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A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis
Open accessAbstract
BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH is not known. METHODS: We conducted a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo. The primary end point was resolution of NASH with no worsening of fibrosis. The confirmatory secondary end point was an improvement of at least one fibrosis stage with no worsening of NASH. The analyses of these end points were performed only in patients with stage F2 or F3 fibrosis; other analyses were performed in all the patients. RESULTS: In total, 320 patients (of whom 230 had stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P = 0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group. The incidence of nausea, constipation, and vomiting was higher in the 0.4-mg group than in the placebo group (nausea, 42% vs. 11%; constipation, 22% vs. 12%; and vomiting, 15% vs. 2%). Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group; no pattern of occurrence in specific organs was observed. CONCLUSIONS: This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo. However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT02970942.).
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The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Clinically, GLP-1 RAs are indicated for the treatment of type 2 diabetes (all) and obesity (liraglutide and semaglutide only) and have beneficial effects on patient-important outcomes such as weight loss, cardiovascular and kidney events, hepatic steatosis, and mortality.5,7–9,11,30”
From Glucagon-Like Peptide-1 Receptor Agonists and Thyroid Cancer: A Narrative Review (2024) · cites this paper as [30]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The primary outcome for all three studies was resolution of fatty liver disease without worsening of fibrosis, and significant improvements were noted.”
From GLP-1 receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits (2026) · cites this paper as [82]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Notably, a 2020 clinical trial involving patients with nonalcoholic steatohepatitis (NASH) revealed a 15% incidence of tumors (benign, malignant, or unspecified) (35/239) among those administered semaglutide, compared to 8% (6/80) in the control group [108].”
From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [108]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Fibrosis improvement (43% vs. 33%) did not reach significance, likely due to study duration.”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [54]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In a 72-week phase 2 RCT of 1197 participants with biopsy-confirmed MASH and F2–F3 fibrosis, semaglutide 0.4 mg/day achieved a significant MASH resolution in 59% vs. 17% with placebo [54].”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [54]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In MASLD and MASH, semaglutide induces histological improvement, including MASH resolution and fibrosis regression, with > 60% of patients achieving resolution in F2–F3 stages.”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [54]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Both treatments were accompanied by a weight loss of 5.5 % and 12.5 % as well as a HbA1c reduction of 0.5 % and 1.2 %, respectively.”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [109]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Both treatments were accompanied by a weight loss of 5.5 % and 12.5 % as well as a HbA1c reduction of 0.5 % and 1.2 %, respectively.”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [109]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The largest available trial on semaglutide in MASH ( vs . placebo over an 18-month treatment period) demonstrated resolution of steatohepatitis but no fi brosis improvement.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [401]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Accruing randomized clinical trial data suggest that pioglitazone, GLP-1 RA, and a dual GIP and GLP-1 RA have potential benefits in terms of decreasing hepatic steatosis and in the resolution of MASH without worsening of fibrosis in individuals with biopsy-proven MASH or those at higher risk of clinically significant liver fibrosis identified with noninvasive tests (146-153).”
From 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025 (2025) · cites this paper as [150]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Weight loss achieved with use of GLP-1 RAs and the GIP/GLP-1 RA is also beneficial for obstructive sleep apnea (132), knee osteoarthritis (133), and metabolic dysfunction–associated steatohepatitis (MASH) (134–136).”
From 13. Older Adults: Standards of Care in Diabetes—2026 (2026) · cites this paper as [136]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“semaglutide showed a trend for improvements in fibrosis stage, 82”
From GLP-1 receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits (2026) · cites this paper as [82]
The cited source says what the claim attributes to it.
In the citing paper
“Pioglitazone therapy, GLP-1 RA therapy, and metabolic surgery have all been shown to reduce NASH activity; pioglitazone therapy and metabolic surgery may also improve hepatic fi brosis (188,292 -298).”
The cited source says what the claim attributes to it.
In the citing paper
“Studies conducted with semaglutide showed relevant weight losses, accompanied by consistent metabolic benefits, while investigations in patients with steatohepatitis demonstrated a significant increase in the rates of resolution of liver disease”
From RETATRUTIDE USE IN THE TREATMENT OF METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE (MASLD) AND OBESITY: AN INTEGRATIVE REVIEW (2026) · cites this paper as NEWSOME et al., 2021
The cited source says what the claim attributes to it.
In the citing paper
“The glucagon‐like peptide‐1 receptor agonist semaglutide has shown a significantly higher percentage of patients with NASH resolution (and no worsening of fibrosis) compared to placebo in a 72‐week, double‐blind phase 2 trial involving 320 patients with biopsy‐confirmed NASH and fibrosis stage 1–340.”
From Current treatment of non‐alcoholic fatty liver disease (2022) · cites this paper as [40]
The cited source says what the claim attributes to it.
In the citing paper
“Improvement in fibrosis stage was seen in 43% of NASH patients and 33% of placebo patients, but this difference was not statistically significant [40].”
From Current treatment of non‐alcoholic fatty liver disease (2022) · cites this paper as [40]
The cited source says what the claim attributes to it.
In the citing paper
“around 38% of patients in the study had no (!) diabetes mellitus, however all had at least a BMI >25.”
From Current treatment of non‐alcoholic fatty liver disease (2022) · cites this paper as [40]
The cited source says what the claim attributes to it.
In the citing paper
“However, no overall improvement in fibrosis grade was detected, despite lower reported rates of fibrosis progression for liraglutide [108,109].”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [109]
The cited source says what the claim attributes to it.
In the citing paper
“MASH resolution was mainly driven by improvements in steatosis and ballooning for liraglutide [108], whereas semaglutide also reduced inflammation [109].”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [109]
The cited source says what the claim attributes to it.
