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GLP-1 RAs are effective for glycemic control, but can a phase II study show the drug is also effective for nonalcoholic steatohepatitis?
The glucagon-like peptide (GLP)-1 analogue liraglutide successfully resolved nonalcoholic steatohepatitis (NASH) in about 40% of patients enrolled in a phase II study published recently in The Lancet, and improved several components of metabolic syndrome, including weight loss and glycemic control.
“The unique combination of histological efficacy and improvement of the metabolic syndrome with liraglutide render it an attractive therapy for patients with nonalcoholic steatohepatitis and warrant further investigation in larger studies,” wrote Matthew James Armstrong, PhD, of the National Institute for Health Research, Birmingham, United Kingdom, and colleagues.
GLP-1 analogues are currently licensed for the treatment of type 2 diabetes. However, studies have shown that liraglutide successfully suppresses appetite, delays gastric emptying, and induces weight loss, making it a possible treatment option for patients with NASH. Therefore, Armstrong and colleagues conducted a phase II study of liraglutide in patients with NASH to determine its safety and efficacy.
The small phase II study included patients who were overweight and had clinical evidence of NASH. Patients were randomly assigned to subcutaneous injections of liraglutide (n=26) or placebo (n=26). The primary endpoint of the study was resolution of NASH with no worsening of fibrosis.
The mean total non-alcoholic fatty liver disease (NAFLD) score was similar between the two treatment groups. According to the researchers, the primary endpoint was resolution of disease and not NAFLD score “as keeping with guidance from an expert consortium.”
“Notably, the NAFLD activity score does not predict liver-related morbidity or mortality, whereas the presence of non-alcoholic steatohepatitis (as opposed to simple NAFLD) is associated with a significant increase in liver-related outcomes and all-cause mortality,” the researchers explained.
At the end of treatment at 48 weeks, 39% of patients assigned liraglutide had resolution of definitive NASH compared with 9% of patients assigned placebo (P=0.019).
“A predefined sensitivity analysis of the primary outcome measure, in which patients with a missing end-of-treatment liver biopsy were defined as non-responders, showed that nine (35%) of 26 patients receiving liraglutide versus two (8%) of 26 patients receiving placebo achieved the primary outcome,” the researchers wrote. “This equated to patients receiving liraglutide having a relative risk of 4â5 (95% CI 1â1–18â9; Ï² test P=0â017) of achieving the primary outcome compared with patients in the placebo group.”
Only 9% of patients assigned liraglutide had a worsening of fibrosis compared with 36% of patients assigned placebo (P=0.04). No differences between the study groups were observed for lobular inflammation and overall NAFLD activity score.
“Although patients in the liraglutide group met the primary endpoint, liraglutide did not result in significant mean changes in the composite NAFLD activity score, as reported with pioglitazone, vitamin E, and obeticholic acid,” the researchers wrote. “Notably, a greater proportion of patients receiving liraglutide had improvements in steatosis and hepatocyte ballooning, indicating that the overall pattern of changes is in keeping with a reduction in histological damage with liraglutide.”
Patients assigned to liraglutide had significant reductions in bodyweight, body mass index, and HbA1c at 48 weeks compared with patients assigned placebo. The researchers noted that most of the reductions in weight were achieved by week 12 and sustained throughout the study period.
The majority of adverse events was grade 1 or 2 and was similar between the two treatment groups. Two serious adverse events occurred in patients assigned liraglutide but were not related to the study drug.
Reference: Armstrong MJ, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicenter, double-blind, randomized, placebo-controlled phase 2 study. Lancet. 2015 Nov 19; [Epub ahead of print].