Current status of glucagon-like peptide-1 receptor agonists in metabolic dysfunction-associated steatotic liver disease: A clinical perspective

The term "nonalcoholic fatty liver disease" (NAFLD) has long been used to describe liver steatosis not related to excessive alcohol consumption. However, growing recognition of its close association with metabolic dysfunction has led to the adoption of a more precise terminology: metabolic dysfunction-associated steatotic liver disease (MASLD). This term was proposed in 2020 and was endorsed in 2023 by a multisociety consensus panel. MASLD refers to hepatic steatosis occurring in the context of at least one cardiometabolic risk factor (CMRF), such as obesity, type 2 diabetes, hypertension, or dyslipidemia. The global prevalence of MASLD is substantial, with estimates ranging from 30% to 32%, and the incidence of associated conditions like liver fibrosis is expected to rise dramatically in the coming years. Despite the widespread burden, therapeutic options remain limited. Current treatments primarily focus on lifestyle interventions; however, they often fail to provide long-term solutions, highlighting the need for more effective pharmaceutical interventions.

Mechanisms of GLP-1RAs in MASLD

GLP-1 is a gut-derived hormone that plays a crucial role in glucose metabolism, appetite regulation, and the modulation of fat storage. GLP-1 receptor agonists (GLP-1RAs) mimic the action of endogenous GLP-1 and have been shown to provide substantial benefits in the management of type 2 diabetes and obesity. Their potential role in MASLD management is multifaceted, acting on multiple levels to improve metabolic dysfunction.

1. Systemic Metabolic Benefits: GLP-1RAs exert beneficial effects on glucose and lipid metabolism, two critical factors in MASLD. By enhancing insulin secretion, inhibiting glucagon release, and delaying gastric emptying, GLP-1RAs help reduce blood glucose levels, improve insulin sensitivity, and lower body weight. These metabolic effects are particularly important in patients with MASLD, where insulin resistance and obesity exacerbate liver fat accumulation. Furthermore, GLP-1RAs promote beneficial changes in lipid metabolism, including reduced visceral fat and improvements in lipid profiles, which are known to influence liver health and contribute to the progression of MASLD.
2. Neuromodulation: There is increasing evidence that the central nervous system (CNS) plays a role in regulating liver metabolism, inflammation, and regeneration. GLP-1RAs are known to influence appetite and satiety by acting on the hypothalamus and brainstem. Additionally, GLP-1 receptors are expressed in various parts of the CNS, suggesting that GLP-1RAs may also affect hepatic metabolism through the brain-liver axis. Although the exact mechanisms remain unclear, it is believed that GLP-1RA activation of neural pathways may help modulate hepatic lipid metabolism and reduce inflammation, contributing to the improvement of MASLD.
3. Direct Hepatic Effects: The direct effects of GLP-1RAs on the liver have been a subject of ongoing debate. While some studies suggest that GLP-1 receptors are expressed in liver cells, other research challenges this notion, indicating that these effects might be mediated by extrahepatic mechanisms, such as neuroregulation or systemic metabolic changes. Nonetheless, preclinical studies suggest that GLP-1RAs may modulate liver inflammation, fibrosis, and lipid metabolism by influencing cellular pathways involved in oxidative stress, endoplasmic reticulum stress, and macrophage activation. Although the exact hepatic targets remain uncertain, these findings highlight the potential of GLP-1RAs as a therapeutic option for liver-related complications in MASLD.

Clinical Applications and Evidence

Several GLP-1RAs have been tested in clinical trials for their effects on MASLD, with liraglutide, semaglutide, and tirzepatide showing promising results in improving liver histology, reducing liver fat, and enhancing metabolic parameters.

• Liraglutide: The most widely used GLP-1RA, liraglutide, has demonstrated significant benefits in patients with MASLD and metabolic comorbidities like type 2 diabetes. In the LEAN trial, liraglutide 1.8 mg daily significantly improved liver histology, including the resolution of MASH and reduced liver fibrosis progression. In addition to its metabolic benefits, liraglutide has been shown to reduce liver fat content and improve liver enzymes, making it a valuable therapeutic agent in MASLD management.
• Semaglutide: Semaglutide, a more potent GLP-1RA with a longer duration of action, has also shown promising results in managing MASLD. Clinical trials have demonstrated that semaglutide improves liver fibrosis and steatosis, especially in patients with advanced fibrosis (F2/F3). The drug has demonstrated clear benefits in weight loss, metabolic control, and liver-related outcomes, with ongoing studies further investigating its effects on liver fibrosis and cirrhosis.
• Tirzepatide: Tirzepatide, a dual GLP-1R/GIP receptor agonist, has shown superior efficacy in reducing liver fat content and improving metabolic outcomes in patients with MASLD. Early clinical trials indicate that tirzepatide not only enhances glucose control but also has potential benefits for liver fibrosis and MASH regression. The drug's dual receptor action provides a novel approach, potentially offering greater therapeutic efficacy than traditional GLP-1RAs.

Challenges and Future Directions

Despite the encouraging results, several challenges remain in optimizing the use of GLP-1RAs for MASLD treatment. One of the major obstacles is the lack of reliable clinical endpoints for assessing long-term liver benefits. Traditional endpoints like liver transplant, cirrhosis progression, or liver-related mortality require extensive and long-term clinical trials, making them difficult to use in the short term. Histological endpoints, including the resolution of MASH or the improvement of liver fibrosis, are currently the most accepted measures, but variability in pathological readings and placebo responses complicate their use.

Furthermore, while the metabolic benefits of GLP-1RAs are clear, their direct effects on liver fibrosis remain uncertain. Ongoing studies will help clarify these aspects and determine whether GLP-1RAs can be incorporated into broader treatment regimens for advanced liver disease.

Conclusions

GLP-1RAs represent a promising therapeutic class for the management of MASLD. These drugs offer multiple benefits beyond glucose control, including improvements in lipid metabolism, weight management, and liver health. As clinical research continues to evolve, GLP-1RAs may play an increasingly pivotal role in the treatment of MASLD, offering a new paradigm of metabolic modulation. Further investigation into their long-term efficacy, safety, and impact on liver fibrosis will be crucial in shaping the future of MASLD therapy, especially in patients with comorbidities such as type 2 diabetes and obesity.

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https://www.xiahepublishing.com/2310-8819/JCTH-2024-00271

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

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