Resmetirom for Nonalcoholic Steatohepatitis (NASH)
Introducing resmetirom for NASH
Resmetirom (Rezdiffra) is anticipated to be the first FDA-approved treatment for nonalcoholic steatohepatitis (NASH) with fibrosis in adults.
- About 5% of U.S. adults are affected by NASH, a condition increasingly referred to as metabolic dysfunction-associated steatohepatitis (MASH) to emphasize its association with cardiometabolic risk factors like diabetes, dyslipidemia, and obesity.
- Until now, management has focused on lifestyle modification, optimizing comorbidities, and medications such as pioglitazone and semaglutide.
Mechanism of action and clinical outcomes
Resmetirom works by activating the thyroid hormone receptor-beta in the liver to enhance fat metabolism and reduce hepatic fat accumulation. Over 12 months, when combined with diet and exercise, resmetirom has been shown to achieve MASH resolution in approximately 1 in 6 patients and to improve fibrosis in about 1 in 10 patients compared to placebo.
Long-term considerations and comparison with other therapies
Currently, resmetirom’s effects on reducing the risk of cirrhosis, liver transplantation, or mortality remain uncertain, as most data are short-term. Ongoing trials aim to provide more insights, and preliminary evidence suggests that medications like semaglutide and tirzepatide can lead to MASH resolution in about one-third of patients, although they haven’t shown significant fibrosis improvement yet.
Patient selection and safety precautions
Targeted use for moderate to advanced fibrosis
Specialists may reserve resmetirom for patients with MASH and moderate to advanced fibrosis who have not achieved adequate results with diet, exercise, and management of related comorbidities like diabetes and obesity. Inform patients that gastrointestinal side effects (e.g., diarrhea, nausea) may persist initially, and urge them to report severe GI pain, which could indicate rare gallbladder complications. Regular liver function monitoring is essential to ensure safety.
Dosing and drug interactions
Liver injury is a potential side effect of resmetirom, so patients should report symptoms like nausea or jaundice. Typically, patients weighing less than 100 kg are dosed at 80 mg/day, while those over 100 kg may receive 100 mg/day. Monitor for drug interactions carefully: limit rosuvastatin or simvastatin to a maximum of 20 mg/day and pravastatin or atorvastatin to 40 mg/day to reduce the risk of statin-associated side effects.
References
- Harrison SA, Bedossa P, Guy CD, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med. 2024;390(6):497-509.
- Tice JA, Suh K, Fahim SM, et al. Resmetirom and Obeticholic Acid for Non-Alcoholic Steatohepatitis (NASH); Draft Evidence Report. Institute for Clinical and Economic Review, May 25, 2023. Available at: https://icer.org/assessment/non-alcoholic-steatohepatitis-2023.
- European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-1402.
- Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797-1835.
- Cusi K, Isaacs S, Barb D, et al. American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD). Endocr Pract. 2022;28(5):528-562.
