Key Clinical Summary: 

• A real-world study of 5158 patients with metabolic dysfunction-associated steatohepatitis (MASH) found that semaglutide was associated with greater reductions in liver enzymes, body weight, and hemoglobin A1c compared with resmetirom.
• At 6 months, patients receiving semaglutide experienced a mean weight reduction of 20.2 pounds compared with 3.6 pounds among those receiving resmetirom, with the difference increasing to 31.6 versus 4.1 pounds at 12 months.
• Adjusted analyses demonstrated significantly greater improvements in alanine aminotransferase, aspartate aminotransferase, body weight, and hemoglobin A1c with semaglutide at 3 and 6 months, although the study did not directly evaluate liver fibrosis or histologic outcomes.

Patients with MASH treated with semaglutide experienced greater improvements in liver enzymes and cardiometabolic markers than those receiving resmetirom, according to real-world research presented at the American Association for the Study of Liver Diseases (AASLD) meeting.

The observational study, Real-World Comparative Effectiveness of Semaglutide Versus Resmetirom on Liver Enzymes and Cardiometabolic Markers in Patients With MASH (Abstract 2461), evaluated treatment outcomes using electronic medical records from 30 US health systems. The findings provide comparative evidence that may help inform treatment selection and disease management strategies as therapeutic options for MASH continue to expand.

Real-World Analysis Compares MASH Treatment Outcomes

Researchers conducted a retrospective cohort study using electronic medical record data from the Truveta database between June 2021 and March 2026.

The analysis included 5158 adults diagnosed with MASH who initiated injectable semaglutide (n = 2873) or resmetirom (n = 2285). Patients with evidence of cirrhosis or other chronic liver diseases were excluded.

Investigators assessed changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), body weight, and hemoglobin A1c at 1, 3, 6, and 12 months following treatment initiation.

To account for differences between treatment groups, researchers used inverse probability of treatment weighting and generalized estimating equations, adjusting for demographic characteristics, baseline clinical measurements, comorbidities, and prescription medication use.

Patients were required to remain on treatment, allowing a maximum 45-day gap, to be included at each assessment.

Baseline characteristics differed significantly between the treatment groups.

Patients receiving semaglutide were younger than those receiving resmetirom (mean age, 48 vs 59 years), more frequently female (67% vs 58%), and had a higher mean body mass index (39 vs 34).

The semaglutide group also had higher baseline body weight (243 vs 218 pounds) and greater prevalence of hypertension (51% vs 45%) and hyperlipidemia (60% vs 44%).

However, baseline ALT, AST, and hemoglobin A1c levels were lower among patients receiving semaglutide.

Semaglutide Associated With Greater Liver Enzyme Reductions

In unadjusted analyses, patients receiving semaglutide experienced greater reductions in liver enzymes during the first month of treatment.

Mean ALT levels decreased by 6.0 U/L in the semaglutide group, compared with an increase of 5.4 U/L among patients receiving resmetirom.

Similarly, AST levels decreased by 4.5 U/L with semaglutide, compared with an increase of 4.0 U/L with resmetirom. Both between-group differences were statistically significant (P < .05).

After adjustment for baseline characteristics and other potential confounding factors, semaglutide remained associated with significantly greater reductions in ALT and AST at both 3 and 6 months.

Similar relative improvements were observed in a subgroup of patients with abnormal baseline ALT levels, defined as greater than 33 U/L for men and greater than 25 U/L for women.

Although these findings suggest differences in liver enzyme responses, the investigators did not evaluate histologic MASH resolution or fibrosis improvement. Therefore, the results do not establish that semaglutide provides superior liver disease outcomes compared with resmetirom.

Weight Loss and Glycemic Improvements Favor Semaglutide

Semaglutide was also associated with greater reductions in body weight and hemoglobin A1c.

At 6 months, patients receiving semaglutide experienced a mean weight reduction of 20.2 pounds, compared with 3.6 pounds among those receiving resmetirom.

By 12 months, mean weight reductions reached 31.6 pounds with semaglutide and 4.1 pounds with resmetirom.

Glycemic improvements followed a similar pattern.

At 6 months, hemoglobin A1c decreased by 0.36 percentage points in the semaglutide group compared with 0.09 percentage points in the resmetirom group.

At 12 months, reductions were 0.4 and 0.2 percentage points, respectively.

All reported unadjusted differences were statistically significant (P < .05).

Adjusted analyses also demonstrated significantly greater reductions in weight and hemoglobin A1c with semaglutide at 3 and 6 months.

These findings highlight the potential importance of considering cardiometabolic outcomes when evaluating treatment strategies for patients with MASH, particularly those with coexisting obesity or metabolic risk factors.

Implications for Managed Care

The findings provide additional real-world evidence for managed care organizations evaluating treatment options for MASH, a condition frequently associated with obesity, type 2 diabetes, and cardiovascular risk factors.

The greater reductions in body weight and hemoglobin A1c observed with semaglutide may be relevant when considering the broader metabolic health needs of patients with MASH.

However, treatment selection requires consideration of outcomes beyond liver enzymes and cardiometabolic markers, including fibrosis severity, clinical eligibility, safety, and long-term liver-related outcomes.

The study also has several limitations. As a retrospective observational analysis, it cannot establish a causal relationship between treatment selection and outcomes. Although statistical adjustments were performed, residual confounding may remain, particularly given the substantial baseline differences between treatment groups.

Additionally, the requirement for treatment persistence at each assessment may limit generalizability to patients who discontinue or switch therapy.

The analysis did not directly compare treatment acquisition costs, health care resource utilization, adverse events, or long-term clinical outcomes.

Consequently, the findings do not establish the comparative cost-effectiveness of semaglutide and resmetirom.

For payers and clinicians, additional studies evaluating fibrosis outcomes, treatment persistence, resource utilization, and overall costs will be important for understanding the comparative value of these therapies in routine practice.

Conclusion

This real-world study found that semaglutide was associated with significantly greater improvements in liver enzymes, body weight, and hemoglobin A1c compared with resmetirom among adults with MASH.

Although the findings suggest potential advantages for semaglutide in managing cardiometabolic risk factors, further research is needed to determine whether these improvements translate into superior long-term liver outcomes or economic benefits. 

Reference 

Arora P, Shi D, Aly A, et al. Real-world comparative effectiveness of semaglutide versus resmetirom on liver enzymes and cardiometabolic markers in patients with MASH. Abstract presented at: AASLD The Liver Meeting 2026; November 5-9, 2026; Denver, CO.