The ESSENCE of hope: what semaglutide’s Food and Drug Administration approval means for metabolic dysfunction-associated steatohepatitis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined as hepatic steatosis with at least one associated cardiometabolic risk factor and the absence of other causes. MASLD is recognized as the most common cause of chronic liver disease affecting one in three adults in the U.S. (1). Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by fat accumulation in hepatocytes along with necro-inflammatory changes that may lead to progressive fibrosis and possible liver-related complications. Although cardiovascular disease is the leading cause of mortality in patients with MASLD and MASH without significant hepatic fibrosis, patients with moderate to advanced fibrosis are at higher risk of liver-related events, such as cirrhosis and associated complications such as hepatocellular carcinoma (2). The prevalence of MASLD and MASH has been projected to increase from 86.3 million in 2020 to 121.9 million in 2050, and from 14.9 million in 2020 to 23.2 million in 2050 (3).

Until recently, management of MASLD and MASH was limited to weight loss, increased physical activity, diet changes, and management of risk factors such as diabetes, hypertension, and hyperlipidemia. A landmark randomized controlled trial in 2015 by Vilar-Gomez et al. of 293 patients found that patients with >10% weight loss had 90% resolution of MASH, and 45% of the patients had regression of fibrosis (4). However, it has been long recognized that lifestyle recommendations are difficult to sustain, and patients tend to gain weight over a period of time (5). Thus, there is a need to develop medical therapies for patients with MASH and fibrosis to improve liver-related morbidity and mortality.

In 2024, resmetirom became the first drug to be approved by the U.S. Food and Drug Administration (FDA) based on the positive results of the MAESTRO-NASH, phase 3 clinical trial. In the study, the use of resmetirom was associated with significant improvement in inflammation and fibrosis among patients with MASH and fibrosis stages 2 or 3. The use of resmetirom was associated with 25.9–29.9% of patients achieving MASH resolution, and 24.2–25.9% achieving fibrosis progression (6).

In August 2025, the FDA approved semaglutide as a therapeutic option for patients with MASH and fibrosis stages 2 or 3 (7). This was based on the ESSENCE trial with 800 patients in the phase 3 multicenter, randomized, double-blind, placebo-controlled trial (8). This study included 534 patients in the semaglutide group and 266 patients in the placebo group (8). In the study, the use of semaglutide was associated with the resolution of steatohepatitis, without worsening of fibrosis compared to placebo (62.9% vs. 34.3%, P<0.001) (8). Semaglutide use also led to a reduction in liver fibrosis, without worsening of steatohepatitis, compared to placebo (36.8% vs. 22.4%) (8). In the study, the combined resolution of steatohepatitis and reduction in liver fibrosis was seen in 32.7% of patients in the semaglutide group, compared to 16.1% in the placebo group (8). Patients on semaglutide had a mean body weight change of −10.5%, compared to −2% among patients with placebo (8). Gastrointestinal side effects such as nausea, vomiting, diarrhea, and constipation were common in the semaglutide group compared to the placebo group (8). Both resmetirom and semaglutide are now conditionally approved in the U.S., based on improvement in histological endpoints, and studies assessing their impact on clinical outcomes are currently underway (8,9).

There are some limitations to the trial including low representation of black patients and those with “lean” MASH (8). Hence, the findings may not be accurately generalizable to these populations.

The approval of resmetirom and semaglutide signals a paradigm shift in the therapeutic landscape of MASH. Although lifestyle modification of risk factors remains central, they can now be paired with medications to help treat patients with MASH. Furthermore, both these therapeutic options have different mechanisms of action. Resmetirom is a thyroid hormone receptor-β agonist that targets hepatic lipid metabolism, while semaglutide modulates weight loss, insulin sensitivity, and inflammation. This also raises the possibility of combination therapy in the future.

