By Kristina Fiore, Staff Writer, MedPage Today
Published: October 31, 2010
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
BOSTON -- One of the newer classes of diabetes medications -- the glucagon-like peptide-1 (GLP-1) agonists -- appears to mitigate fatty liver disease in people with type 2 diabetes, according to two studies reported here.
Separate studies of treatment with daily liraglutide (Victoza) or weekly exenatide (Bydureon) -- both GLP-1 agonists -- found that the drugs lowered levels of alanine aminotransferase (ALT) compared with other diabetes medications and placebo.
Both studies were reported in poster presentations at the annual meeting of the American Association for the Study of Liver Diseases (AASLD).
Fatty liver disease and steatohepatitis are common complications of type 2 diabetes.
GLP-1 analogues have been shown to improve hepatic steatosis and markers of liver inflammation in murine models, since insulin resistance is thought to play a role in the pathophysiology of non-alcoholic fatty liver disease.
Other antidiabetic therapies -- including metformin and thiazolidinedione drugs, particularly pioglitazone (Actos) -- have shown promise in treating fatty liver disease, although thiazolidinediones are associated with weight gain.
The liraglutide investigators reported data from the LEAD-2 study, a 26-week phase III trial with a one-and-a-half year open-label extension.
LEAD-2 patients received the GLP-1 agonist liraglutide (at a dose of 1.8, 1.2, or 0.6 mg/day), or glimepiride 4 mg/day or a placebo -- all in combination with metformin 1.5 or 2 g/day.
DEXA and computed tomography (CT) scans were used to measure body fat composition and hepatic steatosis, which was defined by a liver-to-spleen attenuation ratio less than one.
At baseline, 65.7% of the LEAD-2 patients had steatosis and 74% had metabolic syndrome, according to M.J. Armstrong, MD, of the University of Birmingham in England, and colleagues.
The LEAD-2 researchers found that patients with elevated ALT levels at baseline had a significant reduction from baseline with liraglutide (-8.53, P<0.0001).
This was a significant improvement over glimepiride -- 37% of patients on liraglutide had normalized ALT compared with 21% of those on glimepiride (P<0.05).
The effect of liraglutide on ALT appears to be independent of improvements in glycemic control, Armstrong and colleagues reported.
They also found that the liver-to-spleen attenuation ratio significantly increased with liraglutide, indicating reduced hepatic steatosis compared with both glimepiride and placebo (P<0.05).
The LEAD-2 investigators concluded that liraglutide reduces markers of liver inflammation and hepatic steatosis in patients with type 2 diabetes, but noted that the effects are dose-dependent -- results with 1.8 mg/day weren't as dramatic or significant as for the 1.2 mg or 0.6 mg daily doses.
In a second poster, Naga P. Chalasani, MD, of Indiana University in Indianapolis, and colleagues reported that weekly exenatide -- which was recently denied FDA approval -- also improved markers of fatty liver disease in diabetes patients.
Chalasani's group looked at pooled data from one 30-week and two 26-week trials totaling 541 patients with type 2 diabetes.
ALT was elevated at baseline in 60% of the study population.
The researchers saw a decrease in ALT among patients on exenatide, compared with a slight rise among those in the placebo group (-18.3% versus 2.1%).
Just over 13% of exenatide patients with elevated baseline levels achieved at least a 50% reduction in ALT, Chalasani and colleagues reported.
Levels of aspartate aminotransferase (AST) and alkaline phosphatase (ALP) also improved among the exenatide patents, the researchers noted.
Chalasani's group added that the reduction in ALT was mildly correlated to a reduction in weight.
They concluded that weekly exenatide improved markers of non-alcoholic fatty liver disease in patients with type 2 diabetes "likely because of its combined effects on ALT, weight, and other cardiometabolic risk factors."
Armstrong reported relationships with the Wellcome Trust.
The liraglutide study was supported by Novo Nordisk.
Chalasani reported relationships with Johnson & Johnson, Debiovision, Advanced Life Sciences, Eli Lilly, Teva, Atherogenics, Amylin, Salix, Abbott, Karobio, Genentech, Medpace, Phenomix, and Gilead.
The exenatide trial was sponsored by Amylin.
Primary source: American Association for the Study of Liver Diseases meeting
Source reference:
Chalasani NP, et al "Effect of once-weekly exenatide on ALT cardiometabolic risk factors in adults with type 2 diabetes" AASLD 2010; Abstract 661.
Additional source: American Association for the Study of Liver Diseases
Source reference:
Armstrong MJ, et al "Effects of two years of liraglutide treatment on fatty liver disease in patients with type 2 diabetes: Analysis of the LEAD-2 extension trial" AASLD 2010; Abstract 625.
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