Semaglutide adds liver disease improvements to its list of benefits

Semaglutide may also confer hepatoprotective benefits, with interim efficacy data from the ongoing phase III ESSENCE study showing that the glucagon-like peptide-1 (GLP-1) receptor agonist helps dial down disease activity in patients with metabolic dysfunction–associated steatohepatitis (MASH) and moderate-to-severe fibrosis.

After 72 weeks, significantly more patients who received once-weekly semaglutide injections achieved the first primary endpoint of steatohepatitis resolution without worsening of fibrosis (62.9 percent vs 34.3 percent (estimated difference, 28.7 percentage points, 95 percent confidence interval [CI], 21.1–36.2; p<0.001) and the second primary endpoint of liver fibrosis reduction without worsening of steatohepatitis (36.8 percent vs 22.4; estimated difference, 14.4 percentage points, 95 percent CI, 7.5–21.3; p<0.001) compared with those who received placebo. These outcomes were consistent across subgroups defined by age, sex, BMI, diabetes status, and fibrosis stage. [N Engl J Med 2025;doi:10.1056/NEJMoa2413258]

Results for secondary endpoints also favoured semaglutide. Compared with placebo, treatment with the GLP-1 receptor agonist resulted in a substantially greater reduction in body weight (mean change, −10.5 percent vs −2.0 percent; estimated difference, −8.5 percentage points, 95 percent CI, −9.6 to −7.4; p<0.001) and higher percentage of patients with both resolution of steatohepatitis and reduction in liver fibrosis (32.7 percent vs 16.1 percent; estimated difference, 16.5 percentage points, 95 percent CI, 10.2–22.8; p<0.001).

However, the estimated difference in the mean change in the bodily pain score on the 36-Item Short Form Health Survey (SF-36) between semaglutide and placebo (0.9 vs −0.5; estimated difference, 1.3, 95 percent CI, 0.0–2.7; p=0.05) did not meet the prespecified criteria for statistical significance (p<0.0045).

More benefits

Noninvasive liver assessments at week 72 indicated better outcomes with semaglutide than placebo, with reductions in aminotransferase levels observed as early as week 12. Compared with those on placebo, more patients on semaglutide met the prespecified definition of a decrease in the enhanced liver fibrosis (ELF) score of at least 0.5 (55.8 percent vs 25.5 percent) and met the response criteria for a decrease in liver stiffness of at least 30 percent (52.0 vs 30.3 percent).

The GLP-1 receptor agonist also exerted positive effects on glycaemia, HOMA-IR, high-sensitivity C-reactive protein, and lipids. Among patients not using insulin, the improvement in insulin resistance with semaglutide was slightly more pronounced for those with vs without type 2 diabetes (T2D).

Patients receiving semaglutide were more likely to have reductions in steatosis, ballooning, and total nonalcoholic fatty liver disease activity score. Additionally, semaglutide treatment led to less fibrosis progression compared with placebo among patients with fibrosis stage 2.

Promising treatment option

“Building on encouraging data from the phase II study, our current trial shows improvement in two areas of disease activity: steatohepatitis and fibrosis stage. On the basis of biologic characteristics of MASH, resolution of steatohepatitis is expected to reduce fibrogenesis—and the reduction in fibrosis stage is particularly relevant because higher stages are associated with poorer outcomes,” the authors said.  [N Engl J Med 2021;384:1113-1124; Nat Med 2018;24:908-922; N Engl J Med 2021;385:1559-1569]

“The demonstration of fibrosis regression in this trial, but not in the previous phase II study, may be due to the differences in study design, including sample size, selection of patients, pathological evaluation, and dose regimens of semaglutide. Together, these data support the benefits of semaglutide for the treatment of MASH with stage 2 or 3 fibrosis,” they added.

One of the study authors, Prof Philip Newsome, Director of the Roger Williams Institute of Liver Studies at King’s College London in London, UK, was thrilled by the ESSENCE data.

“I’ve been working with GLP-1 treatments for 16 years, and these results are hugely exciting. MASLD is a growing problem worldwide and this trial will provide real hope for patients with MASH,” Newsome said. “While these results must be treated with caution, the analysis shows semaglutide can be an effective tool to treat this advanced liver disease.”

ESSENCE population

For ESSENCE, 1,197 patients with biopsy-defined MASH and fibrosis stage 2 or 3 were randomly assigned to receive once-weekly subcutaneous semaglutide at 2.4 mg or placebo for 240 weeks. The interim analysis included the first 800 patients who completed 72 weeks of treatment, including 534 on semaglutide and 266 on placebo. Among patients on semaglutide, 88.0 percent continued to receive the 2.4 mg target dose until week 72.

Baseline characteristics were similar between the two treatment arms. The mean age of the total population was 56.0 years, and the mean BMI was 34.6 kg/m². Most patients were White (67.5 percent) and female (57.1 percent). More than half of the patients (55.9 percent) had T2D. Fibrosis stage was advanced (stage 3) in 550 patients (68.8 percent) and moderate (stage 2) in 250 (31.3 percent). Of the patients, 25.1 percent were from Asia, 25.3 percent were from Europe, 35.0 percent were from North America, 7.9 percent were from South America, and the remaining 6.8 percent were from locations listed as “other.”

In terms of safety, adverse events (AEs) occurred in 86.3 percent of patients on semaglutide and in 79.7 percent of those on placebo, with 13.4 percent of the patients in each group having a serious AE. AEs led to premature trial discontinuation in 2.6 percent of the patients in the semaglutide group and in 3.3 percent of those in the placebo group.

The most common AEs were gastrointestinal disorders in both groups, with nausea, diarrhoea, constipation, and vomiting being more common with semaglutide. The incidence of acute pancreatitis was similar in the two groups. Three patients on semaglutide and six on placebo died, with no clear common cause identified.