Revolutionizing MASLD treatment with GLP-1 receptor agonists

By Vijay Kumar MalesuReviewed by Benedette Cuffari, M.Sc.Dec 16 2024

GLP-1 receptor agonists emerge as promising therapies for MASLD, addressing metabolic dysfunction and offering potential improvements in liver health and fibrosis management.

Study: Current Status of Glucagon-like Peptide-1 Receptor Agonists in Metabolic Dysfunction-associated Steatotic Liver Disease: A Clinical Perspective. Image Credit: crystal light / Shutterstock.com

In a recent review published in the Journal of Clinical and Translational Hepatology, researchers explore the therapeutic potential and clinical insights of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the management of metabolic dysfunction-associated steatotic liver disease (MASLD).

MASLD: Prognosis and treatments

MASLD, formerly referred to as nonalcoholic fatty liver disease, represents a significant global health burden, with rising prevalence and associated risks of fibrosis, cirrhosis, and mortality. Defined by hepatic steatosis and at least one cardiometabolic risk factor such as type 2 diabetes mellitus (T2DM), obesity, or hypertension, MASLD affects over 30% of the global population.

Current management for MASLD primarily relies on lifestyle modifications, with limited pharmacological options. Although the recent approval of resmetirom shows promise, its long-term efficacy and economic feasibility remain unclear. Thus, further research is crucial to expand effective therapies, particularly those targeting metabolic dysfunction and improving clinical outcomes.

GLP-1RAs: a potential breakthrough in MASLD management

GLP-1RAs, which are a class of drugs originally developed for managing T2DM, mimic the effects of GLP-1, an incretin hormone involved in glucose regulation, appetite suppression, and metabolic balance. In addition to their established benefits for the management of diabetes and obesity, GLP-1RAs have shown potential in managing MASLD through mechanisms such as reducing hepatic lipogenesis, improving insulin sensitivity, and modulating inflammation. By addressing key drivers of MASLD pathogenesis, GLP-1RAs may serve as effective pharmacological tools in managing the disease.

The ability of GLP-1RAs to promote weight loss is particularly relevant for MASLD due to the close association between obesity and liver fat accumulation. Furthermore, the anti-inflammatory and antifibrotic effects of GLP-1RAs offer additional benefits in reducing liver injury and slowing fibrosis progression. These multifaceted effects position GLP-1RAs as a promising therapeutic option in MASLD, thus warranting further investigation through clinical trials.

Evidence from clinical trials

Several GLP-1RAs, including liraglutide, semaglutide, and tirzepatide, have been evaluated in clinical trials for their efficacy in the management of MASLD.

Liraglutide, a once-daily subcutaneous injection, was assessed in a 48-week phase II trial involving patients with metabolic dysfunction-associated steatohepatitis (MASH). The study reported a significant improvement in the resolution of MASH, with 39% of patients achieving this outcome as compared to 9% in the placebo group.

Although liraglutide also reduced fibrosis progression, improvements in fibrosis scores were not statistically significant. Gastrointestinal side effects, including nausea and diarrhea, were the most commonly reported adverse events.

Semaglutide, a weekly GLP-1RA, has shown promising results in multiple trials. For example, a 72-week phase II trial involving 320 patients with MASH, reported MASH resolution rates of up to 59% at the highest dose of 0.4 mg daily as compared to 17% in the placebo group.

However, the impact on fibrosis improvement was less consistent, with no significant differences observed between semaglutide and placebo in some trials. Like liraglutide, gastrointestinal symptoms were the most common side effects, though generally well-tolerated.

Tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, has also been studied for the treatment of MASLD. In a 52-week phase II trial involving patients with MASH and advanced fibrosis, tirzepatide demonstrated dose-dependent benefits in resolving MASH, with the highest dose achieving a resolution rate of 62%. Improvements in fibrosis were observed in up to 55% of patients, although these results did not consistently reach statistical significance.

Similar to other GLP-1RAs, tirzepatide was associated with mild to moderate gastrointestinal side effects.

Challenges 

Despite promising results, several challenges are associated with the use of GLP-1RAs for MASLD. Histological outcomes, such as fibrosis regression and MASH resolution, are the primary endpoints in clinical trials; however, these assessments are subject to variability and placebo effects. The development of reliable non-invasive biomarkers is essential for reducing the dependency on liver biopsies and improving the accuracy of clinical trials.

Future directions for GLP-1RAs in MASLD

The future of GLP-1RAs in MASLD management lies in addressing these challenges through innovative research and clinical trials. Combination therapies that pair GLP-1RAs with other drugs targeting different pathways, such as antifibrotic agents or anti-inflammatory drugs, may enhance their therapeutic efficacy. Trials exploring such combinations could pave the way for more comprehensive treatment strategies.

MASLD is a heterogeneous disease influenced by genetic, metabolic, and environmental factors. Identifying patient subgroups that are most likely to benefit from GLP-1RAs based on these factors could improve treatment outcomes and minimize side effects.

Ongoing trials are expected to provide further insights into the role of GLP-1RAs in MASLD. For example, a phase III trial of semaglutide aims to evaluate its effects on MASH resolution, fibrosis improvement, and survival outcomes over an extended period. Similarly, trials investigating dual and triple receptor agonists, such as tirzepatide and survodutide, are expected to yield valuable data on the efficacy of these novel agents.

Conclusions

By addressing key metabolic dysfunctions, GLP-1RAs have the potential to reduce hepatic steatosis, resolve MASH, and mitigate fibrosis progression. Although clinical trials show encouraging results, challenges such as variability in histological outcomes, limited long-term data, and high costs persist. GLP-1RAs may ultimately provide an effective adjunct to lifestyle modifications, improving outcomes for patients with MASLD.