title: Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.
abstract: 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.
  
  
  RESULTS
  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%]).
  
  
  CONCLUSIONS
  Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies.
  
  
  BACKGROUND
  Wellcome Trust, National Institute of Health Research, and Novo Nordisk.
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK; Liver and Hepatobiliary Unit, Queen Elizabeth Hospital Birmingham, Birmingham, UK.
authors.forename: Matthew James
authors.initials: MJ
authors.lastname: Armstrong
authors.affiliation: NIHR Birmingham Liver Biomedical Research Unit Clinical Trial group (EDD), CRUK Clinical Trials Unit, University of Birmingham, Birmingham, UK.
authors.forename: Piers
authors.initials: P
authors.lastname: Gaunt
authors.affiliation: NIHR Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospital NHS Trust and University of Nottingham, Nottingham, UK.
authors.forename: Guruprasad P
authors.initials: GP
authors.lastname: Aithal
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK; NIHR Birmingham Liver Biomedical Research Unit Clinical Trial group (EDD), CRUK Clinical Trials Unit, University of Birmingham, Birmingham, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: Barton
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK; NIHR Birmingham Liver Biomedical Research Unit Clinical Trial group (EDD), CRUK Clinical Trials Unit, University of Birmingham, Birmingham, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Hull
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK; Liver and Hepatobiliary Unit, Queen Elizabeth Hospital Birmingham, Birmingham, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Parker
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, and NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Hazlehurst
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK; NIHR Birmingham Liver Biomedical Research Unit Clinical Trial group (EDD), CRUK Clinical Trials Unit, University of Birmingham, Birmingham, UK.
authors.forename: Kathy
authors.initials: K
authors.lastname: Guo
authors.affiliation: Department of Hepatology and Gastroenterology, Hull Royal Infirmary, Hull, UK.
authors.forename: George
authors.initials: G
authors.lastname: Abouda
authors.affiliation: Liver Unit, St James's University Hospital, Leeds, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Aldersley
authors.affiliation: Newcastle University, Newcastle Clinical Trial Unit, Institute of Health and Society, Newcastle, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Stocken
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, and NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Gough
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, and NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Tomlinson
authors.affiliation: Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, Birmingham, UK.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Brown
authors.affiliation: Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, Birmingham, UK; School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Hübscher
authors.affiliation: National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit and Centre for Liver Research, University of Birmingham, Birmingham, UK; Liver and Hepatobiliary Unit, Queen Elizabeth Hospital Birmingham, Birmingham, UK. Electronic address: p.n.newsome@bham.ac.uk.
authors.forename: Philip N
authors.initials: PN
authors.lastname: Newsome
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D054795:Incretins / Q000008:administration & dosage* / Q000009:adverse effects; D007279:Injections, Subcutaneous; D000069450:Liraglutide / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D054795:Incretins; D000069450:Liraglutide