In the citing paper
“Two RCTs with liraglutide and semaglutide in mixed collectives of people with and without type 2 diabetes provided evidence for higher rates of histological MASH resolution without worsening of fibrosis compared to placebo (Table 1).”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [109]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“In 3 studies of 56-week duration involving persons with obesity and dyslipidemia or hypertension, weight loss ranged from 6.2% to 8.0% with 3 mg liraglutide vs 0.2% to 2.9% with placebo.754–756”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [756]
Experimental — accuracy not yet measuredIn the citing paper
“Growing evidence supports the positive impact of GLP-1 RAs in reducing hepatic cytolysis enzymes [56,61,69,70,71,72,73,74,75,76,77,78,79,80,81] (Table 2).”
From GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives (2023) · cites this paper as [61]
In the citing paper
“If semaglutide at a dosage of 0.4 mg/day leads to resolution of steatohepatitis in 59% of cases, no significant difference emerged in the improvement of fibrosis compared to placebo.”
From GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives (2023) · cites this paper as [61]
In the citing paper
“In this regard, GLP-1 RAs have been proven to significantly improve hepatic steatosis.”
From GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives (2023) · cites this paper as [61]
In the citing paper
“Furthermore, an improvement in NAS was observed in 83% of patients treated with semaglutide 0.4 mg/day, 80% of those treated with 0.2 mg/day, 71% of those treated with 0.1 mg/day and only 44% of those treated with placebo.”
From GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives (2023) · cites this paper as [61]
In the citing paper
“After 72 weeks, treatment with semaglutide at a dose of 0.4 mg/day resulted in the histological resolution of NASH without progression of fibrosis in 59% of patients, compared with 17% in the placebo group.”
From GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives (2023) · cites this paper as [61]
In the citing paper
“However, the treatment was shown to be effective in reducing the progression of fibrosis (5% vs. 19% of the placebo group), in accordance with what previously demonstrated [56].”
From GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives (2023) · cites this paper as [61]
In the citing paper
“As GLP-1 agonism has promoted NASH resolution in a phase II trial,48”
From An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH (2023) · cites this paper as [48]
In the citing paper
“Among adults with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3, semaglutide 0.4 mg s.c.versus placebo daily for 72 weeks improved steatohepatitis resolution with no worsening of fibrosis, but there was no between-group difference in improvement of fibrosis stage.115”
From Management of type 2 diabetes, obesity, or nonalcoholic steatohepatitis with high‐dose GLP‐1 receptor agonists and GLP‐1 receptor‐based co‐agonists (2024) · cites this paper as [115]
In the citing paper
“In people with MASH (with and without diabetes), semaglutide 0.4 mg once daily for 72 weeks demonstrated that 59% of them could achieve MASH resolution with no worsening of fibrosis compared to placebo, however there was not improvement in fibrosis stage [57].”
In the citing paper
“Nevertheless, GLP-1 RAs such as liraglutide 1.8 mg once daily and semaglutide 2.4 mg once weekly have demonstrated their benefits in MASH resolution compared to placebo, without however improvement in fibrosis [57,88].”
In the citing paper
“Glucagon-like peptide 1 receptor agonist (GLP-1RA) therapies deliver histological benefit in people with metabolic dysfunction-associated steatotic liver disease (MASLD).”
From Randomised trial comparing weight loss through lifestyle and GLP-1 receptor agonist therapy in people with MASLD (2025) · cites this paper as [16]
In the citing paper
“More recently, semaglutide, a more potent GLP1-RA, has achieved resolution of MASH in up to 59% of people and this was associated with a 13% reduction in weight.16”
From Randomised trial comparing weight loss through lifestyle and GLP-1 receptor agonist therapy in people with MASLD (2025) · cites this paper as [16]
In the citing paper
“However, the impact on liver fibrosis is less clear.16,17”
From Randomised trial comparing weight loss through lifestyle and GLP-1 receptor agonist therapy in people with MASLD (2025) · cites this paper as [16]
In the citing paper
“There is now an established body of evidence demonstrating the beneficial impact of GLP-1RA in people with MASLD to decrease hepatic steatosis and resolve MASH15,16,30,31”
From Randomised trial comparing weight loss through lifestyle and GLP-1 receptor agonist therapy in people with MASLD (2025) · cites this paper as [16]
In the citing paper
“of GLP-1 receptor agonists has recently been demonstrated by phase 2 studies with liraglutide194 and semaglutide,195”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [195]
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Self-citation
Metadata
- Authors
- Newsome, P. N., Buchholtz, K., Cusi, K., Linder, M., Okanoue, T., Ratziu, V., Sanyal, A. J., Sejling, A.-S., & Harrison, S. A.
- Affiliations
- University Hospitals Birmingham NHS Foundation Trust (GB)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2021-03-25
- Volume
- 384
- Issue
- 12
- Pages
- 1113-1124
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W3102426258
- Cited by
- 2,039
- References
- 28
- Citations by year
- 2026: 352 · 2025: 458 · 2024: 417 · 2023: 334 · 2022: 264 · 2021: 205
- FWCI
- 145.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Funders
- Novo Nordisk A/S
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- nonalcoholic steatohepatitis, semaglutide, GLP-1 receptor agonists, liver fibrosis, NASH resolution, weight loss, adverse events, nausea, constipation, vomiting, dose comparison, obesity-related liver disease, drug safety and efficacy, GIP/GLP-1 receptor agonist
- MeSH terms
- Semaglutide, Adolescent, Adult, Aged, Amylases, Biopsy, Diabetes Mellitus, Type 2, Dose-Response Relationship, Drug, Double-Blind Method, Glucagon-Like Peptides, Female, Humans, Injections, Subcutaneous, Lipase, Liver, Liver Cirrhosis, Male, Middle Aged, Young Adult, Non-alcoholic Fatty Liver Disease
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