Resmetirom for Nonalcoholic Steatohepatitis (NASH)

Resmetirom (Rezdiffra) is set to become the first medication approved for treating nonalcoholic steatohepatitis (NASH) with fibrosis in adults. About 5% of adults in the US have NASH. You will start to hear NASH called metabolic dysfunction-associated steatohepatitis (MASH) to reflect its link with cardiometabolic risk factors (diabetes, dyslipidemia, obesity, etc). Until now, we’ve relied on lifestyle changes, controlling comorbidities, and in some cases meds (pioglitazone, semaglutide, etc).

Understand that resmetirom activates thyroid hormone receptor-beta in the liver to enhance liver fat metabolism and reduce fat accumulation. Note that after 12 months, resmetirom plus diet and exercise results in MASH resolution (minimal to no inflammation) in about 1 in 6 patients versus placebo, and about 1 in 10 patients see an improvement in fibrosis.

NPS-adv

Keep in mind, these outcomes are based on short-term data. It’s too soon to say if resmetirom decreases risk of cirrhosis, liver transplant, or death or has long-term safety risks. Head-to-head data are lacking, and many trials are ongoing. For instance, limited evidence shows semaglutide or tirzepatide leads to MASH resolution in about 1 of 3 patients treated versus placebo. But they don’t seem to improve fibrosis yet.

Anticipate that specialists will save resmetirom for patients who have MASH with moderate to advanced liver fibrosis despite optimizing diet, exercise, and meds for other comorbidities (diabetes, obesity, etc). If patients get resmetirom, caution that GI side effects (diarrhea, nausea, etc) may persist for a few months and to promptly report severe GI pain, which can be a red flag for rare gallbladder problems. Ensure periodic liver function monitoring.

Resmetirom can cause liver injury. Tell patients to report nausea, jaundice, etc. Expect patients who weigh less than 100 kg to usually get resmetirom 80 mg/day and those 100 kg or more to get 100 mg/day. Stay alert for interactions. For instance, if a patient is taking resmetirom, use a max of 20 mg/day of rosuvastatin or simvastatin or 40 mg/day of pravastatin or atorvastatin to limit statin side effects.

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References

1. 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.
2. 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
3. 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.
4. 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.
5. 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.

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