As the global prevalence of metabolic associated steatohepatitis (MASH) continues to rise, it has become a major public health challenge. Lifestyle intervention remains the core strategy for MASH treatment, but drug development has long faced bottlenecks. In recent years, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as research focal points due to their potential to improve metabolic disorders. Among them, the ESSENCE trial of semaglutide—a representative GLP-1RA—has drawn extensive attention as the world’s first phase III clinical trial evaluating GLP-1RA for MASH treatment.
Recently, the mid-term results of this trial were officially announced and published in the authoritative journal The New England Journal of Medicine (NEJM). The findings show that semaglutide significantly outperforms placebo in improving liver histology and multiple metabolic parameters, with efficacy partially independent of weight loss effects. This breakthrough is set to revolutionize MASH treatment.
To delve into these results and their clinical implications, our journal exclusively invites Professor Jia Jidong from Beijing Friendship Hospital, Capital Medical University—one of the Chinese experts involved in this large international clinical study—to provide an in-depth interpretation.
Breakthrough Progress: Unveiling Semaglutide's Potential in Treating MASH Through the ESSENCE Trial
Professor Jia Jidong: The path of drug development for metabolic associated steatohepatitis (MASH) has been long and challenging, marked by numerous setbacks and failures. Researchers have explored various drug targets in search of effective therapeutic strategies. Among these directions, drug development based on glucagon-like peptide-1 receptor agonists (GLP-1RAs) has gradually shown promising prospects. The ESSENCE trial of semaglutide, a representative GLP-1RA, is at the global forefront of this research field. As the world's first phase III clinical trial evaluating GLP-1RAs for MASH treatment, it holds landmark significance. Additionally, another highlight of the ESSENCE trial is its confirmation that GLP-1RAs may not only play a pivotal role in MASH treatment but also bring multiple metabolic benefits to patients—an important reason why the industry deems it highly promising.
The ESSENCE trial is a multicenter, randomized, double-blind, placebo-controlled phase III clinical trial [3]. A total of 1,197 patients with biopsy-confirmed MASH and liver fibrosis stages 2 or 3 were enrolled, randomized in a 2:1 ratio to receive 2.4 mg of semaglutide via weekly subcutaneous injection or placebo for 240 weeks or until liver-related clinical events occurred. The New England Journal of Medicine (NEJM) recently published the first part of the ESSENCE trial results, presenting the planned mid-term analysis of the first 800 patients at week 72. The primary endpoints were MASH resolution without worsening of liver fibrosis and liver fibrosis improvement without worsening of MASH.
The results showed that after 72 weeks of treatment, semaglutide outperformed placebo in both endpoints:
MASH resolution without worsening of liver fibrosis: 62.9% in the semaglutide group vs. 34.3% in the placebo group (P < 0.001, Figure 1A).
Liver fibrosis improvement by at least one stage without worsening of MASH: 36.8% in the semaglutide group vs. 22.4% in the placebo group (P < 0.001, Figure 1B).
Both differences were statistically significant. Notably, these two liver histology endpoints showed significant clinical benefits across various subgroups, including different age groups, genders, baseline liver fibrosis levels, diabetes statuses, and BMI levels. This suggests that semaglutide may also be effective in non-diabetic and non-obese patients with MASH.
Figure 1. Semaglutide significantly outperforms placebo in both MASH resolution without liver fibrosis worsening and liver fibrosis improvement without MASH worsening
Additionally, while liver biopsy remains the gold standard for diagnosing MASH and liver fibrosis, its clinical application is highly limited due to being an invasive procedure. Therefore, the ESSENCE trial specifically focused on multiple key non-invasive test (NIT) markers, including baseline levels of FIB-4, ELF, CAP, LSM, and PRO-C3. The results showed that after semaglutide treatment, patients demonstrated significant improvements in ELF, CAP, LSM, and PRO-C3 levels compared to the placebo group (Figure 2).
Under the current trend of advocating NIT as a substitute for biopsy, these findings facilitate the future use of NIT for selecting eligible populations and monitoring drug efficacy, thereby bringing greater convenience to clinical diagnosis and treatment.
Figure 2. Semaglutide significantly outperforms placebo in improving hepatic fibrosis NITs such as ELF and LSM
Based on these encouraging results, we have reason to believe that semaglutide will bring enormous benefits to MASH patients worldwide in the future.
From Weight Loss to Liver Protection: The Diverse Mechanisms of Semaglutide in MASH Treatment
Professor Jia Jidong: Diabetes, hypertension, dyslipidemia, obesity, and cardiovascular diseases are all closely linked to systemic metabolic function. Broadly speaking, they fall under the category of metabolic diseases. These conditions are not isolated; their pathogenic mechanisms may act synergistically and influence each other, often co-occurring in the same patient. At the therapeutic level, they are also intricately connected—treatment strategies for one disease often trigger ripple effects on the management of related conditions.
In the treatment of these metabolic disorders, weight management is undoubtedly a critical component. Semaglutide has successfully gained regulatory approval in the U.S., Europe, and China, thanks to its remarkable weight-loss efficacy demonstrated in the STEP series of trials.
Notably, in the ESSENCE trial, patients in the semaglutide group achieved an average weight loss of 10.5%, compared to only 2.0% in the placebo group, with the difference between the two groups being highly statistically significant (P < 0.001). This finding undoubtedly provides more robust clinical evidence for the weight-loss effect of semaglutide in MASH patients.
It is particularly important to note that while weight loss is emphasized, semaglutide's treatment of MASH is not entirely dependent on weight reduction. At the 2025 European Congress on Obesity (ECO) held from May 11 to 14, researchers reported a post-hoc analysis of the first part of the ESSENCE trial results [4]. The analysis showed that slightly more than half of the hepatic histological improvements brought about by semaglutide—both in MASH resolution and fibrosis improvement—were independent of weight loss (51.9% and 55.5%, respectively).
Figure 3. Correlation analysis between semaglutide's effects on MASH resolution/fibrosis improvement and weight loss
Owing to its diverse mechanisms of action—including improving insulin sensitivity, reducing hepatic fat content, alleviating inflammation and injury—semaglutide brings extensive benefits to the liver, body weight, blood glucose, blood lipids, and even cardiovascular system. Currently approved for treating type 2 diabetes mellitus (T2DM) and obesity, semaglutide has demonstrated promising results in the ESSENCE trial. We anticipate its approval for MASH and believe such medications will play an increasingly broader and more critical role in the field of metabolic diseases.
