Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.

By M. Armstrong, P. Gaunt, G. Aithal, D. Barton, D. Hull, R. Parker, J. Hazlehurst, K. Guo, G. Abouda, M. Aldersley and 6 more. The Lancet, 2016

1,869 citations recorded by the source corpus.

BACKGROUND Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogues are licensed for type 2 diabetes, but their efficacy in patients with non-alcoholic steatohepatitis is unknown. We assessed the safety and efficacy of the long-acting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis. METHODS This multicentre, double-blinded, randomised, placebo-controlled phase 2 trial was conducted in four UK medical centres to assess subcutaneous injections of liraglutide (1·8 mg daily) compared with placebo for patients who are overweight and show clinical evidence of non-alcoholic steatohepatitis. Patients were randomly assigned (1:1) using a computer-generated, centrally administered procedure, stratified by trial centre and diabetes status. The trial was designed using A'Hern's single-group method, which required eight (38%) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinically significant. Patients, investigators, clinical trial site staff, and pathologists were masked to treatment assignment throughout the study. The primary outcome measure was resolution of definite non-alcoholic steatohepatitis with no worsening in fibrosis from baseline to end of treatment (48 weeks), as assessed centrally by two independent pathologists. Analysis was done by intention-to-treat analysis, which included all patients who underwent end-of-treatment biopsy. The trial was registered with ClinicalTrials.gov, number NCT01237119. FINDINGS Between Aug 1, 2010, and May 31, 2013, 26 patients were randomly assigned to receive liraglutide and 26 to placebo. Nine (39%) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with two (9%) of 22 such patients in the placebo group (relative risk 4·3 [95% CI 1·0-17·7]; p=0·019). Two (9%) of 23 patients in the liraglutide group versus eight (36%) of 22 patients in the placebo group had progression of fibrosis (0·2 [0·1-1·0]; p=0·04). Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the two treatment groups for all organ classes and symptoms, with the exception of gastrointestinal disorders in 21 (81%) of 23 patients in the liraglutide group and 17 (65%) of 22 patients in the placebo group, which included diarrhoea (ten [38%] patients in the liraglutide group vs five [19%] in the placebo group), constipation (seven [27%] vs none), and loss of appetite (eight [31%] vs two [8%]). INTERPRETATION Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies. FUNDING Wellcome Trust, National Institute of Health Research, and Novo Nordisk.

Subfields: Endocrinology, Diabetes and Metabolism, Epidemiology

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In Endocrinology, Diabetes and Metabolism

1. Z. Younossi
2. M. Rinella
3. Q. Anstee
4. F. Marra
5. G. Svegliati-Baroni
6. K. Cusi
7. A. Sanyal
8. Bart Staels

In Epidemiology

1. Z. Younossi
2. M. Rinella
3. A. Sanyal
4. K. Cusi
5. E. Brunt
6. Q. Anstee
7. Shira Zelber-Sagi
8. J. Lavine

Citations in the corpus

• A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. (2020, neutral): “Abdominal distension 1 (1) 8 (10) 4 (5) 4 (5)”
• Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A State-of-the-Art Review (2023, background): “63 Another phase 2 RCT compared the efficacy and safety of injectable semaglutide at 0.1, 0.2, and 0.4 mg daily (equivalent to 2.4 mg weekly) among 320 people with BMI ≥25 kg/m 2 and biopsy-proven MASH.”
• Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. (2018, background): “Given the importance of weight loss in the therapeutic approach to NASH, together with potential confounding indirect contributions arising from GLP-1R-dependent reductions in postprandial lipemia, glycemia, and inflammation, a mechanistic understanding of how GLP-1R agonists attenuate NASH remains ”
• Aging and aging-related diseases: from molecular mechanisms to interventions and treatments (2022, background): “Additionally, semaglutide reduces hepatic fat accumulation in patients with NASH, but the effect on fibrosis has not been proven.(589) PPARs agonizts play critical roles in regulating hepatic fatty acid β-oxidation.”
• Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. (2016, background): “experts and recommended by regulatory agencies for ongoing trials.(19,20) It defines resolution of NASH as disappearance of ballooning (score 1⁄4 0), together with either disappearance of”
• Lipotoxicity and the gut-liver axis in NASH pathogenesis. (2018, background): “A recent trial in subjects with NAFLD showed that 48 weeks of therapy with liraglutide improves glucose and lipid metabolism and reduces hepatic fat content with resolution of NASH in 39% of the treated subjects compared to 9% in the placebo treated group [127].”
• Treatment of NAFLD with diet, physical activity and exercise. (2017, background): “placebo.(157) NASHRES calculator allowed the correct classification of patients with a diagnostic accuracy of 94% to detect lack of NASH resolution.”
• NAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications (2020, neutral): “150 The authors suggested that the beneficial effects of liraglutide on the histological liver endpoints were due both to its direct hepatic effect and to concomitant weight loss as liraglutide is a potent treat-ment to effect weight loss.”
• The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases (2018, background): “A liver biopsy to establish a diagnosis of NASH should be obtained before starting children on pharmacological therapy for NASH.”