Use of Disease-modifying Therapy in Metabolic Dysfunction-associated Steatohepatitis: Benefits to Trump Challenges

The accelerated approval of two drugs for metabolic dysfunction-associated steatohepatitis (MASH), resmetirom and semaglutide, is a decisive event in our struggle against the disease, providing relief for both people suffering from the disease and the physicians managing it. The approval is for the treatment of noncirrhotic MASH with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis) in adults. It is not approved for people with cirrhosis or metabolic dysfunction-associated steatotic liver disease (MASLD) with mild fibrosis (F0/F1). These therapies aim to prevent the progression or reverse the disease state in people who are at high risk for progression to cirrhosis, decompensated liver disease, and death.[1,2] Since these events take years to occur, these trials depend on liver biopsy as a reasonably likely surrogate endpoint (RLSE) to assess their efficacy and safety.[3–5] These published trials are the first part of long-term trials with primary clinical liver-related outcomes, as mandated by the Food and Drug Administration (FDA).[3] Hence, these drug approvals are conditional and based on histological outcomes rather than clinical endpoints. Since both the inclusion criteria for choosing eligible subjects and the primary outcomes were based on histology, clinicians would find it challenging to translate these trials into clinical practice. Despite the limited availability of resmetirom outside the US, semaglutide has been used worldwide in the management of obesity and type 2 diabetes. It is expected that semaglutide will be used more frequently for MASH (not a label indication in India at the time of writing this editorial), especially in countries like India, when it goes off patent in March 2026, and cheaper generic versions will be available. This editorial examines the Effect of Semaglutide in Subjects with Non-cirrhotic Non-alcoholic Steatohepatitis (ESSENCE) and MAESTERO-NASH trials and highlights the challenges involved in identifying eligible patients for these medicines and monitoring of people treated with them. SCREENING FOR “AT-RISK METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS” The aim will be to identify people with “at-risk MASH,” i.e., those with MASH and ≥ F2 fibrosis who are at high risk of liver-related morbidity and mortality and are most likely to benefit from these therapies.[6] The current guidelines recommend the use of noninvasive tests (NITs) for screening purposes. People with high risk of MASLD include those with diabetes, prediabetes, or obesity and ≥ 1 CV risk factor.[6–8] The screening is two-tiered. The first tier comprises a comprehensive metabolic panel, a complete blood count, and calculation of the FIBROSIS 4 (FIB-4). FIB-4 is calculated using age, aspartate transaminase (AST), alanine transaminase (ALT), and platelet count. A FIB-4 of <1.3 has a high negative predictive value (>90%) for excluding advanced fibrosis. A score of 2.67 has a high positive predictive value (60%–80%) for clinically significant fibrosis. Those with an FIB-4 score >1.3 should undergo a tier 2 test for further assessment.[6–8] The tier 2 tests include liver stiffness measurement (LSM) using imaging or enhanced liver fibrosis (ELF), a blood biomarker test. LSM is most commonly done with Vibration Controlled Transient Elastography (VCTE). A VCTE assessed LSM <8 kPa excludes significant liver fibrosis.[6,7] Other imaging biomarkers include regular ultrasound and magnetic resonance imaging (MRI) – proton density fat fraction (PDFF) for hepatic steatosis, and ultrasound shear wave elastography (SWE), and magnetic resonance elastography (MRE) for hepatic fibrosis.[6,8] The ELF test is a blood test that measures three molecules involved in matrix turnover: hyaluronic acid, tissue inhibitor of metalloproteinase-1, and N-terminal procollagen III peptide. An ELF score of >9.8 identifies patients at increased risk for progression to cirrhosis or liver-related clinical events. Other composite scores involving imaging and biochemical biomarkers for the identification of “at-risk MASH” include FAST (FibroScan-AST), MAST (Score from MRI-PDFF, MRE, and AST), MEFIB (FIB-4 >1.6 and MRE >3.3 kPa), and cT1 (corrected T1).[6–8] In people at risk of progression to cirrhosis or decompensated liver disease and death, FIB-4, ELF scores, and LSM have been used not only in initial diagnosis but also in serial follow-up of subjects with MASLD. Trajectories of FIB-4 were associated with cirrhosis and liver-related events over time.[8,9] Strategies that use FIB-4 followed by VCTE or ELF have been predictive of mortality, hepatocellular carcinoma, liver-related events, and decompensation proxies.[6–9] Liver biopsies are invasive, expensive, and associated with risks of bleeding. Furthermore, sampling errors and differences in reporting standards may influence outcomes. It is reserved for indeterminate or NITs discordant with clinical or imaging, diagnostic uncertainty, and persistent (>6 months) elevated transaminases.