Resmetirom vs Semaglutide in MASH: A Real-World Assessment of Clinical Outcomes, Safety Events, and Biochemical Trajectories

Presenter: Lee R.

This retrospective cohort study compared clinical outcomes and biochemical trends associated with resmetirom and semaglutide in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Resmetirom, a thyroid hormone receptor beta agonist recently approved for MASH, was evaluated against semaglutide. Adults with MASLD or MASH receiving either therapy were identified across 165 healthcare organizations. Propensity score matching was performed for age, sex, race, and concurrent metabolic therapies, resulting in 2,581 matched patients in each cohort.

Compared with resmetirom, semaglutide was associated with significantly lower rates of nausea and vomiting (p<0.01), while rates of diarrhoea, cholelithiasis, and pancreatitis were similar between groups. For cardiovascular outcomes, semaglutide demonstrated a trend toward lower major adverse cardiac events, achieving statistical significance for stroke (p<0.003) and arrhythmia (p<0.0003). Semaglutide was also associated with a modest but significant reduction in hospitalization risk (p<0.0001).

Both therapies produced progressive improvements in metabolic and hepatic biomarkers over 12 months, including reductions in LDL cholesterol, total cholesterol, BMI, and liver-related parameters (p<0.0001). However, semaglutide demonstrated faster and greater reductions in ALT, AST, and bilirubin compared with resmetirom. Thyroid function markers and HbA1c showed minimal fluctuations without consistent clinical significance.

Overall, semaglutide demonstrated a more favourable safety and clinical profile than resmetirom in patients with MASLD and MASH, with lower adverse event rates, reduced cardiovascular risk, fewer hospitalizations, and more rapid biochemical improvement.

Interim Analysis of a Randomized Controlled Trial Evaluating Elobixibat vs Vitamin E for Metabolic Associated Steatotic Liver Disease (MASLD): Effects on Steatosis, Liver Stiffness, and Metabolic Parameters

Presenter: Lesmana C.

This randomized controlled trial evaluated the short-term hepatic and metabolic effects of elobixibat, a selective ileal bile acid transporter (IBAT) inhibitor, in patients with metabolic associated steatotic liver disease (MASLD). Adult patients with hepatic steatosis, defined by controlled attenuation parameter (CAP) >260 dB/m, were randomized to receive elobixibat 10 mg daily, elobixibat 15 mg daily, or vitamin E 400 IU daily for 12 weeks.

Among 31 initially enrolled patients, 8 discontinued treatment due to drug-related adverse effects, leaving 23 patients for interim analysis, including 8 patients receiving elobixibat 10 mg, 5 receiving elobixibat 15 mg, and 10 receiving vitamin E. Baseline characteristics were comparable across treatment groups.

Within-group analyses demonstrated no significant improvement in CAP across the vitamin E (305→313 dB/m; p=0.461), elobixibat 10 mg (293→298 dB/m; p=0.729), or elobixibat 15 mg (316→310 dB/m; p=0.701) groups. Liver stiffness remained largely unchanged with vitamin E and elobixibat 10 mg, although a non-significant reduction was observed in the elobixibat 15 mg group (10.2→7.9 kPa; p=0.080).

Between-group comparisons at 12 weeks similarly showed no significant differences between elobixibat and vitamin E across hepatic or metabolic outcomes. Overall, short-term treatment with elobixibat did not demonstrate significant improvements in steatosis, fibrosis, or metabolic markers compared with vitamin E in this interim analysis.

Real World Practice Patterns in a Cohort of At-Risk MASH Patients on 12 Months of Treatment with Resmetirom

Presenter: Ramkissoon R.

This real-world retrospective study evaluated clinical practice patterns and outcomes associated with resmetirom use in patients with at-risk metabolic dysfunction-associated steatohepatitis (MASH) within a large U.S. health system following FDA approval. This study aimed to characterize how fibrosis staging, treatment decisions, and follow-up assessments were implemented in routine clinical practice over 12 months.

