A Review on Resmetirom: An Oral Thyroid Hormone Receptor-β Agonist for the Treatment of Metabolically dysfunction-Associated Steatohepatitis (MASH)

Abstract

Metabolically dysfunction-associated steatohepatitis (MASH) is a progressive liver condition associated with type 2 diabetes (T2D), obesity, and dyslipidaemia, all of which are components of metabolic syndrome. In 2024, resmetirom, a selective thyroid hormone receptor-β (THR-β) agonist, became the first treatment for non-cirrhotic MASH with mild to advanced fibrosis to receive FDA approval, and in 2025, it was conditionally approved by the European Medicines Agency (EMA) for fibrotic MASH. Resmetirom enhances β-oxidation and lipid metabolism, leading to a reduction in hepatic fat, inflammation, and fibrosis, while minimizing systemic effects on the thyroid or heart. It is intended to be used alongside lifestyle modifications, such as dietary changes and exercise, to optimize patient outcomes. Nevertheless, discrepancies between clinical trial populations and real-world payer criteria reveal access challenges that necessitate policy reform. Effective screening programs rely on educating healthcare providers from various disciplines and establishing consistent standards. Future research should investigate the potential of resmetirom in combination with agents such as GLP-1 receptor agonists, SGLT2 inhibitors, and statins, particularly in light of recent long-term safety data regarding these drug classes and their effects on the thyroid axis. Achieving equitable access will require fair payer endpoints, cost-effectiveness evaluations, and consideration of patient-reported outcomes. Resmetirom signifies a significant advancement in the management of MASH, providing metabolic advantages in conjunction with clinical and lifestyle interventions. Metabolically-dysfunctional-associated steatotic liver disease (MASLD) impacts nearly one-third of adults globally, with 10–30% of cases progressing to MASH or fibrosis, especially in individuals with obesity or type 2 diabetes. Current guidelines endorse resmetirom for non-cirrhotic fibrotic MASH (typically LSM-VCTE 10–20 kPa or MRE 3.1–4.4 kPa), while excluding patients with cirrhosis, active liver disease, substantial alcohol consumption, or untreated thyroid disorders. Monitoring protocols include assessing hepatic safety, thyroid function when necessary, and evaluating response through non-invasive tests and ALT measurements after 6–12 months. Data from the real world indicate a swift adoption of non-invasive eligibility tools, initial enhancements in liver stiffness, and a common concurrent use of GLP-1 receptor agonists, with the response being independent of weight-loss therapies. With the recent approval of semaglutide for fibrotic MASH, determining the optimal integration of resmetirom within treatment algorithms, exploring combination strategies with GLP-1 receptor agonists, and assessing the long-term impacts on liver and cardiometabolic outcomes are essential priorities. This review consolidates the evidence supporting the conditional approval of resmetirom, delineates current clinical guidelines, shares early real-world experiences, and emphasizes the ongoing challenges and future directions in the management of fibrotic MASH.