, *p < 0.05 vs Model (Source: WuXi AppTec internal data)

About WuXi Biology Liver Disease Platform

WuXi Biology has developed a comprehensive portfolio of liver disease models, including MASH, ASH, liver fibrosis, cirrhosis, acute/chronic liver injury, liver failure, liver cancer, and various biliary diseases (Fig.6), in mice and rats. The platform is committed to providing high-quality in vivo pharmacology research services to accelerate the development of novel therapies for liver diseases. To date, the team has successfully conducted drug testing for global clients across a wide range of molecular profiles and therapeutic targets, several of which have advanced into clinical stages or received FDA approval.

Fig.6 WuXi Biology Liver Disease Models

References

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