A total of 58 patients were treated, including 57% females with a mean age of 57 years. Baseline fibrosis assessment was performed using liver biopsy in 40% of patients and NITs in 59%, primarily FibroScan, with many patients also undergoing ELF testing or MR elastography. Baseline fibrosis stages included F2, F3, F2–F3, and F3–F4 disease, while 7% of patients-initiated therapy outside FDA-approved fibrosis criteria, including patients with F0–F1 fibrosis, F4 fibrosis, or no fibrosis assessment.

At 1 year, 66% of patients remained on therapy, while 32% discontinued treatment and one patient was lost to follow-up. Reasons for discontinuation included drug intolerance (15%), non-response (7%), treatment cessation after response (5%), hepatic decompensation, and medication cost. Follow-up fibrosis assessment was predominantly performed using NITs, with only one patient undergoing repeat liver biopsy.

Among evaluable patients, 68% demonstrated fibrosis regression by at least one METAVIR stage after 1 year, including patients with baseline F3–F4 fibrosis who improved during follow-up. This response rate appeared higher than rates reported in the MAESTRO NASH trial. However, the occurrence of hepatic decompensation in two patients highlighted the potential clinical vulnerability of patients with advanced fibrosis, even in the absence of established cirrhosis.

Overall, this real-world analysis demonstrates substantial variability in fibrosis assessment and treatment continuation practices following resmetirom initiation, while suggesting encouraging rates of fibrosis improvement in clinical practice.

Safety of Resmetirom in MASLD: A Propensity Score–Matched Real-World Cohort Analysis

Presenter: Sohail A.

This real-world cohort study evaluated the hepatic and biliary safety profile of resmetirom in adults with metabolic dysfunction–associated steatotic liver disease (MASLD). Adults with MASLD were identified and patients with liver transplantation, hepatocellular carcinoma, viral hepatitis, significant alcohol-related liver disease, pregnancy, or cholestatic autoimmune disease were excluded. The resmetirom cohort included 2,981 patients, with 2,056 matched 1:1 to untreated MASLD controls following propensity score matching.

At 90 days, resmetirom-treated patients demonstrated significantly lower rates of new cirrhosis compared with controls (2.8% vs 15.7%; OR 0.153, 95% CI 0.115–0.204; p=0.000). Liver enzyme elevation was also less frequent in the resmetirom group (5.5% vs 13.4%; OR 0.379, 95% CI 0.302–0.475; p=0.000), along with lower rates of biliary complications (0.7% vs 4.7%; OR 0.148, 95% CI 0.086–0.257; p=0.000).

These benefits persisted at 180 days. New cirrhosis occurred in 4.6% of resmetirom users versus 18.5% of controls (OR 0.214, 95% CI 0.169–0.270; p=0.000). Liver enzyme elevations remained lower with resmetirom (7.6% vs 15.6%; OR 0.449, 95% CI 0.367–0.549; p=0.000), as did biliary complications (1.5% vs 6.1%; OR 0.236, 95% CI 0.159–0.352; p=0.000). Kaplan–Meier analyses further demonstrated significantly improved event-free survival across all evaluated hepatic outcomes among resmetirom-treated patients.

Overall, resmetirom demonstrated a favourable early hepatic and biliary safety profile in patients with MASLD, with significantly lower risks of cirrhosis progression, liver enzyme abnormalities, and biliary complications compared with matched untreated controls.

Are Eligible ‘At Risk’ MASH Patients Getting the Recommended Medication Treatments?

Presenter: Schneider C.

This multicenter real-world study evaluated the gap between the number of patients potentially eligible for treatment of metabolic dysfunction-associated steatohepatitis (MASH) and the number of patients receiving prescriptions for resmetirom (Rezdiffra) across community-based clinics in the United States.

Patient data were collected from three U.S. community clinics performing non-invasive liver assessment using FibroScan or Velacur for metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH evaluation. Eligibility for treatment was defined according to current recommendations and the Rezdiffra prescribing information, using non-invasive testing parameters including liver elasticity and attenuation/VDFF to identify patients with at-risk MASH (F2–F3 fibrosis). Clinics also reported the number of Rezdiffra prescriptions written during the same time period.