Semaglutide has the additional advantage of improving cardiometabolic parameters. It is also currently approved in the U.S. for diabetes and obesity and therefore may potentially address the extrahepatic metabolic risks that drive morbidity and mortality among patients with MASLD (10,11). Semaglutide may also be indicated for treatment in patients with other fibrosis stages if they otherwise meet criteria for its use. Studies have shown semaglutide use to be safe in patients with cirrhosis, although data on the possible effects of glucagon-like peptide-1 (GLP-1) agonists on sarcopenia remain incomplete, and this may be a particular concern in patients with cirrhosis as we recently published (12,13). A recent randomized placebo-controlled phase 2 trial by Loomba et al. including 71 patients with MASH cirrhosis reported −8.83% weight loss in the semaglutide group, compared to −0.09% in the placebo group. Furthermore, the mean hemoglobin A1c decrease in the semaglutide group was noted to be −1.39% (13). Albeit a small study with 71 patients, no statistically significant difference was noted between semaglutide and placebo in terms of fibrosis and MASH resolution (13). Adequately powered, well-designed studies examining the safety and efficacy of GLP-1 agonists in MASH are necessary before its use in patients with cirrhosis.

More recently, tirzepatide—a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist were approved for treating type 2 diabetes and obesity—has shown emerging potential in improving liver fibrosis (14). A recent randomized, placebo-controlled phase 2 trial by Loomba et al., involving 190 patients with biopsy-confirmed MASH and stage F2 or F3 fibrosis showed that the proportion of patients achieving resolution of MASH without worsening fibrosis was 10% in the placebo group, compared to 44%, 56%, and 62% in the 5 mg, 10 mg, and 15 mg tirzepatide groups (14). Additionally, improvement in fibrosis stage without worsening MASH was observed in 30% of placebo patients compared to 55%, 51%, and 51% in the 5 mg, 10 mg, and 15 mg tirzepatide groups (14). These findings support tirzepatide’s expanding role in managing MASH.

Additionally, survodutide—a dual agonist of the glucagon and GLP-1 receptors—has demonstrated promising therapeutic potential in MASH (15). In a randomized, placebo-controlled phase 2 trial involving 293 patients with biopsy-confirmed MASH and fibrosis stages F1 to F3, a reduction in liver fat content of ≥30% was achieved in 63% of participants receiving 2.4 mg, 67% in the 4.8 mg group, and 57% in the 6.0 mg group, compared to 14% in the placebo group (15). Improvement in fibrosis by at least one stage was observed in 34%, 36%, and 34% of patients in the respective survodutide groups, vs. 22% in the placebo arm (15). Survodutide is currently undergoing evaluation in phase 3 clinical trials.

In the last two years, we have made significant advances in the therapeutic field of MASH, and multiple therapeutic options are currently under investigation. Further studies are needed for understanding the role of combination therapies in patients with MASLD and MASH. Building on the promising results thus far in MASH cirrhosis, studies are underway to explore use of GLP-1 agonists for treatment of metabolic dysfunction-associated and alcohol-related liver disease (Met-ALD). In addition, different combinations of therapies with GLP-1/GIP/glucagon agonists are exploring the range of therapeutic effects in this class. Semaglutide’s FDA approval for MASH has been an important advance for a disease historically underserved by pharmacologic innovation; we hope that this advancement portends a promising future in the treatment of steatotic liver disease.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-732/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-732/coif). K.V.K. declares grants and/or contracts from Akero, 89Bio, Boehringer Ingelheim, Boston Pharmaceuticals, Genfit, Gilead, GlaxoSmithKline, Hanmi, HighTide, Intercept, Madrigal, Mirum, NGM, Pfizer, Pliant, Regor, and Viking; participation on a Data Safety Monitoring Board or Advisory Board of CTI, Medpace, and Labcorp; receipt of equipment, materials, drugs, medical writing, gifts or other services from Sonic Insight; royalties/licenses from UpToDate; consulting fees from Akero, Boehringer Ingelheim, 89Bio, Calliditas Therapeutics, Gilead, GSK, Inipharm, Intercept, Madrigal, Mirum, NGM, Novo Nordisk, and Pliant; payment/honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Gilead, Ipsen, Intercept, and Novo Nordisk; stock or stock options for Inipharm. The other authors have no conflicts of interest to declare.

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