Insights into the results of Resmetirom trials: Can a thyroid hormone receptor agonist be the holy grail of MASH therapy?

Despite the heavy individual patient and socioeconomic burden of metabolic dysfunction-associated steatohepatitis (MASH), until recently, no pharmacological therapy for MASH was approved, with available treatment options geared towards associated cardiometabolic risk factors. Accelerated approval of resmetirom, a thyroid hormone receptor-β agonist to be used in conjunction with diet and exercise, marks a significant step forward in the treatment of MASH, offering tempered optimism to healthcare providers and millions of patients around the world for more effective management. Evidence from phase 2 and 3 clinical trials suggests that resmetirom has the potential to alleviate hepatic fibrosis and inflammation and significantly reduce liver lipid content. Notwithstanding this landmark event, the clinical implementation of resmetirom comes with important challenges, for example, ensuring patient access to treatment and demonstrating effects on hard MASH-related outcomes, such as progression to cirrhosis and hepatocellular carcinoma. Additional considerations include the evaluation of co-administration with other hepatoprotective treatments and the assessment of the efficacy in specific MASH sub-phenotypes. Furthermore, the accumulation of real-world data and experience is expected to help answer the remaining questions about the (long-term) effectiveness and safety profile of the drug. The purpose of this article is to provide an updated and critical review of the mechanisms of action, efficacy, and safety of resmetirom based on the latest clinical trials, to define its place within the broader landscape of MASH management, and to highlight current knowledge gaps and opportunities for future research in the field.