Resmetirom is an orally administered, liver-targeted thyroid hormone receptor-β (THRβ) selective agonist that has recently gained FDA approval, marking a significant advancement in the treatment of MASH (metabolic dysfunction-associated steatohepatitis). It activates THRβ, a nuclear hormone receptor predominantly expressed in the liver, regulating metabolic pathways involved in fat synthesis, fatty acid oxidation, cholesterol metabolism, mitochondrial function, inflammation, and fibrosis.
In a phase III randomized controlled trial involving 966 patients with mild-to-moderate MASH, resmetirom demonstrated significant efficacy. Patients treated with 80 mg or 100 mg of resmetirom daily showed MASH resolution rates of 25.9% and 29.9%, respectively, compared to 9.7% in the placebo group. Additionally, fibrosis improvement was observed in 25% of resmetirom recipients, with the drug being safe and well-tolerated, despite common adverse events like diarrhea and nausea.
GLP-1 agonists, traditionally used for diabetes and obesity, are also being investigated for MASH treatment. These drugs may indirectly benefit MASH by reducing calorie intake, body weight, and insulin resistance, thereby decreasing liver lipid accumulation and inflammation. However, their effectiveness in improving fibrosis remains uncertain, with some studies, such as those involving semaglutide, showing no significant fibrosis improvement.
Combining resmetirom with GLP-1 agonists offers a synergistic approach to MASH treatment, targeting both intrahepatic and extrahepatic mechanisms. This combination could address the multifaceted nature of MASH and liver fibrosis more effectively. However, challenges such as the anti-fibrosis effects of GLP-1 agonists, long-term tolerability, and weight rebound after discontinuation of GLP-1 medication need to be addressed.
Resmetirom's oral administration and safety profile make it a convenient and accessible option for long-term use, especially for patients who may not be candidates for GLP-1 therapies. The FDA's accelerated approval of resmetirom, which does not require a biopsy diagnosis, further facilitates its use in clinical practice.
In conclusion, resmetirom and GLP-1 agonists represent promising avenues for MASH treatment, each with its unique mechanisms and challenges. Their combined use could offer a comprehensive approach to managing this complex condition.
