Key points are not available for this paper at this time.
BACKGROUND Resmetirom received accelerated approval from the United States Food and Drug Administration (FDA) in March 2024 for the treatment of metabolic dysfunction-associated steatohepatitis (MASH; formerly known as nonalcoholic steatohepatitis or NASH) with moderate to advanced liver fibrosis consistent with stages F2 to F3 fibrosis (F2-F3).1 The approval was based on findings from the MAESTRO-NASH clinical trial2 combined with safety data from the MAESTRO-NAFLD-1 trial.3 In the MAESTRO-NASH trial, treatment with resmetirom achieved the 2 primary endpoints of resolution of steatohepatitis without worsening of fibrosis (26%-30% compared with 10% for resmetirom and placebo, respectively) and improvement in fibrosis without worsening of steatohepatitis at 52 weeks (24%-26% compared with 14% for resmetirom and placebo, respectively).2 This article serves as an update to the 2023 AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease.4 Since the FDA-approved resmetirom prescribing information1 does not include implementable guidance for practicing clinicians about whom to treat and how to monitor for response and safety, the writing group (nominated by the AASLD governing board) assimilated data from AASLD practice guidelines on noninvasive liver disease assessments (NILDA) of fibrosis and steatosis,5,6 published data regarding resmetirom,2,3,7 publicly available FDA documents,8 and selected unpublished data (Madrigal Pharmaceuticals, unpublished data, 2024). While the resmetirom FDA prescribing information represents the official regulatory document to be followed by practitioners, the guidance statements herein were developed to provide timely, implementable recommendations for practicing clinicians. Additional clinical trial and real-world data may necessitate revision of these recommendations in the future. WHOM TO TREAT The MAESTRO-NASH trial included participants with metabolic syndrome (≥3 of 5 metabolic risk factors)9 and stage 1b, 2, or 3 liver fibrosis, and biopsy-confirmed MASH. The resmetirom FDA approval, however, includes only persons with MASH and F2-F3.1 Notably, the FDA-approved label does not require liver biopsy to confirm the diagnosis of fibrotic MASH. While MASH can only be definitively diagnosed by histologic examination, patient selection in practice is based on evidence of steatosis and fibrosis as determined by NILDA methodologies among persons with cardiometabolic risk factors without other causes of steatosis, notably alcohol consumption of more than 20 g/d for women and more than 30 g/d for men.10 There are no FDA-approved noninvasive tests to diagnose MASH with F2-F3 or to monitor response to pharmacotherapy. The aforementioned AASLD guidelines for the use of blood-based and image-based NILDA tests5,6 in the assessment of liver steatosis and fibrosis were developed in recognition of the limitations of liver biopsy in practice settings. In general, imaging-based NILDAs, such as liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) or magnetic resonance elastography (MRE),4–6,11–13 yield better accuracy in gauging fibrosis compared with blood-based NILDAs. Magnetic resonance examination utilizing the LiverMultiScan image acquisition protocol with corrected T1 imaging has recently been shown to detect fibrotic MASH.14 However, its utility to confidently rule out clinically inapparent stage 4 fibrosis has not been well demonstrated, thereby limiting its usefulness in selecting candidates for resmetirom therapy.14 A detailed discussion of NILDA methodologies to diagnose and quantify hepatic steatosis is beyond the scope of this update. In general, magnetic resonance spectroscopy and magnetic resonance imaging proton density fat fraction (MRI-PDFF) are considered the most accurate quantitative measures of hepatic steatosis, followed by VCTE-controlled attenuation parameter score and gray scale ultrasonography. However, for the purpose of selecting resmetirom treatment candidates, nonquantitative imaging evidence of hepatic steatosis (eg, ultrasonographic evidence) in persons with at least 1 cardiometabolic risk factor and F2-F3 may be sufficient. In settings where imaging-based NILDA is unavailable, blood-based NILDA may be utilized. Figure 1 describes the use of imaging-based or blood-based NILDA for the selection of patients for whom resmetirom therapy is suitable. As NILDA research evolves, the modalities and thresholds proposed herein to identify MASH with F2-F3 may change.FIGURE 1: Selection of Patients for Resmetirom Therapy. Abbreviations: F2-F3, stage 2 to 3 liver fibrosis; LSM, liver stiffness