Miriam E. Tucker

April 23, 2015

VIENNA, Austria — Two diabetes drugs, one approved and one investigational, show promise in treating fatty liver disease, according to new research presented here at the European Association for the Study of the Liver (EASL) International Liver Congress 2015.

The glucagon-like peptide-1 analogue liraglutide (Victoza, Novo Nordisk) resolved nonalcoholic steatohepatitis in more than a third of patients in a phase 2 study.

Post hoc findings from another phase 2 study of the investigational sodium-glucose cotransporter-2 inhibitor remogliflozin etabonate suggest benefit in nonalcoholic fatty liver disease.

"If you look at the mechanism of action of liraglutide, it clearly makes sense in the setting of fatty liver disease. And given the paucity of any available therapies, the possibility of new treatment in this condition is exciting," Philip Newsome, MD, from the University of Birmingham, United Kingdom, told Medscape Medical News.

Liraglutide is approved in Europe, the United States, and elsewhere for the treatment of type 2 diabetes, and in both Europe and the United States it also has an indication for obesity.

"At the moment, liraglutide's use is very much driven by the conventional indications of diabetes and obesity," Dr Newsome explained. "Its use in nonalcoholic fatty liver disease is experimental. What we would hope is that further confirmatory licensing studies would allow us to use it in patients with significant fatty liver disease; namely, nonalcoholic steatohepatitis," he said.

The LEAN Study

In the 48-week Liraglutide Efficacy and Action in Nonalcoholic Steatohepatitis (LEAN) trial, the primary endpoint was improvement in liver histology, defined as resolution of definite nonalcoholic steatohepatitis and no worsening in fibrosis.

The endpoint was achieved in 9 (39%) of 23 overweight patients with nonalcoholic steatohepatitis who received 1.8 mg daily liraglutide, but in just 2 (9%) of 22 patients randomly assigned to receive placebo. In addition, as expected with liraglutide, improvements were also seen in body mass index and fasting glucose levels.

The liraglutide data were presented at a news conference by Matthew Armstrong, MD, from Birmingham's Liver Biomedical Research Unit. Responding to a reporter's question about why the 1.8-mg dose was used rather than the 3.0-mg dose currently approved for obesity, he pointed out that at the time of the study design, safety data were only available for the 1.8-mg dose, but that the 3.0-mg dose might be more effective, pending tolerability.

"If they could tolerate it, we might use 3.0 mg," Dr Armstrong said. "Patients with more advanced liver disease didn't seem to have more significant side effects than patients with early stages, but then costs come into it as well."

Post Hoc Data Suggest Liver Benefit

The liver-related data on remogliflozin etabonate from a randomized, double-blind, placebo-controlled trial of 336 patients with type 2 diabetes were presented by William Wilkison, PhD, chief operating officer of Islet Sciences, which is codeveloping the drug for the treatment of type 2 diabetes along with BHV Pharma.

The 12-week study involved treatment-naive patients who were randomly assigned to receive remogliflozin etabonate, with doses ranging from 50 to 1000 mg; placebo; or 30 mg a day of pioglitazone.

The active drug improved insulin sensitivity by 6% to 39% and beta cell function by 23% to 43%, and also produced significant decreases in mean plasma glucose after oral glucose tolerance tests.

Post hoc analyses showed 32% to 42% reductions from baseline in alanine aminotransferase levels. In addition, measurements of antioxidant activity by the oxygen radical antioxidant capacity assay showed that remogliflozin etabonate had significantly greater antioxidant activity compared with the currently available sodium-glucose cotransporter-2 inhibitors canagliflozin and dapagliflozin.

Those data, together with reduction in serum markers of oxidative stress in animal models of steatohepatitis, suggest that "remogliflozin demonstrated strong potential for safe and effective treatment," said Dr Wilkison.

Islet Sciences is planning a phase 2b study of nonalcoholic steatohepatitis to start in the second half of 2015.

My question is whether these drugs would have an effect independent of weight loss. Dr Markus Peck-Radosavljevic

During a news conference, however, EASL Secretary-General Markus Peck-Radosavljevic, MD, who served as moderator, questioned whether in both studies the positive effect on the liver might simply be a result of the weight loss induced by the drugs.

"My question is whether these drugs would have an effect independent of weight loss," he said. "In both trials, we see weight loss, and we know that no matter how you lose weight, it will have a positive effect on nonalcoholic fatty liver disease, but we have patients who are nonobese and nondiabetic. Here the question is, are such drugs really a potential remedy for those patients?" Dr Peck-Radosavljevic asked.

"It will be very interesting to see," he said. "The trials are still too small — they're phase 2 — you need larger trials where you have subgroups included where you don't see weight loss because they're not obese, but still you see an effect on histology, for example. That would be fantastic."

The study was supported by the Wellcome Trust and the National Institute for Health Research Birmingham Liver Biomedical Research Unit, with support in the form of free trial drugs from Novo Nordisk. Dr Armstrong is the recipient of an educational grant from Novo, Nordisk and Dr Newsome has received an educational grant and honoraria for lectures from Novo Nordisk. The remogliflozin study was funded by Islet Sciences, and Dr Wilkison is an employee of the company. Dr Peck-Radosavljevic has financial relationships with AbbVie, ArQule, Bayer, BMS, Gilead, Lilly MSD, Boehringer-Ingelheim, and Roche.

European Association for the Study of the Liver (EASL) International Liver Congress 2015: Abstract 0047. Presented April 23, 2015.


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