What is the latest information on subcutaneous semaglutide for MASLD/MASH?

Introduction
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly referred to as nonalcoholic fatty liver disease (NAFLD), affects an estimated 32% of adults.1 Patients are diagnosed with MASLD if they have hepatic steatosis in ≥5% of hepatocytes, ≥1 of 5 cardiometabolic risk factors, and no other apparent cause of steatosis. Obesity and type 2 diabetes increase the risk of MASLD; it is estimated that 60% to 70% of people with type 2 diabetes and 70% to 80% of people who are obese have co-occurring MASLD.2 Metabolic dysfunction-associated steatohepatitis (MASH), previously referred to as nonalcoholic steatohepatitis (NASH), is a progressive form of MASLD in which hepatocellular inflammation and injury eventually leads to fibrosis, cirrhosis, hepatocellular carcinoma, and other severe complications.3,4

Lifestyle modifications are the primary treatment for MASLD/MASH, and pharmacologic treatment options are limited.5-7 The American Association for the Study of Liver Diseases (AASLD) states that some medications may be considered for off-label use in MASH (eg, vitamin E, pioglitazone, glucagon-like peptide-1 [GLP-1] receptor agonists), but notes that none of these therapies have specifically demonstrated an antifibrotic benefit.6 A novel agent, resmetirom, became the first drug specifically approved for MASH in March 2024; information on this agent was previously summarized in another frequently asked question (FAQ), available here.8 On August 15, 2025, subcutaneous semaglutide (Wegovy®) became the second drug to receive formal approval for MASLD/MASH; it was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for noncirrhotic MASH in adults with moderate to advanced liver fibrosis (stage F2 to F3).9,10

Potential Therapeutic Benefits of Semaglutide
Although the mechanism of action in MASLD/MASH is not completely understood, semaglutide is thought to improve MASLD/MASH in several ways.4,10,11 The pathogenesis of MASLD/MASH is closely associated with metabolic abnormalities such as obesity, insulin resistance, and type 2 diabetes.6 Semaglutide and other GLP-1 receptor agonists are known to improve glycemic control and promote weight loss by modulating satiety signals in the brain, inhibiting glucagon secretion, and stimulating insulin production.4,11 These effects may indirectly improve MASLD/MASH by reducing fat accumulation in the liver and thereby decreasing liver inflammation. Semaglutide has also been shown to modulate lipid metabolism and attenuate liver inflammation independently of its weight loss effects (eg, by downregulating certain lipogenic signaling pathways and limiting the infiltration and recruitment of GLP-1 receptor-expressing macrophages).4

Guideline Recommendations and Previous Evidence
The AASLD published guidelines on MASLD/MASH in 2023 and a guideline update regarding resmetirom in 2024.6,7 Although a specific update has not been published to address the approval of semaglutide, the 2023 guideline discussed semaglutide as a potential treatment option, citing evidence from a phase 2b trial.6,12 This 72-week, randomized, double-blind, placebo-controlled trial enrolled 320 patients with biopsy-confirmed MASH and stage F1, F2, or F3 liver fibrosis.12 Subcutaneous semaglutide was administered at a dose of 0.1, 0.2, or 0.4 mg daily. The primary endpoint was resolution of MASH (defined as no hepatocyte ballooning, no worsening of liver fibrosis, and no more than mild residual inflammatory cells) at week 72 in patients with stage F2 or F3 fibrosis. The confirmatory secondary endpoint was improvement in fibrosis by at least 1 stage and no worsening of MASH at week 72. The percentage of patients with resolution of MASH at week 72 was greater for all doses of semaglutide compared to placebo (59%, 36%, 40%, and 17% for semaglutide 0.4 mg, semaglutide 0.2 mg, semaglutide 0.1 mg, and placebo respectively; p<0.001 for the highest dose of semaglutide versus placebo). However, no significant difference was observed in the proportion of patients achieving improvement of at least 1 fibrosis stage without worsening of MASH (43% versus 33% for semaglutide 0.4 mg and placebo respectively; p=0.48). The AASLD stated that, although no antifibrotic benefit has been demonstrated, semaglutide can be considered for the treatment of type 2 diabetes or obesity in patients with MASH, as it is approved for those indications and may confer a cardiovascular benefit as well as improve MASH.6 The AASLD guideline noted that semaglutide has not been well-studied in patients with MASH/MASLD and cirrhosis. A small placebo-controlled trial failed to find a benefit in terms of fibrosis improvement or resolution of MASH when semaglutide was administered to patients with MASH and compensated cirrhosis (stage F4 fibrosis).13