measurement; MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; MRE, magnetic resonance elastography; NILDA, noninvasive liver disease assessment; VCTE, vibration-controlled transient elastography.In the MAESTRO-NASH trial, participants were screened with VCTE and those with LSM >8.5 kPa in whom liver histology demonstrated MASH with F2-F3 were enrolled. Among enrolled participants, the median (interquartile range) LSM by VCTE was 12 kPa (10-15 kPa) and the mean LSM by MRE was 3.5 kPa. The median (interquartile range) of the enhanced liver fibrosis score was 9.7 (9.2-10.4).2 These data indicate that there may be individuals who have MASH with F2-F3 who do not fit the criteria for recommended resmetirom therapy (see the green box in Figure 1). For example, 50% of participants with biopsy-proven F2-F3 in the MAESTRO-NASH trial had LSM by VCTE that was outside the interquartile range of 10 kPa to 15 kPa.2 Thus, practitioners may consider expanded noninvasive criteria in making treatment decisions (see the yellow box in Figure 1). Ultimately, it is the prescriber’s prerogative and responsibility to adjudicate a patient’s fibrosis status. Utilizing a NILDA test for patient selection at baseline provides the added benefit of allowing for later retesting using the same assay to gauge therapeutic response during or after resmetirom treatment. While liver biopsy is not typically recommended for fibrosis staging in current clinical practice, histologic examination remains the gold standard to quantify fibrosis if performed previously (historical biopsy obtained reasonably recently, eg, within 3 years) or for other indications, including suspicion of concomitant liver disease (eg, autoimmune hepatitis). Since NILDA is more readily available than liver biopsy, more current data (eg, within 6-12 months) should be utilized to determine resmetirom treatment candidacy. CONCOMITANT THERAPY Regardless of resmetirom treatment status, best practices in metabolic dysfunction-associated steatotic liver disease (MASLD) management should include comprehensive lifestyle modification (nutrition, exercise, and behavior modification) and optimal control of comorbid metabolic conditions.4,15,16 AASLD guidance previously recognized that in the absence of approved therapy, pharmacologic treatment with semaglutide, pioglitazone, and vitamin E could be considered in appropriate patients.4 Glucagon-like peptide 1 (GLP-1) and GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists are FDA approved for the treatment of type 2 diabetes and overweight/obesity. They reduce the risk of cardiorenal complications in addition to their effects on glycemic control and weight loss.17–25 While these pharmaceutical agents are not currently approved for the treatment of MASH, phase 2 randomized, placebo-controlled clinical trials of liraglutide, semaglutide, and tirzepatide have demonstrated their efficacy in reducing steatohepatitis without worsening fibrosis and, in the case of tirzepatide, decreasing fibrosis without worsening of steatohepatitis as well.26–28 Although not FDA approved for the treatment of MASH, vitamin E and pioglitazone may also improve steatohepatitis.29–31 The MAESTRO-NASH trial notably excluded individuals who initiated or dose-modified drugs with GLP-1 receptor agonist activity, thiazolidinediones, or vitamin E within 6 months of randomization.2 Among persons already taking any of these medications with potential efficacy for treating MASH, data are insufficient to guide prescribers about whether or when to initiate resmetirom therapy. Decisions may be made based on the patient’s comorbidity profile, response (if any) to the ongoing therapy, and the fibrosis stage and concern for further liver disease progression. Similarly, in the absence of data supporting specific guidance, among persons receiving neither a GLP-1 or GLP-1/GIP receptor agonist nor resmetirom but who meet treatment criteria for both, clinical judgement may be exercised weighing between concerns for progressive liver fibrosis and the severity of extrahepatic comorbidity. This is not to be construed as an endorsement of off-label therapy for MASH but rather an acknowledgement of uncertainty about comparative efficacy of these drugs in light of the MAESTRO-NASH exclusion criteria. Resmetirom is a substrate for cytochrome P450 enzyme 2C8 and organic anion transporting polypeptides 1B1 and 1B3, and a weak cytochrome P450 enzyme 2C8 inhibitor.1 If resmetirom is used concurrently with a cytochrome P450 2C8 inhibitor (a common example being clopidogrel), a resmetirom dose reduction is recommended (80 mg/d for persons who weigh 100 kg or more; 60 mg/d for persons who weigh