Key Clinical Summary: GLP-1 Receptor Agonists in the Treatment of MASH and Metabolic Syndrome

This is a micro-learning module summary of Prof Arun Sanyal's MASH Academy session which you can find here.

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The MASH Academy was supported by an independent medical education grant from Novo Nordisk.

Editors Note:

Since this live education, the results of the ESSENCE trial (Phase 3 trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis) have been published:

https://pmc.ncbi.nlm.nih.gov/articles/PMC11784563/

Introduction:

This education provides an overview of the evolving role of GLP-1 receptor agonists (GLP-1 RAs) in the management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), previously known as NAFLD, and its more progressive form, MASH (Metabolic Dysfunction-Associated Steatohepatitis), within the broader context of metabolic syndrome. The liver in MASLD is often a "victim" of the systemic metabolic environment, highlighting the strong association and interplay between MASLD and comorbidities such as obesity, type 2 diabetes, cardiovascular disease, and chronic kidney disease. A holistic treatment approach targeting the underlying metabolically driven inflammation, rooted in excess adiposity, is crucial. The development of GLP-1 RAs represents a significant advancement in this area, offering a range of therapeutic options with varying potencies.

Weight Loss and Liver Outcomes:

While weight loss is a cornerstone of MASLD management, the traditional paradigm linking specific percentages of weight loss to histological improvements needs refinement. Studies show that:

Resolution of Steatohepatitis: While greater weight loss is generally associated with higher rates of MASH resolution, achieving 5% weight loss does not guarantee it. A significant proportion of non-responders achieve this level of weight reduction.
Fibrosis Improvement: Similarly, fibrosis regression can occur at weight loss levels below the traditionally cited 10%. Conversely, achieving 10% weight loss does not always lead to fibrosis improvement.
Key Takeaway: Weight loss is beneficial, but the relationship between the degree of weight loss and specific histological outcomes is complex and not a simple linear correlation. Approximately 20% or greater weight loss appears to be associated with more robust rates of MASH resolution.

GLP-1 Receptor Agonists: Mechanisms and Impact on Early-Stage MASLD:

GLP-1 RAs exert multiple metabolic effects, primarily outside the liver, including promoting weight loss, improving glucose control, and potentially offering cardiovascular and renal benefits. Semaglutide, a widely used GLP-1 RA, can achieve significant weight loss (up to 14% in the earlier studies from 2018, with higher doses now available). Newer agents, such as the triple agonist retatrutide, have also demonstrated substantial weight loss.

Early-Stage Disease: In individuals with early-stage MASLD and comorbid obesity or type 2 diabetes (established indications for GLP-1 RA use), these agents can effectively reduce liver fat content, potentially normalizing MRI-PDFF. While long-term data on preventing progression to advanced disease are still needed, early intervention with GLP-1 RAs for metabolic comorbidities may have a beneficial impact on the liver.
Liver Fat Mobilization: Liver fat reduction appears to plateau around 24 weeks of GLP-1 RA therapy, whereas visceral adipose tissue continues to decrease up to 48 weeks, suggesting sustained metabolic benefits.

GLP-1 Receptor Agonists in MASH with Fibrosis (Stage 2-3):

Studies have investigated the efficacy of GLP-1 RAs in patients with established MASH and significant fibrosis:

MASH Resolution: Semaglutide and tirzepatide have demonstrated significant rates of MASH resolution (up to 59% and 73%, respectively) in clinical trials, often associated with weight loss in the range of 12-15%. Higher degrees of weight loss (around 20%) appear to correlate with even greater rates of MASH resolution (approaching 90%).
Histological Components: GLP-1 RAs have shown improvement in hepatocellular ballooning, a key feature of MASH. The impact on inflammation appears more variable. Overall, these agents can reduce the NAFLD Activity Score (NAS).
Fibrosis Improvement: While early data with semaglutide showed a trend towards fibrosis improvement, more pronounced effects were observed in patients with stage 3 fibrosis. Tirzepatide studies suggest that achieving 20% or greater weight loss is associated with higher rates of fibrosis improvement (70% and above).
GLP-1/Glucagon Co-agonists: Agents like survodutide, targeting both GLP-1 and glucagon receptors, have shown promising results in MASH with fibrosis, demonstrating significant fibrosis improvement even with potentially less weight loss compared to pure GLP-1 RAs. This suggests a potential benefit from direct or indirect liver targeting through glucagon receptor activation.

Current Treatment Landscape for MASH with Fibrosis:

It's important to note that while GLP-1 RAs show significant promise, resmetirom is currently the only conditionally approved drug specifically for MASH with fibrosis and should be considered a frontline therapy in this population. GLP-1 RAs, vitamin E, and obeticholic acid are currently not approved for this indication and represent off-label uses. The results of ongoing Phase 3 trials with semaglutide in MASH with fibrosis are eagerly awaited. (Editors Note: these have now been published: https://pmc.ncbi.nlm.nih.gov/articles/PMC11784563/)

Role of GLP-1 Receptor Agonists in Patients with Cirrhosis:

Compensated Cirrhosis: A trial with semaglutide in patients with cirrhosis did not show significant benefits in MASH resolution or fibrosis improvement. However, retrospective data on metabolic surgery in patients with compensated cirrhosis suggest that significant weight loss (around 20%) can reduce major adverse liver outcomes, including progression to decompensation and mortality. This area requires further research to define the safety and efficacy of aggressive weight loss in this vulnerable population. Concerns regarding sarcopenia need careful consideration.
Decompensated Cirrhosis: The role of significant weight loss interventions in decompensated cirrhosis remains largely investigational and requires cautious evaluation.

Heterogeneity of Response and Future Directions:

The response to GLP-1 RA therapy in MASLD can be heterogeneous, likely due to the complex and multifactorial nature of the disease. Factors such as the stage of disease progression at the time of intervention, the degree of improvement in systemic metabolic parameters, changes in lipotoxic lipid delivery, adipokine profiles, AMP kinase activation, fibrogenic cytokine levels, and the gut microbiome may all play a role. Future research needs to focus on identifying patient subgroups who are most likely to benefit from GLP-1 RA therapy and understanding the underlying mechanisms of response.

Conclusion:

GLP-1 RAs represent a valuable and evolving therapeutic strategy in the management of MASLD and its associated metabolic comorbidities. Their ability to induce significant weight loss and exert pleiotropic metabolic benefits translates to histological improvements in MASH, particularly in early to moderate stages of fibrosis. While not yet approved specifically for MASH (with the exception of resmetirom for MASH with fibrosis), their established benefits in obesity and type 2 diabetes make them important considerations in the holistic management of patients with MASLD and metabolic syndrome. Achieving a weight loss of 20% or greater appears to be associated with more robust histological responses. Further research is needed to optimize their use across the spectrum of MASLD, including in patients with advanced fibrosis and cirrhosis, and to better understand the factors influencing individual patient responses. The ongoing clinical trials will provide crucial insights into the definitive role of GLP-1 RAs in improving long-term liver-related outcomes.