The ESSENCE Trial
The approval of semaglutide for the treatment of MASH was based on an interim analysis from the ongoing phase 3 ESSENCE trial.5,10 The ESSENCE trial is a 2-part, randomized, double-blind, placebo-controlled trial.5,14 The first part was 72 weeks in length and focused on histologic outcomes; the second part is ongoing but will examine clinical outcomes after 240 weeks of treatment. The total planned enrollment for the ESSENCE trial is 1200 patients; the interim analysis included data from the first 800 patients enrolled. In order to be eligible, patients had to have histologically documented steatohepatitis, stage 2 or 3 liver fibrosis, and a nonalcoholic fatty liver disease activity score (NAS) ≥4.5 Patients were randomly assigned in a 2:1 ratio to receive semaglutide 2.4 mg subcutaneously once weekly or placebo in addition to standard of care. Semaglutide was initiated at a dose of 0.25 mg weekly and titrated up to a target dose of 2.4 mg weekly during a 16-week dose escalation period. Other medications for MASH (eg, vitamin E, pioglitazone, resmetirom), lipid-lowering medications, weight-loss medications, and glucose-lowering agents other than glucagon-like peptide-1 (GLP-1) receptor agonists could be used concomitantly if doses had been stable for at least 90 days prior to screening.5,14 Treatments approved for MASH could not be initiated during part 1 of the trial but could be initiated during part 2 at the discretion of the investigator; other medications could be initiated during the trial in accordance with local treatment guidelines.5

The co-primary endpoints for part 1 of ESSENCE were resolution of steatohepatitis without worsening of liver fibrosis and reduction of liver fibrosis with no worsening of steatohepatitis.5 Both endpoints were measured after 72 weeks of treatment. Resolution of steatohepatitis was defined as a NAS of 0 for ballooning and 0 to 1 for inflammation. Reduction in liver fibrosis was defined as a ≥1-stage reduction on the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) fibrosis scale.

The mean age of patients included in the interim efficacy analysis was 56 years; 67.5% of patients were white, 25.1% were Asian, 18% were Hispanic/Latino, 57.1% were female, and 55.9% had type 2 diabetes.5 The mean body mass index (BMI) at baseline was 34.6 kg/m2. Most patients (68.8%) had stage 3 hepatic fibrosis. Resolution of steatohepatitis without worsening of liver fibrosis was achieved in significantly more patients receiving semaglutide at week 72 (62.9% versus 34.3% of patients receiving placebo; difference, 28.7%; 95% confidence interval [CI], 21.1 to 36.2; p<0.001). Similarly, more patients receiving semaglutide had a reduction in liver fibrosis with no worsening of steatohepatitis at week 72 (36.8% versus 22.4%; difference, 14.4%; 95% CI, 7.5 to 21.3; p<0.001). A secondary endpoint of steatohepatitis resolution plus fibrosis reduction at week 72 was achieved in 32.7% of patients receiving semaglutide and 16.1% of patients receiving placebo (difference, 16.5%; 95% CI, 10.2 to 22.8; p<0.001). The mean percentage change in body weight from baseline to week 72 was -10.5% with semaglutide and -2% with placebo (difference, -8.5%; 95% CI, -9.6 to -7.4; p<0.001). Gastrointestinal adverse events were more common in the semaglutide group: these included nausea (36.2% versus 13.2%), diarrhea (26.9% versus 12.2%), constipation (22.2% versus 8.4%), and vomiting (18.6% versus 5.6%). Rates of serious adverse events and adverse events leading to trial discontinuation were similar between groups.

