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

Armstrong, Matthew James; Gaunt, Piers; Aithal, Guruprasad P.; Barton, Darren; Hull, Diana; Parker, Richard; Hazlehurst, Jonathan M.; Guo, Kathy; Abouda, George; Aldersley, Mark A.; Stocken, Deborah; Gough, Stephen C.; Tomlinson, Jeremy W.; Brown, Rachel M.; Hübscher, Stefan G.; Newsome, Philip N.

Authors

Matthew James Armstrong

Piers Gaunt

Guruprasad P. Aithal

Darren Barton

Diana Hull

Richard Parker

Jonathan M. Hazlehurst

Kathy Guo

George Abouda

Mark A. Aldersley

Deborah Stocken

Stephen C. Gough

Jeremy W. Tomlinson

Rachel M. Brown

Stefan G. Hübscher

Philip N. Newsome



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.
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.

Citation

Armstrong, M. J., Gaunt, P., Aithal, G. P., Barton, D., Hull, D., Parker, R., …Newsome, P. N. (in press). Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet, 387(10019), doi:10.1016/S0140-6736(15)00803-X

Journal Article Type Article
Acceptance Date Feb 1, 2015
Online Publication Date Nov 19, 2015
Deposit Date Dec 12, 2016
Journal Lancet
Print ISSN 0140-6736
Electronic ISSN 1474-547X
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 387
Issue 10019
DOI https://doi.org/10.1016/S0140-6736%2815%2900803-X
Public URL http://eprints.nottingham.ac.uk/id/eprint/39309
Publisher URL http://www.sciencedirect.com/science/article/pii/S014067361500803X
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf