FibrosisLab
Article
2025-12-08

Semaglutide (Wegovy): A Metabolic Approach Changing the Landscape of MASH Treatment

Semaglutide demonstrated remarkable results in the ESSENCE trial. This article explores its mechanism (direct vs. indirect), efficacy on non-invasive markers like ELF score, and the debate surrounding its application for "Lean MASH".

A "Metabolic" Approach to MASH Treatment

On August 15, 2025, Semaglutide (brand name Wegovy), which had already taken the world by storm as an obesity treatment, finally obtained FDA approval as a treatment for MASH (non-cirrhotic, F2-F3). This signifies the dawn of an era where MASH is treated not just as a "liver disease," but as a systemic "Syndromic disease."

ESSENCE Trial: Overwhelming Efficacy and Detailed Data

The results of the Phase 3 ESSENCE trial (Part 1, 1197 participants) cemented the potential of GLP-1 receptor agonists in MASH treatment.

Primary Endpoint Results (Semaglutide 2.4mg Group)

  • MASH Resolution (NASH Resolution):
    • Semaglutide Group: 62.9% (vs. Placebo 34.3%, p<0.001)
    • [Regarding High Placebo Response]: Even the placebo group showed a high resolution rate of approximately 34%. This is attributed to improved quality of lifestyle counseling and appropriate patient selection via non-invasive tests (NITs) in recent trials, leading to an overall trend of improvement. The fact that a clear difference was shown despite the raised hurdle for proving significant difference in active drug groups is highly significant.
  • Fibrosis Improvement:
    • Semaglutide Group: 36.8% (vs. Placebo 22.4%, p<0.001)
    • [Interpretation of Data]: The figure might appear lower compared to the MASH resolution rate (approx. 63%). However, physical improvement of fibrosis (remodeling) takes more time than the resolution of inflammation (a time lag). A larger difference is expected to emerge with long-term administration.

Important Secondary Endpoints: Improvement in Non-Invasive Markers

In addition to histological evaluation, improvement in non-invasive fibrosis markers was also confirmed.

  • ELF Score (Enhanced Liver Fibrosis Score):
    • In the Semaglutide group, a significant reduction of -0.6 units (between-group difference) compared to the placebo group was observed. The ELF score is known for its high prognostic ability, suggesting a reduction in the risk of future liver-related events.
  • Liver Enzymes:
    • Parallel to weight loss, significant reductions of ALT approx. 40%, AST approx. 30%, and GGT approx. 40% have been reported in many trials, supporting the sedation of liver inflammation.

Mechanism Debate: "Weight Loss" Effect or "Direct" Action?

Hot debate continues regarding the mechanism of why Semaglutide improves liver tissue so powerfully.

1. Weight Loss Dependent (Indirect) Action

This is currently the mainstream view.

  • In the ESSENCE trial (at week 72), weight loss of -10.5% in the Semaglutide group vs. -2.0% in the placebo group was confirmed.
  • [The 10% Rule]: Past lifestyle intervention studies have reported that weight loss of 10% or more achieves MASH resolution in approx. 90% and fibrosis improvement in approx. 45% of cases. Semaglutide is thought to exert its effect by pharmacologically reproducing this "powerful weight loss."
  • Improvement in the systemic environment, such as reduced influx of free fatty acids from adipose tissue and increased adiponectin, contributes to this.

2. Weight Loss Independent (Direct) Action

On the other hand, although GLP-1 receptor expression is scarce in hepatocytes, its presence is suggested in Kupffer cells (macrophages) and sinusoidal endothelial cells.

  • Contribution of "Pleiotropic effects" such as anti-inflammatory action and reduction of oxidative stress is also considered, but these are mainly based on animal models and in vitro data, and further verification is needed to determine the extent of their contribution in humans.

Comparison with Other Drugs and Usage Differentiation

Difference from Tirzepatide (GLP-1/GIP)

Comparing with Tirzepatide (SYNERGY-NASH trial), another incretin-related drug, reveals interesting differences.

  • MASH Resolution Rate: The SYNERGY-NASH trial showed dose-dependent improvement (5mg: 51.8%, 10mg: 62.8%, 15mg: 73.3%), with the high-dose group showing a high figure exceeding 70%.
  • [Difference in Trial Scale]: However, SYNERGY-NASH is a Phase 2 trial (190 participants), differing greatly in scale from ESSENCE (Phase 3 trial with 1197 participants). Since direct comparison trials have not been conducted at this point, caution is needed in simple superiority comparisons.

Side Effects and Consideration for "Muscle Mass"

  • Gastrointestinal Symptoms: Observed in more than half of the patients overall. The breakdown is reported as roughly nausea 36%, diarrhea 27%, constipation 22%, vomiting 19%. In many cases, these are manageable with dose titration.
  • [Important] Maintenance of Muscle Mass (Sarcopenia risk):
    • There is concern that rapid weight loss caused by GLP-1 agents is accompanied by loss of muscle mass (Lean body mass), not just fat.
    • Especially in elderly MASH patients, muscle loss risks leading to decline in physical function (sarcopenia) and worsened prognosis. Therefore, it is strictly important to not just "inject the medicine" but to combine sufficient protein intake and exercise therapy to maintain muscle mass.

Conclusion

Semaglutide is undoubtedly "one of the most potent options (Ideal candidate)", especially for MASH patients with obesity (BMI ≥ 30) or Type 2 Diabetes.

On the other hand, for "Lean MASH (BMI < 25)," challenges remain regarding risks such as muscle mass decline due to excessive weight loss. For this segment, Resmetirom, which acts specifically on the liver without accompanying weight loss, may be more suitable. "Differentiation" according to the patient's body type and complications will be the key to future treatment.