[6] Thus, the diagnosis and follow-up of MASLD/MASH in clinical practice are predominantly based on clinical, biochemical, imaging NITs, with biopsies being rarely performed. CHALLENGES IN NONINVASIVE TEST USE IN CLINICAL PRACTICE FIB-4 is a readily available marker in clinical practice. The limitations of FIB-4 include changes with age, coexistent alcohol use, obesity, and diabetes, and technical challenges with platelet count estimation.[6–8] Tests like the ELF score, although available, are expensive for routine clinical use. For imaging biomarkers, the challenges are manifold. VCTE, although the most widely used method in clinical trials, is performed with expensive equipment (FibroScan, Echosens) and is not readily accessible. However, the ultrasound SWE is more readily available. Limitations for both these modalities include severe obesity (>40 kg/m2), severe steatosis, and low inter-rib spaces for testing. Differing guidelines and vendor protocols have led to substantial heterogeneity in recommended cutoff values for imaging biomarkers assessing steatosis and fibrosis. In addition, major vendors also recommend different cutoff values. Hence, the Society of Radiologists in Ultrasound has issued a consensus statement addressing this by endorsing vendor-neutral cutoffs (“rule of four”) for acoustic radiation force impulse techniques, including VCTE and SWE, recognizing that variation between vendors is less than the overlap among fibrosis stages themselves.[10] MRI-PDFF and MRE, though accurate, are, however, expensive, less accessible, and limited mainly to specialized centers. They have limitations related to liver iron content, patient factors such as obesity, and MRI protocols.[11] Substantial knowledge gaps remain among medical practitioners regarding indications, limitations, and optimal interpretation of imaging NITs. The lack of standardized, multidisciplinary guidelines further compounds inconsistency, leading to under-reporting, under-diagnosis, and missed intervention opportunities. A lack of normative data for ethnic populations, such as Indians, is a notable deficiency.[12,13] MAESTRO-NASH AND ESSENCE The regulatory trials of resmetirom and semaglutide used liver biopsy to document steatohepatitis and fibrosis for randomization and for primary and secondary outcomes.[1,2] In ESSENCE, prescreening criteria involving FIB4, VCTE, MRI-PDFF, or FAST score or past liver biopsy were used to avoid histological failure.[5] In MAESTRO-NASH, a prescreening VCTE (FibroScan) within the past 3 months showing a controlled attenuation parameter (CAP) of 280 dB per meter or more and a liver-stiffness measurement of 8.5 kPa was used as a criterion for liver biopsy before randomization.[4] The inclusion criteria for ESSENCE included histologically documented steatohepatitis and liver fibrosis of stage 2 or 3, according to the Non Alcoholic Steatohepatitis (NASH) Clinical Research Network classification, and a nonalcoholic fatty liver disease (NAFLD) activity score (NAS) of ≥4.[5] In addition to the above, MAESTRO-NASH inclusion criteria required ≥ 3 metabolic risk factors and included fibrosis stage F1B and a small proportion of subjects with F1(A/C), adhering to strict criteria. In MAESTRO-NASH, MRI-PDFF and FIB-4 scores were used at baseline and at the end of the study.[4] Thus, NITs were not included in the inclusion criteria for either trial. OUTCOME ASSESSMENT IN TRIALS The primary endpoints of both ESSENCE and MAESTRO-NASH were a resolution of steatohepatitis with no worsening of liver fibrosis and a reduction in liver fibrosis with no worsening of steatohepatitis. A central pathology group adjudicated these.[1,2] In ESSENCE, resolution of steatohepatitis with no worsening of liver fibrosis after 72 weeks (the first primary end point) occurred in 62.9% of the patients in the semaglutide group and in 34.3% of those in the placebo group (95% confidence interval [CI] for difference, 21.1–36.2; P < 0.001). A reduction in liver fibrosis with no worsening of steatohepatitis (the second primary end point) was reported in 36.8% of the patients in the semaglutide group and in 22.4% of those in the placebo group (95% CI for difference, 7.5–21.3; P < 0.001).[2] In the MAESTRO-NASH trial, at 52 weeks, NASH resolution with no worsening of fibrosis was achieved in significantly more patients who received resmetirom than in those who received placebo (25.9% in the 80-mg group and 29.9% in the 100-mg group, vs. 9.7% in the placebo group; P < 0.001 for both comparisons with placebo). An improvement in fibrosis by at least one stage with no worsening of the NAFLD activity score was also achieved in significantly more patients who received resmetirom than in those who received placebo (24.2% in the 80-mg group and 25.9% in the 100-mg group, vs. 14.2% in the placebo group; P < 0.001 for both comparisons with placebo).[1] Thus, significant improvement in both trials occurred in steatohepatitis resolution rather than in fibrosis. These trials also examined NITs as outcomes. In ESSENCE, there were improvements in CAP, LSM, FAST score, ELF, PRO-C3, ALT, and gamma-glutamyl transferase (GGT) in subjects on semaglutide versus placebo. An ELF score reduction of >0.5 and a reduction of LSM >30% was a prespecified endpoint. More patients in the semaglutide arm achieved cutoffs of >25% and >30% reductions in liver stiffness, as well as an ELF score reduction of >0.5.