Elsevier

The Lancet

Volume 387, Issue 10019, 13–19 February 2016, Pages 679-690
The Lancet

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

https://doi.org/10.1016/S0140-6736(15)00803-XGet rights and content

Summary

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.

Introduction

Non-alcoholic steatohepatitis is now the most common cause of liver disease and is predicted to be the main indication for liver transplantation by 2020.1 Patients with non-alcoholic steatohepatitis have an increased risk of morbidity and mortality related to liver and cardiovascular disease2 compared with patients who have simple steatosis and the general population.3, 4 Moreover, there are currently no licensed therapies for non-alcoholic steatohepatitis.

Lifestyle modifications are the mainstay of treatment for non-alcoholic steatohepatitis,5 yet most patients do not achieve or maintain dietary goals and weight loss.6 In the two largest randomised controlled trials in patients with non-alcoholic steatohepatitis thus far, treatment with pioglitazone, vitamin E (PIVENS trial),7 and obeticholic acid (FLINT trial)8 were associated with improvements in liver histology relative to placebo, with the findings of the PIVENS trial relevant to patients without type 2 diabetes. However, concerns about the side-effects and long-term safety profile of both pioglitazone and vitamin E has reduced enthusiasm for their use.9 Obeticholic acid also reduced liver fibrosis in the FLINT trial and was associated with an elevated concentration of LDL cholesterol, which will be studied further in a phase 3 trial.8

The strong association of non-alcoholic steatohepatitis with the metabolic syndrome, particularly obesity and type 2 diabetes, provides a compelling rationale for the investigation of therapies such as the gut-derived incretin hormone, glucagon-like peptide-1 (GLP-1), that induce weight loss and insulin sensitivity. Native GLP-1 has potent blood glucose-lowering action, mediated by its ability to induce insulin secretion and reduce glucagon secretion in a glucose-dependent manner, suppresses appetite, and delays gastric emptying.10 Endogenous GLP-1 is degraded within minutes in vivo by the enzyme dipeptidyl peptidase-4, whereas liraglutide is a long-acting human GLP-1 analogue (t1/2=13 h)11 that has been shown to cause weight loss,12 decrease the concentration of glycated haemoglobin (HbA1c), lower systolic blood pressure, and improve beta-cell function.13 Liraglutide is licensed for glycaemic control in patients with type 2 diabetes.

Research in context

Evidence before this study

Non-alcoholic steatohepatitis is now the most common cause of chronic liver disease worldwide and incurs a significantly increased risk of both liver-related and cardiovascular disease-related morbidity and mortality. Yet no therapies are licensed for non-alcoholic steatohepatitis. To date, clinical trials of pioglitazone, vitamin E (PIVENS trial), and obeticholic acid (FLINT trial) in patients with biopsy-proven non-alcoholic steatohepatitis have yielded results showing improvements in liver histology compared with placebo. With the exception of the FLINT trial, these trials have excluded patients with type 2 diabetes. Thus the effect of these drugs in patients with diabetes is unknown. Moreover, concerns remain about the side-effects and long-term safety of pioglitazone and vitamin E, which has reduced enthusiasm for their use.

In 2009, the longacting glucagon-like peptide-1 (GLP-1) analogue, liraglutide, was licensed for glycaemic control in overweight patients with type 2 diabetes. Liraglutide also suppresses appetite centrally, delays gastric emptying, and induces weight loss, rendering it an attractive therapeutic option for patients with non-alcoholic steatohepatitis.

We searched PubMed for clinical studies published in English between Jan 1, 1965, and Apr 1, 2015, with terms (“NAFLD”, “NASH”, “fatty liver”, “steatohepatitis” or “liver injury”) and (“glucagon-like peptide 1”, “GLP-1”, “liraglutide”, “exenatide”, or “incretin”). GLP-1 analogues, including liraglutide, improved liver enzymes, oxidative stress, and hepatic steatosis in murine models in vivo and in isolated in-vitro murine and human hepatocyte studies. Human studies investigating the effect of GLP-1 analogues on liver injury were limited to single case reports and large retrospective studies of liver enzymes in patients with type 2 diabetes. An individual patient-level meta-analysis of more than 4000 patients with type 2 diabetes was performed, comparing 26 weeks of treatment with liraglutide to placebo. Liraglutide significantly improved liver enzyme concentrations in a dose-dependent manner, with comparable safety profiles in patients with and without abnormal liver biochemistry. These findings informed the basis for this phase 2 randomised, placebo-controlled trial of liraglutide for non-alcoholic steatohepatitis.