Black patients were not well-represented in the ESSENCE trial, accounting for only 0.6% of patients enrolled.5 Patients with cirrhosis were excluded from the trial, and only 2.6% to 3% of patients in each treatment group were considered “lean” (ie, not obese). It is therefore unclear whether the benefits observed with semaglutide in the ESSENCE trial would be observed in these patient populations. Additionally, it is important to note that the endpoints examined in part 1 of the ESSENCE trial are surrogate histologic markers. Although semaglutide received accelerated approval for MASH based on these data, continued approval for this indication will depend on the final results from part 2 of the ESSENCE trial, which will examine how semaglutide impacts long-term clinical outcomes such as death, liver transplant, and other liver-related events.9,10 The comparative efficacy of semaglutide and resmetirom remains unclear, and potential benefits of combination therapy have not specifically been studied.7 Selection between these therapies may depend on the patient’s comorbidity profile, as semaglutide has been additionally studied and approved to treat type 2 diabetes and obesity.

Conclusion
Subcutaneous semaglutide was recently approved for the treatment of MASH, making it the second drug to be approved by the FDA for this indication. Although final results of the pivotal ESSENCE trial are still pending, semaglutide has demonstrated positive impacts on steatohepatitis and liver fibrosis in patients with MASH and stage F2 or F3 fibrosis. Because semaglutide is also approved to treat type 2 diabetes and obesity, it may be a particularly useful treatment option for MASH patients with these comorbidities. Results from part 2 of the ongoing ESSENCE trial will clarify the long-term impact of semaglutide on clinical outcomes such as death, liver transplant, and liver-related events.

References

  1. Nowak K, Łupina K, Romac A, Kalisz A, Ilkiewicz Ł, Janczura J. Therapeutic potential of GLP-1 receptor agonists in metabolic associated steatotic liver disease. Ann Pharmacother. 2025;59(10):928-936. doi: 10.1177/10600280251322002
  2. Mantovani A, Morandin R, Fiorio V, et al. Glucagon-like peptide-1 receptor agonists improve MASH and liver fibrosis: a meta-analysis of randomised controlled trials. Liver Int. 2025;45(9):e70256. doi: 10.1111/liv.70256
  3. Kanwal F, Neuschwander-Tetri BA, Loomba R, Rinella ME. Metabolic dysfunction-associated steatotic liver disease: Update and impact of new nomenclature on the American Association for the Study of Liver Diseases practice guidance on nonalcoholic fatty liver disease. Hepatology. 2024;79(5):1212-1219. doi: 10.1097/HEP.0000000000000670
  4. Ezhilarasan D. Mechanism of semaglutide in MASLD treatment: where is the master key? J Gastroenterol Hepatol. 2025;40(9):2163-2175. doi: 10.1111/jgh.17037
  5. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. doi: 10.1056/NEJMoa2413258
  6. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797-1835. doi: 10.1097/HEP.0000000000000323
  7. Chen VL, Morgan TR, Rotman Y, et al. Resmetirom therapy for metabolic dysfunction-associated steatotic liver disease: October 2024 updates to AASLD practice guidance. Hepatology. 2025;81(1):312-320. doi: 10.1097/HEP.0000000000001112
  8. FDA approves first treatment for patients with liver scarring due to fatty liver disease. U.S. Food and Drug Administration. March 14, 2024. Accessed October 16, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease
  9. FDA approves treatment for serious liver disease known as ‘MASH.’ U.S. Food and Drug Administration. August 15, 2025. Accessed October 16, 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-serious-Sliver-disease-known-mash
  10. Wegovy. Package insert. Novo Nordisk; 2025
  11. Concepción-Zavaleta MJ, Fuentes-Mendoza JM, Gonzáles-Yovera JG, et al. Efficacy and safety of anti-obesity drugs in metabolic dysfunction-associated steatotic liver disease: An updated review. World J Gastroenterol. 2025;31(37):111435. doi: 10.3748/wjg.v31.i37.111435
  12. Newsome PN, Buchholtz K, Cusi K, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384(12):1113-1124. doi: 10.1056/NEJMoa2028395
  13. Loomba R, Abdelmalek MF, Armstrong MJ, et al. Semaglutide 2.4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol Hepatol. 2023;8(6):511-522. doi: 10.1016/S2468-1253(23)00068-7
  14. Newsome PN, Sanyal AJ, Engebretsen KA, et al. Semaglutide 2.4 mg in participants with metabolic dysfunction-associated steatohepatitis: baseline characteristics and design of the phase 3 ESSENCE trial. Aliment Pharmacol Ther. 2024;60(11-12):1525-1533. doi: 10.1111/apt.18331

Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago Retzky College of Pharmacy

November 2025

The information presented is current as of October 13, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.