less than 100 kg). Given the comorbidity profile of persons with MASLD, cardiovascular risk management is an important aspect of medical management, including the use of statin pharmacotherapy. Because resmetirom is a substrate for organic anion transporting polypeptides 1B1 and 1B3, concomitant administration of resmetirom and a statin may influence statin metabolism. When taken concurrently with resmetirom, the recommended maximum dosage for rosuvastatin and simvastatin is 20 mg/d; the recommended maximum dosage for atorvastatin and pravastatin is 40 mg/d. Notably, resmetirom decreases low-density lipoprotein but its long-term effects on cardiovascular disease risk remain to be determined.2,3,21 ADVERSE EVENTS AND SAFETY MONITORING Table 1 and Figure 2 summarize recommendations for safety and efficacy monitoring of persons receiving resmetirom. In both the MAESTRO-NASH and the MAESTRO-NAFLD-1 trials, the most common treatment-emergent adverse events were diarrhea and nausea, which developed in 24% to 34% and 12% to 22% of resmetirom-treated participants, respectively.2,3 Typical onset was less than 12 weeks after initiation of resmetirom therapy and often less than 4 weeks. While median duration of diarrhea was 15 days to 20 days and there were no cases of severe diarrhea, the symptoms lasted greater than 4 weeks in approximately half of the participants who developed diarrhea. Resmetirom was associated with increased incidence of symptomatic gallstone disease, although the presence of gallstones and/or a history of biliary colic are not contraindications to resmetirom treatment.TABLE 1: Safety and efficacy assessments at baseline and during 12 months of treatment with resmetiromFIGURE 2: Assessment for Treatment Outcome in Patients Receiving Resmetirom. Abbreviations: ALT, alanine aminotransferase; LSM, liver stiffness measure; MRE, magnetic resonance elastography; MRI-PDFF, magnetic resonance imaging proton density fat fraction; NILDA, noninvasive liver disease assessment; VCTE, vibration-controlled transient elastography.There was a sole case of severe hepatotoxicity in a participant receiving resmetirom. While on therapy, the patient developed jaundice (bilirubin 15 times the upper limit of normal)1 and biopsy showed interface hepatitis consistent with autoimmune hepatitis versus drug-induced autoimmune-like hepatitis. In retrospect, this patient met the criteria for primary biliary cholangitis and had strongly positive antimitochondrial and antinuclear antibodies at baseline. The adjudication committee assessed a 25% to 50% likelihood that resmetirom contributed to this hepatoxicity (Madrigal Pharmaceuticals, unpublished data, 2024). Regular hepatic function panel testing during resmetirom therapy is recommended to screen for hepatotoxicity. Resmetirom should be discontinued if clinically-significant hepatotoxicity develops as defined per the AASLD drug-induced liver injury practice guidance, specifically: AST or ALT greater than 5 times the upper limit of normal or alkaline phosphatase greater than 2 times the upper limit of normal (or pretreatment baseline if baseline is abnormal) on 2 occasions; or total serum bilirubin greater than 2.5 mg/dL plus elevated AST, ALT, or alkaline phosphatase; or INR greater than 1.5 plus elevated AST, ALT, or alkaline phosphatase.32 ENDOCRINOLOGIC CONSIDERATIONS Hypothyroidism occurs commonly in persons with hepatic steatosis, although its relationship with steatohepatitis has been less consistent and confounded by insulin resistance, obesity, and type 2 diabetes.33 For example, 13% of participants in the MAESTRO-NASH trial were receiving treatment for hypothyroidism at enrollment with thyroid hormone therapy dosages up to 75 ug/d. Persons with active hyperthyroidism or untreated hypothyroidism (ie, TSH >10 mIU/L without symptoms, or TSH >7 mIU/L with symptoms) were excluded from the MAESTRO-NASH study. In the trial, the mean plasma free T4 concentration decreased approximately 16% to 21% (up to 24% in those receiving levothyroxine), although rarely leading to abnormal levels.2 TSH and T3 also changed slightly but consistently remained within the normal ranges.3 Development of hypothyroidism requiring levothyroxine replacement occurred in 1.8% of participants receiving resmetirom.2 The FDA integrated review of resmetirom concluded that thyroid axis function was maintained during resmetirom therapy and recommended no thyroid-specific management.8 These data indicate that abnormal thyroid function (hyperthyroidism or hypothyroidism) should be addressed before initiating resmetirom therapy, which necessitates thyroid function assessment with at least a TSH level at