A total of 1,656 liver elastography examinations were included. Across participating sites, more than 60% of evaluated patients were found to have MASLD, while approximately 5–9% met criteria for at-risk MASH and were potentially eligible for treatment. Despite this, substantial variation in prescribing practices was observed between clinics. Reported Rezdiffra prescriptions ranged from 8 to more than 80 across sites during the study period. Consequently, the proportion of potentially eligible patients who did not receive treatment ranged from minimal under-treatment at some centers to more than 90% of eligible patients remaining untreated at others.

These findings highlight a substantial treatment gap among patients with potentially treatable MASH and demonstrate marked variability in treatment access and prescribing patterns across clinical practices.

Real-World Outcomes of Resmetirom Treatment for Metabolic Dysfunction–Associated Steatohepatitis in an Appalachian Population

Presenter: Joshi T.

This retrospective real-world study evaluated the effectiveness, tolerability, treatment persistence, and healthcare utilization associated with resmetirom therapy in patients with metabolic dysfunction–associated steatohepatitis (MASH) treated at a tertiary hepatology clinic serving a rural Appalachian population. A total of 131 patients treated were included. The median age was 55 years, 61.8% were female, and nearly all patients were White.

Resmetirom treatment was associated with significant improvements in several metabolic and hepatic parameters. At 3 months, patients demonstrated reductions in BMI (−0.71 kg/m²; p=0.028) and body weight (−2.5 kg; p=0.010). At 6 months, total cholesterol decreased by 52.3 mg/dL (p=0.023) and LDL cholesterol by 41.6 mg/dL (p=0.035). Hepatic steatosis also improved, with FibroScan CAP reductions of 24 dB/m at 6 months (p=0.001) and 45.3 dB/m at 12 months (p=0.012). The most commonly reported adverse events included gastroesophageal reflux disease, diarrhea, nausea, and constipation. Treatment discontinuation occurred in 10.2% of patients, while insurance denial was reported in over one-fifth of evaluable patients.

Overall, resmetirom demonstrated favorable real-world effects on weight, lipid profiles, and hepatic steatosis in this rural Appalachian MASH cohort. However, the lack of significant fibrosis regression and the observed barriers to treatment implementation highlight the importance of longer-term follow-up and multidisciplinary care strategies to optimize outcomes in underserved populations.

Real-World Persistence, Tolerability, and Non-Invasive Treatment Response to Resmetirom in Patients with MASH at a Tertiary Liver Center in North Texas

Presenter: Sandhu J.

This retrospective real-world cohort study evaluated treatment persistence, safety, and non-invasive test (NIT) responses among adults with metabolic dysfunction-associated steatohepatitis (MASH) treated with resmetirom. The analysis further explored outcomes according to resmetirom dose (≤80 mg vs 100 mg) and concomitant GLP-1 receptor agonist use. A total of 326 patients initiated resmetirom therapy, with approximately two-thirds receiving doses ≤80 mg and one-third receiving 100 mg. Around 40% of patients were treated concurrently with GLP-1 receptor agonists.

Treatment persistence was notably high throughout follow-up. Persistence rates were 96% (298/312) at 3 months, 94% (242/258) at 6 months, and 94% (127/134) at 12 months, with Kaplan–Meier analysis demonstrating minimal early treatment discontinuation and sustained long-term adherence. Serious adverse events were uncommon and included isolated cases of hepatocellular carcinoma and gastric variceal bleeding in a patient receiving off-label treatment for cirrhosis.

Across treatment groups, no significant differences were observed in changes in FibroScan CAP or liver stiffness over 12 months. However, patients receiving ≤80 mg demonstrated greater early reductions in total cholesterol and triglycerides at 3 months, as well as larger improvements in AST and ALT at 12 months compared with the 100 mg cohort. Patients receiving concomitant GLP-1 therapy experienced greater improvements in FIB-4 at 6 months. Resmetirom was generally well tolerated.

Overall, this large real-world analysis demonstrated high long-term persistence and favorable tolerability with resmetirom therapy in patients with MASH. Both dosing strategies produced meaningful biochemical and lipid improvements, while concomitant GLP-1 therapy appeared to enhance fibrosis-related biomarker responses.

