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.