Selective Agonists of Thyroid Hormone Receptor Beta for the Treatment of NASH

Abstract:
This editorial discusses the potential of thyroid hormone receptor beta (THR-β) agonists, such as resmetirom, for treating nonalcoholic steatohepatitis (NASH). The MAESTRO NASH phase 3 trial demonstrated that resmetirom significantly improved NASH resolution and fibrosis reduction compared to placebo, with favorable effects on lipid metabolism and a manageable safety profile. However, the drug's modest efficacy (placebo-subtracted effects of 16.4–20.7% for NASH resolution and 10.2–11.8% for fibrosis improvement) suggests most patients will require combination therapy with existing treatments like GLP 1 receptor agonists or pioglitazone. The editorial highlights endocrine considerations, including effects on sex hormone binding globulin, thyroid axis suppression, and bone metabolism, while emphasizing the need for long term monitoring. It also addresses practical challenges regarding cost, patient selection, and treatment access given the large population with NASH and advanced fibrosis.

Abstract:
This editorial discusses the potential of thyroid hormone receptor beta (THR-β) agonists, such as resmetirom, for treating nonalcoholic steatohepatitis (NASH). The MAESTRO NASH phase 3 trial demonstrated that resmetirom significantly improved NASH resolution and fibrosis reduction compared to placebo, with favorable effects on lipid metabolism and a manageable safety profile. However, the drug's modest efficacy (placebo-subtracted effects of 16.4–20.7% for NASH resolution and 10.2–11.8% for fibrosis improvement) suggests most patients will require combination therapy with existing treatments like GLP 1 receptor agonists or pioglitazone. The editorial highlights endocrine considerations, including effects on sex hormone binding globulin, thyroid axis suppression, and bone metabolism, while emphasizing the need for long term monitoring. It also addresses practical challenges regarding cost, patient selection, and treatment access given the large population with NASH and advanced fibrosis.