Semaglutide erases liver inflammation and cuts fibrosis in MASH patients, study shows

Semaglutide erases liver inflammation and cuts fibrosis in MASH patients, study shows

In a preliminary analysis of an ongoing global trial, semaglutide resolved steatohepatitis and reduced liver fibrosis in 63% of patients, while promoting weight loss and improving metabolic health in people with advanced fatty liver disease.

In a recently published study inThe New England Journal of MedicineA group of researchers examined the effectiveness of semaglutide in resolving steatohepatitis and reducing fibrosis in patients with metabolic dysfunction associated steatohepatitis (MASH).

background

It is estimated that over one billion people worldwide have some form of fatty liver disease. Mash, a progressive form of fatty liver disease, is characterized by liver inflammation, hepatocyte injury, and fibrotic changes. If left untreated, it can lead to cirrhosis, liver failure and hepatocellular carcinoma. MASH is also closely linked to conditions such as type 2 diabetes mellitus and obesity.

Despite its increasing burden, treatment options remain limited, with only resmetirom having received accelerated FDA approval specifically for MASH with significant fibrosis. While lifestyle modification remains the first line, pharmacological interventions have shown mixed results.

Given the systemic nature of MASH and its links to cardiometabolic diseases, new therapies must target both liver and metabolic pathways. Further research is important to evaluate promising interventions.

About the study

The present, randomized, double-blind, placebo-controlled study was conducted at 253 sites in 37 countries. Adults aged 18 years with biopsy-confirmed pulp and stage 2 or 3 liver fibrosis were enrolled. Participants were randomized in a 2:1 ratio to receive once-weekly subcutaneous semaglutide at 2.4 milligrams or placebo for 72 weeks as part of a longer 240-week study evaluating clinical outcomes.

Stratification was based on the presence of type 2 diabetes mellitus, fibrosis stage, and geographic region. After an initial dose escalation period, participants maintained the 2.4 milligram dose unless adjusted for adverse effects.

Liver biopsies were performed at baseline and week 72 to evaluate histological changes. Resolution of steatohepatitis without worsening of fibrosis and reduction of fibrosis without worsening of steatohepatitis were defined as the two co-primary endpoints.

Secondary outcomes included body weight changes, histologic improvement in composite improvement, and change in physical pain score from the 36-item Short Form Health Survey (SF-36). Non-invasive markers such as liver stiffness, enhanced liver fibrosis (ELF) score, Fibroscan-ast (rapid) score, type III collagen N-terminal propeptide (Pro-C3) level and liver enzyme levels were also monitored.

The efficacy analysis followed the intention-to-treat principle and used reference-based multiple imputation for missing data with adjustments for multiple comparisons. Safety was assessed through adverse event reporting and laboratory assessments. An external adjudication committee blindly assessed serious clinical events.

Study results

This interim analysis included 800 patients, of whom 534 received semaglutide and 266 were assigned to the placebo group. Baseline characteristics were well balanced with a mean age of 56 and a mean body mass index of 34.6 kg/m². Approximately 56% of participants had type 2 diabetes mellitus and most (68.8%) had stage 3 fibrosis.

Resolution of steatohepatitis without worsening of fibrosis was achieved in 62.9% of participants in the semaglutide group compared with 34.3% in the placebo group (difference: 28.7 percentage points; 95% confidence interval [CI]21.1 to 36.2; P < 0.001). Reduction in liver fibrosis without worsening of steatohepatitis occurred in 36.8% in the semaglutide group versus 22.4% in the placebo group (difference: 14.4 percentage points; 95% CI, 7.5 to 21.3; P < 0.001). Both resolution and fibrosis reduction were observed in 32.7% of the semaglutide group and 16.1% of the placebo group.

Weight loss was significantly greater in the semaglutide group, with an average reduction of 10.5% versus 2.0% with placebo. The improvement in physical pain scores did not reach the study's predetermined threshold for statistical significance. Non-invasive measures also favored semaglutide, with greater reductions in ELF levels and liver stiffness. Specifically, 55.8% of patients in the semaglutide group had a decrease of at least 0.5 ELF score compared to 25.5% in the placebo group. A reduction in liver stiffness of 30% or greater occurred in 52.0% of patients treated with semaglutide to 30.3% of patients on placebo.

Semaglutide also improved markers of metabolic health. Glycated hemoglobin levels, insulin resistance measured by homeostatic model assessment of insulin resistance (HOMA-IR), high-sensitivity C-reactive protein and lipid parameters showed favorable changes. These histologic and metabolic effects were generally consistent across subgroups, including those with and without type 2 diabetes mellitus and independent of baseline fibrosis stage, age, or gender.

In terms of safety, 86.3% of semaglutide participants experienced an adverse event compared to 79.7% in the placebo group. Gastrointestinal side effects such as nausea, diarrhea, constipation, and vomiting were more common in the semaglutide group but were generally manageable. Serious adverse events occurred at similar rates (13.4%) in both groups and discontinuation due to adverse events was low (2.6% versus 3.3%). No new or unexpected safety signals emerged.

Conclusions

While acknowledging limitations such as the small number of black participants and the lack of data on alcohol consumption biomarkers, this interim analysis found that once-weekly subcutaneous semaglutide at a dose of 2.4 milligrams significantly improved liver histology in patients with Mash and moderate fibrosis. In addition to resolving steatohepatitis and reducing fibrosis, semaglutide also supports weight loss and improves cardiometabolic markers such as insulin resistance and lipid profiles.

These results are relevant to a broad population affected by fatty liver disease, obesity and type 2 diabetes mellitus. The safety profile was consistent with known effects of glucagon-like peptide-1 receptor agonists. Semaglutide presents a promising multi-titrated therapeutic option to address the hepatic and systemic sequelae of MASH, although definitive conclusions on long-term clinical outcomes await completion of the full trial.

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