baseline or up to 6 months prior. In accordance with FDA guidance,8 persons without thyroid function abnormalities at baseline do not require systematic monitoring of thyroid function tests while receiving resmetirom—although clinical vigilance should be exercised to discern and address emergence of adverse effects as with any pharmacologic therapy. Among persons with known thyroid disease, standard clinical monitoring (eg, TSH and free T4 at 3-month to 6-month intervals) should be followed at the discretion of the treating clinician (see Table 1). Resmetirom increases sex hormone binding globulin as seen in the MAESTRO-NAFLD-1 and MAESTRO-NASH trials.2,3 As expected with an increase in sex hormone binding globulin, mean total testosterone in males increased approximately 50% to 100%; free testosterone, however, was unchanged overall. Significant increases of total estradiol were observed in females but data on free estradiol were not reported. The clinical significance of any possible effects of these hormonal changes remains to be established. Management of dyslipidemia remains an essential element in the holistic care of persons with MASH, especially in the presence of type 2 diabetes and/or known atherosclerotic complications. Among persons in whom a statin dosage is reduced as recommended at the initiation of resmetirom therapy, care must be taken to continue to meet cardiovascular risk management targets by monitoring the serum lipid profile (see Table 1) and adjusting statin therapy accordingly during resmetirom treatment. IDENTIFYING EFFICACY AND FUTILITY OF RESMETIROM TREATMENT Resmetirom received accelerated initial FDA approval with final approval contingent upon verification and description of long-term clinical benefit in the ongoing MAESTRO-NASH trial.8 As of the time of writing this guidance these long-term data are not The trial data MASH resolution and fibrosis improvement in to and 24% to of participants, Among the greater than of participants, the primary treatment endpoints were not as of Table 1 and Figure 2 summarize recommendations for safety and efficacy monitoring of persons receiving resmetirom. are from the MAESTRO-NASH trial regarding changes in specific NILDA tests associated with histologic Similarly, evidence to LSM data with histologic changes in liver fibrosis is In general, the AASLD NILDA practice use of imaging-based NILDA as a test to or of liver that in available data may be used to to the of a reduction in LSM by MRE is considered to a reduction in liver In the MAESTRO-NASH trial, the of a or greater reduction in stiffness response to of improvement in histologic a or greater in kPa on MRE may be to a for improvement and, by for worsening (see Figure A reduction in VCTE LSM or a in LSM to less than 10 kPa has been proposed as a clinically that is associated with a risk of although this has not been in the of In the MAESTRO-NASH trial, a 25% in VCTE LSM histologic of participants with resmetirom had at least a 25% in VCTE LSM compared with to and 24% to who had MASH resolution and fibrosis Notably, histologic response was also seen in with no VCTE LSM VCTE LSM is not an to monitor response to resmetirom. However, the writing group that clinicians and patients use VCTE LSM to treatment In the absence of data to a specific and for the of this guidance, the writing group using a 25% in VCTE LSM to for response to resmetirom. a 25% increase in VCTE LSM may These thresholds may as evidence in the enhanced liver fibrosis score and other blood-based NILDA has not consistently with resolution of MASH or of fibrosis in clinical trials, worsening of the from baseline may be construed as evidence of Given its in clinical practice, quantitative assessment of steatosis by should not be a for initiating or resmetirom therapy. Among persons who have to this at a test after 52 weeks of therapy may provide information to the utility of resmetirom therapy. In the MAESTRO-NASH trial, participants with resmetirom who not have a or greater reduction in steatosis on by 52 had a histologic response that not from that of the group Thus, among persons who do not a or greater reduction in after 1 of resmetirom therapy, clinicians should these data in the utility of ongoing therapy and likelihood of with treatment. In a or greater reduction in steatosis as determined by among MAESTRO-NASH participants was associated with histologic compared with to findings from other among persons who achieved this response on resmetirom, histologic response were less than which the writing group a positive to be used to histologic in the attenuation parameter have not been as a of histologic response in clinical