Key Numbers from the MAESTRO-NASH Trial
(vs 10% placebo)
(vs 14% placebo)
(≥100 kg / <100 kg body weight)
on which approval was based
In March 2024, the FDA granted accelerated approval to resmetirom (brand name Rezdiffra) for the treatment of MASH — previously called NASH — in adults with moderate-to-advanced liver fibrosis (stages F2–F3). ref 1 This AASLD practice guidance provides clinicians with implementable recommendations for patient selection, monitoring, and assessing treatment response — details not included in the FDA prescribing label itself. ref 2
Who Qualifies for Resmetirom?
MAESTRO-NASH enrolled patients with biopsy-confirmed MASH and metabolic syndrome (at least 3 of 5 criteria), spanning stages F1b through F3. The FDA approval, however, covers only patients with F2–F3 fibrosis. ref 58 In clinical practice, liver biopsy is not required — the FDA label explicitly does not mandate it. ref 7 Patient selection is instead based on non-invasive evidence of steatosis and fibrosis in people with cardiometabolic risk factors, without other causes of steatosis (including excess alcohol intake above 20 g/day for women or 30 g/day for men). ref 8
Imaging-based tests (FibroScan or MRE) are preferred over blood-based tests for their greater accuracy in gauging fibrosis. ref 9 When imaging is unavailable, blood-based markers such as the ELF score may be used. Importantly, NILDA data should be obtained within the past 6–12 months to be considered current for treatment candidacy. ref 59 A prior liver biopsy showing F2–F3 (obtained within approximately 3 years and without histologically active autoimmune liver disease) is also acceptable. ref 21
About half of MAESTRO-NASH participants with biopsy-proven F2–F3 had VCTE values outside the recommended IQR of 10–15 kPa. ref 14 AASLD acknowledges this variability — patients with values outside the recommended zones can still be considered with individualized specialist assessment. ref 15
NIT Thresholds for Resmetirom Eligibility
| Test | Recommended Range | May Be Used (individualized) | Not Recommended |
|---|---|---|---|
| FibroScan (VCTE) | 8 – 15 kPa ref 10 | Outside IQR ref 15 Specialist judgment required |
> 20 kPa ref 16 Consistent with cirrhosis |
| MRE | 3.1 – 4.4 kPa ref 11 | Outside range ref 15 Specialist judgment required |
> 5.0 kPa ref 16 Consistent with cirrhosis |
| ELF Score | 9.2 – 10.4 ref 13 When imaging unavailable |
Outside IQR Specialist judgment |
Worsening ELF ref 56 Suggests futility |
Monitoring and Dosing
The recommended dose of resmetirom is 100 mg/day for patients weighing 100 kg or more, and 80 mg/day for patients weighing less than 100 kg. ref 22 Resmetirom is taken by mouth once daily.
Before Starting Treatment
Your doctor should obtain a hepatic function panel (liver blood tests), a fibrosis measurement by VCTE or MRE (strongly preferred over blood-based tests), and thyroid function (TSH at baseline or within the past 6 months). ref 30 Abnormal thyroid function — either hyperthyroidism or hypothyroidism — should be corrected before starting resmetirom. ref 31 A lipid profile is also recommended at baseline given the drug's interaction with statin dosing.
During Treatment
Hepatic function panel testing is recommended at 3, 6, and 12 months during resmetirom therapy. ref 27 After 12 months, continuing this monitoring every 6 months is suggested. If you have known thyroid disease, your thyroid function (TSH and free T4) should be checked at standard clinical intervals throughout treatment. For patients with normal thyroid at baseline, the FDA concluded that no additional thyroid-specific monitoring is needed. ref 34
Drug Interactions
Resmetirom is a substrate for the CYP2C8 enzyme, meaning that other drugs affecting this pathway can alter its blood levels. ref 23 If resmetirom is taken with a moderate CYP2C8 inhibitor — the most common example being clopidogrel (Plavix) — your dose must be reduced: 80 mg/day if you weigh 100 kg or more, or 60 mg/day if you weigh less than 100 kg. ref 24
Resmetirom also affects the metabolism of several statins — drugs commonly used for cholesterol management in people with MASLD. When taken concurrently with resmetirom, the following maximum daily statin doses apply: rosuvastatin 20 mg, simvastatin 20 mg, atorvastatin 40 mg, and pravastatin 40 mg. ref 25 Your doctor may need to reduce your statin dose when starting resmetirom, while continuing to monitor your lipid profile to ensure cardiovascular risk targets are met.
