AT THE INTERNATIONAL LIVER CONGRESS 2015
VIENNA (FRONTLINE MEDICAL NEWS) – The oral hypoglycemic liraglutide produced significant histologic resolution of nonalcoholic steatohepatitis after nearly a year of treatment in a phase II randomized trial of 52 patients.
Although liraglutide (Victoza) is already available in the United States and Europe for treating diabetes, its use specifically for treating nonalcoholic steatohepatitis (NASH), advanced fatty liver disease with currently no approved treatment, should await results from a larger, phase III trial, Dr. Matthew J. Armstrong said at the meeting sponsored by the European Association for the Study of the Liver.
“Oral diabetes drugs have been extensively investigated for NASH, but this is the first time a GLP [glucagon-like peptide]-1 analog has been looked at for NASH in a randomized trial with placebo control,” said Dr. Armstrong, a researcher at the Centre for Liver Research of the University of Birmingham, England. “We feel that GLP-1 analogs like liraglutide give you the whole package” of improving lipid levels, weight, and glycemic control while also addressing liver disease.
“One of the biggest killers in patients with NASH is cardiovascular disease. The weight reduction and improved glycemic control and lipids should improve overall cardiovascular outcomes,” Dr. Armstrong said during a press conference at the meeting.
The issue with a drug like liraglutide is “will it have an effect independent of weight loss,” said Dr. Markus Peck-Radosavljevic , vice-chairman at the department of gastroenterology and hepatology at the University of Vienna. “We know that weight loss will help patients with nonalcoholic fatty-liver disease, but the problem is that patients often do not lose weight. What we would like is a drug with a beneficial effect that is independent of weight loss.”
Liraglutide, an analog of the gut satiety hormone GLP-1 but with extended physiologic half-life, “seems to have an effect independent of weight loss,” Dr. Armstrong said. In addition to its documented efficacy for producing weight loss and decreasing glycosylated hemoglobin A1c, liraglutide showed activity in animal and in vitro models for improving liver-enzyme levels, oxidative stress, and hepatic steatosis.
The Liraglutide Efficacy and Action in Nonalcoholic steatohepatitis ( LEAN ) trial randomized 52 patients aged 18-60 years with biopsy-confirmed NASH to daily liraglutide treatment or placebo for 48 weeks. Researchers at four U.K. centers uptitrated patients on liraglutide to 1.8 mg/day over the study’s first 2 weeks and then kept patents at that dosage. The average age of the patients was 51 years, a majority were men, a third had type 2 diabetes, the average hemoglobin A1c was 6.0%, and the average body mass index was more than 35 kg/m2.
After 48 weeks on treatment, follow-up biopsies on 23 of the patients on liraglutide and 22 on placebo showed 9 liraglutide patients (39%) had resolution of their NASH without worsening fibrosis, the study’s primary endpoint, compared with 2 NASH resolutions (9%) in the control arm, Dr. Armstrong reported .
The 39% efficacy rate for resolutions surpassed the study’s prespecified threshold of 38% to define effective treatment.
Liraglutide-treated patients showed improvements in several other clinical and metabolic parameters including fibrosis and steatosis, as well as an average 5-kg greater weight loss compared with placebo and a 0.45% drop in hemoglobin A1c compared with placebo that fell short of statistical significance.
The safety analysis showed that liraglutide was “well tolerated with an acceptable safety profile in NASH patients,” Dr. Armstrong said. The phase II study was “as much about safety as efficacy,” as the feasibility of treating NASH patients with liraglutide had been uncertain until now.
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