Real-World Liver-Related Outcomes After Initiation of Resmetirom vs GLP-1 Receptor Agonists in MASH: A Propensity Score–Matched Cohort Analysis Highlighting the Impact of Fibrosis Coding

Presenter: Eid K.

This retrospective propensity score–matched cohort study evaluated 12-month liver-related outcomes among patients with metabolic dysfunction–associated steatohepatitis (MASH) initiating resmetirom or GLP-1 receptor agonists (GLP-1 RAs), while also examining the impact of fibrosis documentation on comparative real-world analyses.

Investigators identified adults initiating either resmetirom or a GLP-1 RA with documented NASH and hepatic fibrosis. The primary composite endpoint included incident cirrhosis, portal hypertension, ascites, hepatic encephalopathy, gastroesophageal varices, or chronic hepatic congestion within 12 months. Propensity score matching resulted in 883 patients in each treatment cohort.

During follow-up, liver-related events occurred more frequently among resmetirom initiators compared with GLP-1 RA users (11.7% vs 3.4%). This corresponded to a risk ratio of 3.43 (95% CI 2.31–5.10) and a hazard ratio of 3.93 (95% CI 2.61–5.90), with significantly lower event-free survival in the resmetirom cohort at 12 months (86.8% vs 96.5%; log-rank p<0.0001).

Importantly, investigators emphasized that these findings were likely driven by methodological limitations related to fibrosis ascertainment rather than true pharmacologic differences between therapies. In routine practice, many patients receiving resmetirom may have clinically confirmed fibrosis that is not fully captured through structured ICD-10 coding. Conversely, inclusion criteria for the GLP-1 RA cohort required explicit fibrosis documentation, potentially enriching this group for more thoroughly characterized hepatic disease and creating differential misclassification between cohorts.

Overall, the study highlights the substantial influence of fibrosis documentation and phenotype construction on real-world comparative effectiveness analyses in MASH.

 

Comparative Effectiveness of Resmetirom Versus Semaglutide on Mortality and Portal Hypertension Outcomes in NASH Patients

Presenter: Kanu I

This retrospective real-world cohort study compared the clinical outcomes associated with resmetirom and semaglutide in adults with nonalcoholic steatohepatitis (NASH). The study aimed to evaluate the impact of these therapies on mortality and hepatic complications in routine clinical practice. Adults aged ≥18 years with NASH were identified and categorized according to treatment with resmetirom or semaglutide. Following matching, 1,811 patients were included in each cohort. Primary outcomes included all-cause mortality, incident cirrhosis, and development of esophageal varices.

Resmetirom treatment was associated with a significantly lower risk of all-cause mortality compared with semaglutide (RR 0.224; 95% CI 0.117–0.430). In addition, resmetirom users demonstrated a markedly reduced risk of esophageal varices, a key complication of portal hypertension (RR 0.093; 95% CI 0.054–0.161). No significant difference was observed between the two therapies in progression to cirrhosis (RR 0.812; 95% CI 0.392–1.684). The propensity-matched analysis achieved good baseline balance between treatment groups, reducing confounding related to metabolic disease severity and hepatic biochemical abnormalities.

Overall, the findings suggest that resmetirom may provide greater protection against mortality and portal hypertension-related complications compared with semaglutide in patients with NASH, potentially reflecting its liver-directed mechanism of action.

Novel Real-World Head-to-Head Comparison of Semaglutide vs Resmetirom in MASLD: A Propensity-Matched Cohort Study

Presenter: Rajab I.

This retrospective real-world comparative effectiveness study evaluated one-year clinical and biochemical outcomes associated with semaglutide and resmetirom in adults with metabolic dysfunction–associated steatotic liver disease (MASLD). Investigators identified adults with MASLD initiating either therapy between January 2010 and October 2024. Patients with other chronic liver diseases or prior advanced liver disease were excluded. Propensity score matching based on demographics and metabolic comorbidities resulted in 554 balanced patient pairs.

At one year, semaglutide and resmetirom demonstrated comparable short-term clinical outcomes. Rates of incident cirrhosis were similar between groups (3.5% vs 3.5%; HR 1.52; p=0.26), as were gallbladder or biliary complications, diarrhea, and nausea/vomiting. No liver transplant events occurred in either cohort during follow-up.

