Resmetirom (brand name Rezdiffra) is a first ever FDA-approved treatment for adults with noncirrhotic Metabolic Dysfunction-Associated Steatohepatitis (MASH)—formerly known as nonalcoholic steatohepatitis (NASH)—who have moderate to advanced liver scarring (fibrosis stages F2 to F3).
It is a selective thyroid hormone receptor-beta (THR-β) agonist.
By specifically targeting receptors in the liver, it helps reduce liver fat accumulation, inflammation, and scarring while avoiding the heart-related side effects typically caused by other thyroid hormone receptors.
Administration: It is an oral tablet taken once daily. It is available in 60 mg, 80 mg, and 100 mg strengths.
Usage: It is intended for use alongside lifestyle changes, such as a healthy diet and regular exercise.
Clinical trials, such as the MAESTRO-NASH study, demonstrated that resmetirom can:
Resolve MASH: Clear liver inflammation without worsening fibrosis in roughly 26–30% of patients.
Reduce Fibrosis: Improve liver scarring by at least one stage in about 24–26% of patients.
Lower Lipids: Significantly reduce levels of LDL cholesterol and other harmful blood fats.
Common Side Effects The most frequently reported side effects include diarrhea and nausea, which typically occur shortly after starting the medication and often subside over time.
More serious but rare risks include gallstone-related issues like cholelithiasis.
Beyond hepatic benefits, resmetirom demonstrated favorable effects on cardiovascular risk factors, improving plasma concentrations of low-density lipoprotein cholesterol, triglycerides, and lipoprotein(a)—a particularly important finding given that cardiovascular disease is the leading cause of death in MASH patients.
The drug had neutral effects on body weight and insulin resistance.
The drug doe not induce adverse endocrine events, tachyarrhythmias, or major changes in bone mineral density.
Resmetirom reduces circulating levels of free thyroxine by approximately 15 to 20%, independent of thyroxine-replacement status, but has no effect on serum thyrotropin or free triiodothyronine levels.
It has an acceptable side-effect profile, with the most common adverse events being nausea and diarrhea, which were usually transient and mild or moderate in severity.
Resmetirom is a selective THR-β agonist with approximately 28-fold selectivity for THR-β over THR-α.
THR-β is predominantly expressed in the liver, kidney, pituitary, and brain, while THR-α mediates effects in the heart and bone.
By targeting THR-β, resmetirom provides metabolic benefits while minimizing unwanted systemic thyroid hormone effects.
The drug is highly protein-bound (>99%), has poor tissue penetration outside the liver, and shows specific hepatic uptake through liver-targeted transporters.
In MASH, THR-β function in the liver is impaired, leading to reduced mitochondrial function and β-oxidation of fatty acids.
Resmetirom enhances mitochondrial function (promoting mitochondrial biogenesis and mitophagy), increasing hepatic fatty acid β-oxidation, regulating bile acid synthesis, and facilitating LDL uptake in the liver.
Resmetirom is FDA-approved for adults with noncirrhotic NASH with moderate to advanced liver fibrosis, consistent with stages F2 to F3 fibrosis, used in conjunction with diet and exercise under accelerated approval.
Treatment initiation does not require a liver biopsy but has specific guidance for identifying suitable patients using noninvasive tests (NITs), particularly liver stiffness measurement by vibration-controlled transient elastography (VCTE) or magnetic resonance elastography (MRE).
Dosing is weight-based: 80 mg orally once daily for patients.
Key exclusion criteria include:
Compensated or decompensated cirrhosis
Active liver diseases ([autoimmune hepatitis](/rare-disease/autoimmune-hepatitis), [primary biliary cholangitis](/rare-disease/primary-biliary-cholangitis)).
Suboptimally managed hypothyroidism or hyperthyroidism
Ongoing alcohol consumption >20 g/day for women or >30 g/day for men.
A safety trial involving approximately 1,400 adults, treatment-emergent adverse events (TEAEs) occurred in 86.1% (100 mg resmetirom), 88.4% (80 mg resmetirom), and 81.8% (placebo) of patients.
The most common adverse events were gastrointestinal: nausea and diarrhea occurring at treatment initiation, which were generally self-limited, transient, and mild to moderate in severity.
Discontinuation rates due to adverse events were higher with the 100 mg dose (6.8%) compared to 80 mg (1.8%) and placebo (2.2%).
The incidence of serious adverse events was similar across groups (10.9% to 12.7%).
Meta-analyses confirm that overall treatment-emergent adverse events at 80 mg and 100 mg doses were not significantly different from placebo, though gastrointestinal adverse events (diarrhea and nausea) occurred in ≥10% of the resmetirom group compared to placebo.
Resmetirom produces substantial improvements in atherogenic lipid profiles.
In clinical trials, the drug reduced LDL cholesterol by 11-13%, apolipoprotein B by 16-18%, triglycerides by 15-20%, and notably, lipoprotein(a)—a highly atherogenic lipoprotein—by a significant magnitude.
PThese lipid-lowering effects are hypothesized to result from reduced VLDL production and secretion.[3]
Importantly, resmetirom had no significant effects on body weight, HbA1c levels, or insulin resistance, distinguishing it from weight-loss-based therapies.[5][14]
Monitoring and Long-term Considerations
Therapy should be individualized and initiated by a hepatologist or gastroenterologist with expertise in MASH within an interprofessional team, given complexities in patient selection, drug cost, and treatment monitoring.
Monitoring for symptoms of endocrine deficiency, as hypothyroidism and hypogonadism are more prevalent in people with MASLD than in the general population.