Added value of this study

This study is a first-in-class, randomised, placebo-controlled trial of GLP-1 analogue in patients with non-alcoholic steatohepatitis. Liraglutide met the primary endpoint of histological resolution of non-alcoholic steatohepatitis with no worsening in fibrosis. In addition to improvements in histological steatosis and hepatocyte ballooning, fewer patients receiving liraglutide had progression of fibrosis than in the placebo group. Liraglutide improved several key components of the metabolic syndrome, including weight and glycaemic control, which is not only unique for tested therapies in non-alcoholic steatohepatitis, but also important because cardiovascular disease accounts for the majority of deaths in cohorts of patients with non-alcoholic steatohepatitis.

Implications of all the available evidence

Because of the growing global burden of non-alcoholic steatohepatitis and the scarcity of licensed therapies, there is a need for effective interventions. In view of the cardiovascular morbidity and mortality associated with non-alcoholic steatohepatitis, therapies, such as liraglutide, that improve outcomes for patients with non-alcoholic steatohepatitis are needed. Future, longer term studies with liraglutide are needed to confirm its efficacy in patients with non-alcoholic steatohepatitis and to establish the cardiovascular implications.

GLP-1 analogues have been shown to reduce liver enzymes and oxidative stress as well as improve liver histology14 in murine models of non-alcoholic steatohepatitis.15, 16, 17 This activity might reflect the effect of these analogues on obesity and systemic insulin resistance, although studies have also reported that GLP-1 analogues can act directly on human hepatocytes in vitro, reducing steatosis by decreasing de-novo lipogenesis and increasing fatty acid oxidation.15, 18, 19

To date, human studies investigating the effect of GLP-1 analogues on liver injury have been limited to case reports,20, 21 a case series of eight patients,22 and retrospective studies of liver enzymes in patients with type 2 diabetes.23, 24 However, these studies were retrospective and did not have histological data. We therefore designed and conducted a multicentre, randomised, placebo-controlled trial of liraglutide to test its safety and efficacy in the treatment of histologically confirmed non-alcoholic steatohepatitis in overweight patients with and without diabetes.

Section snippets

Study design and patients

The Liraglutide Efficacy and Action in NASH (LEAN) study was a multicentre, double-blind, randomised trial of 48 weeks of liraglutide versus placebo in patients with biopsy-confirmed non-alcoholic steatohepatitis. Participants were enrolled at four participating medical centres in the UK (Birmingham, Nottingham, Hull, and Leeds), all of which obtained approval from their local hospital research and development departments. The National Research Ethics Service (NRES) East Midlands–Northampton

Results

Between Aug 1, 2010, and May 31, 2013, we randomly assigned 52 patients with histologically confirmed definite non-alcoholic steatohepatitis based on the central pathology review to receive liraglutide (n=26) or placebo (n=26; figure 1). With the exception of one patient in the placebo group, all patients received their assigned treatment. Three patients in each treatment group missed the end-of-treatment biopsies and withdrew from treatment. Baseline demographic, clinical, laboratory, and

Discussion

In this double-blind, randomised, placebo-controlled phase 2 trial, the longacting GLP-1 analogue, liraglutide, met the predefined primary endpoint and led to resolution of non-alcoholic steatohepatitis in nine (39%) of 23 patients. Moreover, improvements in weight and glycaemic control with liraglutide might have a favourable effect on the future risk of cardiovascular disease and premature death in patients with non-alcoholic steatohepatitis, although longer-term outcome studies are needed to

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  • Cited by (0)

    LEAN trial members are listed at the end of this paper

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