Biochemical responses differed between therapies. Semaglutide produced significantly greater reductions in aminotransferases, with lower 12-month AST and ALT levels compared with resmetirom (both p<0.001). In contrast, resmetirom demonstrated larger improvements in LDL cholesterol and BMI (both p=0.001). HbA1c, alkaline phosphatase, and triglyceride outcomes were similar between treatment groups.

Overall, semaglutide and resmetirom demonstrated comparable short-term hepatic safety and clinical outcomes, while exhibiting distinct metabolic and biochemical response profiles. These findings suggest that treatment selection in MASLD may benefit from phenotype-driven approaches, with semaglutide potentially favored in patients with obesity and glycemic burden, and resmetirom potentially preferred in those with dyslipidemia or elevated cardiovascular risk.

Comparative Effectiveness for Pharmacotherapy for Patients with MASH

Presenter: Varghese S.

This modelling study evaluated the comparative effectiveness and cost-effectiveness of emerging pharmacotherapies for metabolic dysfunction–associated steatohepatitis (MASH), including resmetirom, semaglutide, and tirzepatide. Investigators developed a monthly-cycle Markov model simulating a hypothetical randomized trial in patients with MASH beginning at fibrosis stage F0 at age 50. Patients were followed over a lifetime horizon and could transition through fibrosis progression, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma (HCC), and death.

In the untreated cohort, 0.58% of patients developed HCC and 4.2% died from liver-related causes, with lifetime healthcare costs estimated at approximately $114,000 per patient. Lower-dose tirzepatide, semaglutide, and resmetirom all demonstrated clinical benefit compared with no treatment; however, these strategies were ultimately dominated by high-dose tirzepatide in cost-effectiveness analyses.

Compared with no treatment, tirzepatide reduced HCC incidence to 0.42% and liver-related mortality to 1.2%. Tirzepatide also demonstrated greater fibrosis improvement (61% vs 34%) and higher rates of MASH resolution (85% vs 47%). The incremental cost-effectiveness ratio for tirzepatide was $38,617 per QALY gained, supporting its favourable economic profile relative to other therapies evaluated.

Overall, tirzepatide emerged as the most cost-effective therapeutic strategy among currently approved and emerging MASH therapies, offering substantial reductions in fibrosis progression, HCC incidence, and liver-related mortality while providing meaningful quality-of-life gains.

Comparative Biochemical Response and Side Effects of Resmetirom Versus GLP-1 RA in Patients with MASLD and Obesity: A Real-World Data Study

Presenter: Ashraf H.

This real-world comparative study evaluated biochemical response and gastrointestinal tolerability among adults with metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity treated with resmetirom or glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Using the TriNetX U.S. Collaborative Network, investigators identified adults with MASLD and obesity (BMI ≥30 kg/m²) receiving either resmetirom or GLP-1 RA therapy. Patients with decompensated cirrhosis, liver transplantation, or alternative chronic liver diseases were excluded, and treatment crossover between cohorts was not permitted. All included patients had at least one metabolic abnormality. Propensity score matching was performed using demographic, clinical, and laboratory variables, resulting in 984 matched patients in each cohort.

At one year, GLP-1 RA therapy was associated with greater biochemical improvement compared with resmetirom. ALT normalization occurred in 43.8% of GLP-1 RA users versus 32.1% of resmetirom users (OR 0.73, 95% CI 0.65–0.82), while AST normalization occurred in 51.7% versus 39.6%, respectively (OR 0.77, 95% CI 0.70–0.85).

In contrast, gastrointestinal adverse events were consistently less frequent among resmetirom-treated patients. Compared with GLP-1 RA therapy, resmetirom was associated with lower rates of nausea and vomiting, diarrhea, GERD, abdominal pain or dyspepsia, and overall composite gastrointestinal intolerance.

Overall, GLP-1 receptor agonists demonstrated greater improvement in liver enzyme normalization, while resmetirom showed a more favorable gastrointestinal tolerability profile.

DDW 2026, May 2-5, Chicago, IL