On the positive side, resmetirom itself decreases LDL cholesterol levels, ref 26 which may partially offset the reduced statin dose. However, its long-term effects on cardiovascular outcomes remain to be established. ref 26
Side Effects and Safety
GI Side Effects (Most Common)
Diarrhea (24–34%) and nausea (12–22%) were the most common adverse events in the MAESTRO-NASH and MAESTRO-NAFLD-1 trials. ref 36 These typically begin within 12 weeks of starting, often within 4 weeks. ref 37 Diarrhea had a median duration of 15–20 days and was never severe in the trials, though it lasted more than 4 weeks in about half of affected participants. ref 38
Gallbladder Disease
Resmetirom was associated with an increased incidence of symptomatic gallstone disease. ref 39 Importantly, having existing gallstones or a prior history of biliary colic is not a contraindication to resmetirom — the caution is around acute, symptomatic conditions like cholecystitis at the time of initiation. ref 40
Liver Safety
Across the MAESTRO trials, there was one case of severe hepatotoxicity: a participant developed jaundice (bilirubin 15 times the upper limit of normal) and biopsy findings consistent with autoimmune hepatitis or drug-induced liver injury. In retrospect, that patient had unrecognized primary biliary cholangitis at baseline. ref 29 AASLD defines clinically significant hepatotoxicity warranting drug discontinuation as: ALT or AST >5× ULN or ALP >2× ULN on two occasions; total bilirubin >2.5 mg/dL plus elevated liver enzymes; or INR >1.5 plus elevated liver enzymes. ref 28
Thyroid Effects
Resmetirom reduced free T4 levels by 16–21% on average in the trials (up to 24% in patients taking levothyroxine), but TSH and T3 levels remained within the normal range throughout. ref 32 Hypothyroidism requiring levothyroxine replacement developed in 1.8% of resmetirom-treated participants. ref 33 Of note, 13% of MAESTRO-NASH participants already had hypothyroidism at enrollment. ref 35
Hormonal Effects
Resmetirom increases sex hormone binding globulin (SHBG). In males, this caused total testosterone to rise approximately 50–100%, while free testosterone remained unchanged. The clinical significance of these hormonal changes is not yet established. ref 41
Regardless of resmetirom treatment status, comprehensive lifestyle modification — including nutrition, exercise, and behavior change — remains the cornerstone of MASLD management. ref 42
Assessing Response to Resmetirom
AASLD recommends formal response assessment at 12 months using the same NIT used at baseline. ref 46 The following framework guides the decision to continue, re-evaluate, or stop resmetirom.
| Finding at 12 Months | Assessment | Action |
|---|---|---|
| VCTE ≥25% decrease or MRE ≥20% decrease + normalization or significant ALT improvement | Beneficial response ref 47 | Continue resmetirom |
| Worsening NILDA or consistent ALT increase | No response ref 48 | Consider stopping resmetirom |
| Minor VCTE reduction (<25%) or MRE (<20%), no significant ALT improvement, MRI-PDFF reduction <30% | Uncertain benefit ref 49 | Re-evaluate strategy (shared decision) |
| ALT decrease ≥17 U/L or reduction to ≤40 U/L by ≥30% | Favorable ALT signal ref 55 | Supports continuation |
| MRI-PDFF reduction <30% at 52 weeks | Histologic response ~10% ref 53 | Consider reassessing utility of treatment |
Important Caveats on VCTE and MRI-PDFF
VCTE (FibroScan) is not an ideal marker for monitoring resmetirom response. In MAESTRO-NASH, 49% of resmetirom patients achieved ≥25% VCTE decrease — far more than the 26–30% who had histologic MASH resolution. ref 50 This means a "good" FibroScan result can overestimate actual liver improvement. Critically, histologic response was also seen in some patients with no VCTE improvement at all. ref 51
MRE is more reliable: the QIBA/RSNA standard confirms that a 19% reduction in MRE is a true change in liver fibrosis, and MAESTRO-NASH data showed that MRE ≥20% decrease aligned well with actual histologic fibrosis improvement. ref 52
For MRI-PDFF (liver fat quantification): participants who did not achieve ≥30% reduction by week 52 had histologic response rates of approximately 10% — no better than placebo. ref 53 A ≥30% reduction was associated with better outcomes, though histologic response was still below 50% in that group — not high enough to be used alone to confirm efficacy. ref 54
Note: changes in the CAP (controlled attenuation parameter, measured by FibroScan) are not associated with histologic treatment response and should not be used to assess whether resmetirom is working. ref 60
For patients without clear improvement or worsening after 12 months, AASLD recommends individualized, shared decision-making — weighing baseline fibrosis severity, response to lifestyle changes, comorbidities, and side effects. Stabilization of fibrosis without regression may still portend important long-term benefits, particularly in advanced fibrosis, and should not automatically mandate stopping the drug. ref 57