trials and was not of response in the MAESTRO-NASH of data from MAESTRO-NASH and other clinical trials may provide information on the of NILDA for treatment in ALT was with of histologic response in the MAESTRO-NASH In among persons with elevated baseline ALT ALT changes associated with MASH resolution without worsening of fibrosis included a or greater in or reduction of ALT to 40 or less and by at least from on these data, or improvement in ALT may be considered a while resmetirom-treated persons ALT remains consistently elevated may be as Figure 2 these monitoring the MRE and VCTE LSM thresholds defined persons with fibrosis improvement as well as those with ALT response should continue resmetirom therapy. Among persons with worsening NILDA for fibrosis or ALT of resmetirom should be Among persons who do not meet criteria for or after 12 months of resmetirom therapy, available data are insufficient to a regarding whether to continue resmetirom. important is that of fibrosis may important long-term for persons with advanced fibrosis, of fibrosis improvement should not of resmetirom therapy. with the patient is baseline fibrosis comorbidity profile associated with progressive liver disease; concomitant therapy including and response to lifestyle changes in liver and NILDA and adverse effects (if any) during resmetirom therapy. The may include lifestyle and other therapy, with or without resmetirom. selection Resmetirom can be considered for treatment of with MASH and moderate to advanced liver fibrosis with for treatment liver disease imaging-based test with MASH with F2-F3, or liver biopsy MASH with F2-F3 without evidence of active autoimmune liver The recommended dosage of resmetirom is 100 mg/d for persons who weigh 100 kg or or mg/d for persons who weigh less than 100 If resmetirom is used concurrently with a moderate cytochrome P450 2C8 inhibitor (eg, clopidogrel), the recommended dosage is mg/d for persons who weigh 100 kg or more or 60 mg/d for persons who weigh less than 100 Resmetirom is not recommended for persons with or concomitant active liver as autoimmune hepatitis and primary biliary or ongoing alcohol consumption greater than 20 g/d for women or greater than 30 g/d for function assessment is recommended before initiating resmetirom treatment. For persons with untreated hyperthyroidism or resmetirom initiation is not recommended thyroid function is Resmetirom initiation is not recommended for patients with symptomatic such as monitoring function panel testing should be obtained at baseline and at (eg, and 12 months) to determine response and adverse events while on resmetirom therapy. Resmetirom should be discontinued if hepatotoxicity as defined by the AASLD drug-induced liver injury practice There are insufficient data to a on monitoring after 12 months of resmetirom treatment but monitoring with hepatic function panel testing 6 months is Among persons with known thyroid disease, standard monitoring (eg, TSH and free per guidelines is recommended while receiving resmetirom therapy. Resmetirom can be used concurrently with however, practitioners should be of the maximum recommended including atorvastatin 40 pravastatin 40 rosuvastatin 20 and simvastatin 20 mg/d. to comorbidity management including is if the statin dose is at the of resmetirom therapy. of efficacy and The recommendations are based on data at 52 weeks after resmetirom treatment Since the MAESTRO-NASH trial is these recommendations may when data The to continue treatment beyond 12 months should be based on whether a patient has evidence of worsening or treatment or disease In persons treatment was determined by liver stiffness or a measurement at 12 months of therapy is recommended to for treatment In the absence of data, the writing group that improvement (or of VCTE of at least 25% or MRE of at least from baseline represents a (ie, clinically beyond measurement of resmetirom treatment in persons with fibrosis improvement is Among persons with evidence of worsening liver disease at 12 months of of resmetirom should be These individuals can be by clinical data of worsening liver disease including consistent increase in ALT or fibrosis as assessed by Among persons without evidence of liver disease improvement or the to continue therapy data from ongoing should be based on holistic and patients should the baseline fibrosis and the potential benefit of or liver fibrosis if no is the comorbidity profile associated with progressive liver disease; concomitant therapy including and response to lifestyle changes in liver and NILDA and adverse effects (if any) during resmetirom therapy.
Chen et al. (Fri,) studied this question.