Resmetirom

Resmetirom and semaglutide are the first drugs to be approved for the pharmacological treatment of metabolic-associated steatohepatitis (MASH) and moderate-to-severe liver fibrosis. However, approval was based on histological endpoints obtained during a relatively short trial period, leaving some important questions unanswered.

Resmetirom acts directly on the liver by activating thyroid hormone receptor β. Semaglutide acts systemically, reducing weight and improving metabolism. Both drugs induce resolution of MASH and improve liver fibrosis in a significant proportion of patients. The drugs are generally well tolerated, but significant gastrointestinal side effects can occur. Patient selection for treatment and efficacy evaluation should be based on noninvasive tests (NITs), but a substantial unresolved issue remains. Further issues include monitoring and the duration of treatment, as well as the impact of treatment on hepatic and systemic disease outcomes. Ensuring fair access to treatment for all is a challenge facing the global health community.

This review explores the current approach to issues and challenges associated with using resmetirom and semaglutide in patients with MASH, proposing reference points to assist physicians in their clinical practice. Furthermore, we emphasize the importance of implementing interventions within the healthcare system to ensure equitable access to therapies.

The approval of new pharmacotherapies for metabolic dysfunction‐associated steatohepatitis (MASH) presents a critical need for value assessment. We evaluated the cost‐effectiveness of resmetirom, semaglutide and tirzepatide for U.S. adults with MASH and F2–F3 fibrosis.

We developed a Markov cohort model with a lifetime horizon from the perspective of a U.S. healthcare payer. The model simulated biopsy‐confirmed patients with MASH progressing through liver‐specific health states. Efficacy inputs for fibrosis regression and MASH resolution were obtained from a Bayesian network meta‐analysis. Each pharmacotherapy was compared individually against standard of care; a formal sequential incremental analysis across active therapies was not performed. Cost‐effectiveness was assessed against the standard of care using a $100 000/QALY willingness‐to‐pay threshold.

In the base‐case analysis, tirzepatide had the largest QALY gain and the lowest incremental cost relative to standard of care, yielding an incremental cost‐effectiveness ratio of ($42 705/QALY). Semaglutide was also cost‐effective (ICER: $80 076/QALY). Resmetirom (ICER: $273 445/QALY) exceeded the WTP threshold. Drug price was the most influential parameter in sensitivity analyses; probabilistic sensitivity analysis showed a 99.5% probability of cost‐effectiveness for tirzepatide and 89.8% for semaglutide at $100 000/QALY.

At current U.S. prices, tirzepatide and semaglutide are cost‐effective for MASH with F2–F3 fibrosis, while resmetirom is not. The tirzepatide finding should be interpreted with caution, given that it is not yet FDA‐approved for MASH and its effect estimate is based on a network meta‐analysis of a phase 2 trial. Payer coverage and equitable access to MASH therapies require value‐based pricing strategies.