[2] In the MAESTRO-NASH trials, improvements were reported for transaminases, GGT, liver stiffness (FibroScan and MR elastography), FibroScan CAP, and MRI-PDFF at 52 weeks in the resmetirom arm compared with placebo. There were improvements in the ELF score and its components, as well as cytokeratin, in the resmetirom arm.[1] CHALLENGES Liver histology documenting inflammation and fibrosis is an RLSE with a strong correlation with the pathophysiology of MASH. However, we do not have a biomarker for liver inflammation that closely tracks changes in liver biopsies. Even for liver fibrosis, existing biomarkers, including imaging biomarkers, do not achieve the sensitivity and specificity required to replace biopsies. In the ESSENCE trial, at baseline, a FIB4 score <1.3 was observed in 34.5% (45% of F2 and 29.6% of F3), and ELF <9.8 was observed in 43.5% (62.4% of F2 and 34.9% of F3). Furthermore, LSM <8kPa was observed in 15.3% (26.8% of F2 and 10% of F3). None of the measured NIT were positive in 15.6% (5.8% of F2, 8.9% of F3).[2] Thus, individual NIT cannot be relied upon to substitute for liver biopsies. WHAT SHOULD THE CLINICIAN DO? Reduction of liver inflammation in histology is one of the primary outcomes of both resmetirom and semaglutide in MASH. However, we do not have an NIT to diagnose or follow-up inflammation. The FDA approval for semaglutide or resmetirom also does not require a liver biopsy to define “at-risk MASH.” With the high prevalence of MASLD/MASH that we now observe, it would be unwise to wait for a biomarker for inflammation or fibrosis to get approved for clinical use before we start using these drugs. With the low sensitivity, FIB4 alone should not be used to screen patients for “at-risk MASH.” A combination of imaging and blood NITs should be used to determine patient eligibility for drug therapy. Studies such as ESSENCE and MAESTRO-NASH have shown that various available NITs, including transaminases, GGT, ELF, and PRO-C3, improved with the use of these medicines.[1,2] Imaging biomarkers, such as VCTE for CAP and LSM, MRE, and MRI-PDFF, also improved in these trials and correlated with histological improvements. In the MAESTRO-NASH trial, a 30% reduction in MRI-PDFF was a strong predictor of both NASH resolution and improvement in fibrosis.[14] A decrease in ALT and CAP from baseline to week 72 was greater in those treated with semaglutide who achieved MASH resolution without worsening of fibrosis than in those who did not reach the endpoint.[15] Validated scoring systems, such as Agile 3+ and FAST scores, may also be used. Hence, for follow-up assessments, clinicians can consider serial assessment of biochemical and imaging biomarkers. Outcomes used in trials, such as > 25% or >30% reductions in liver stiffness, as well as reductions in ELF score of >0.5, can serve as surrogates for treatment response. Composite NIT outcomes, such as an ELF Score decrease of ≥0.5 and an LSM reduction of ≥30%, can also be used.[1,2] More objective tests, such as MRI-PDFF and MRE, can be used at baseline and on follow-up. Since these drugs have significant metabolic benefits, they can also be monitored as surrogates. These include weight, blood pressure, lipids, glucose levels, Homeostatic Model Assessment of Insulin Resistance, high-sensitivity C-reactive protein, and Apoprotein B levels. Protocols for monitoring people for progression to cirrhosis and decompensation must be strictly followed. We can look forward to the long-term clinical outcomes of these trials to see the benefits of these drugs beyond the liver biopsy endpoints. Meanwhile, the American Association for the Study of Liver Diseases has brought out practical guidelines for initiating and monitoring therapy with resmetirom and semaglutide in people with MASLD.[14,15] These expert statements have proposed algorithms for the use of NITs and composite scores (VCTE, MRE, ELF score, FAST, MEFIB) to identify subjects with clinically significant fibrosis (F2 and F3) and to exclude those with cirrhosis and portal hypertension [Table 1]. The current cost of these therapies may justify the use of these expensive tests for follow-up. Nonresponders should be considered for liver biopsy, a detailed workup for an alternate diagnosis, and compliance with drugs. Those with worsening of NITs may be considered for discontinuation of therapy.[14] However, it may be too early to determine whether these subjects may derive any benefit from the drug for liver-related events on long-term follow-up during the trials.Table 1: Recommendations for starting and monitoring subjects on resmetirom and semaglutide based on noninvasive tests (adapted from references 14 and 15)For clinicians with limited access to these investigations, local guidelines should consider using more readily available parameters, such as the ultrasound SWE for decision-making.