Metabolic Dysfunction–Associated Steatohepatitis (MASH) and Emerging Treatments
Overview:
Metabolic dysfunction–associated steatohepatitis (MASH), a prevalent liver disease worldwide, is primarily driven by obesity and currently lacks effective treatments. Glucagon-like peptide-1 (GLP-1) receptor agonists, emerging as promising anti-obesity treatments, may offer a potential therapeutic option for MASH. Recent studies explore the efficacy of these agents, particularly when combined with other incretin hormones or complementary pathway molecules.
Semaglutide Study:
A phase 2 trial investigated , a GLP-1 receptor agonist, in MASH patients. While semaglutide achieved steatohepatitis resolution in 40-59% of participants, it did not significantly reduce liver fibrosis, a crucial surrogate endpoint. Furthermore, it failed to improve histological outcomes in patients with cirrhosis.
Enhanced GLP-1 Receptor Agonist-Based Treatments:
1. Tirzepatide:
- Study by Loomba et al.: Tirzepatide, a dual agonist combining GLP-1 receptor and glucose-dependent insulinotropic polypeptide receptor agonists, was evaluated in MASH patients with stage 2 or 3 fibrosis.
- Results: Resolution of MASH without fibrosis worsening occurred in 44%, 56%, and 62% of participants receiving 5-mg, 10-mg, and 15-mg weekly doses, respectively, compared to 10% with placebo. Liver fibrosis improvement was observed in ~50% of tirzepatide-treated participants, compared to 30% with placebo. Body weight reduction reached up to 16% with the highest dose. Adverse events were mainly mild to moderate gastrointestinal issues, with less than 5% leading to treatment discontinuation.
2. Survodutide:
- Study by Sanyal et al.: Survodutide, a dual GLP-1 receptor and glucagon receptor agonist, was tested in MASH patients with stage 1, 2, or 3 fibrosis.
- Results: MASH improvement without fibrosis worsening was achieved in 47%, 62%, and 43% of participants receiving 2.4-mg, 4.8-mg, and 6.0-mg doses, respectively, compared to 14% with placebo. Fibrosis improvement was observed in 32% of the 6.0-mg group versus 18% with placebo. Weight loss ranged from 10-13%. However, a high dropout rate (~20%) occurred due to adverse events during dose escalation, with gastrointestinal issues, fatigue, elevated pancreatic enzymes, and tachycardia more frequent than with placebo.
Conclusions and Considerations:
- The trials mark significant progress in treating MASH, showing potential histological improvements, including fibrosis reduction. However, limitations include small sample sizes, short trial durations, and limited diversity among participants.
- Treatment applicability remains uncertain, particularly concerning long-term efficacy, cost, and accessibility challenges, potentially exacerbating health inequalities.
- Both trials underscore the need for continued research to refine treatment approaches, assess long-term outcomes, and determine optimal patient selection, especially for those with advanced cirrhosis.
https://www.nejm.org/doi/full/10.1056/NEJMoa2401943