Thiazolidinedione Promising for Nonalcoholic Fatty Liver Disease

SAN ANTONIO. Nov. 29 -- The thiazolidinedione Actos (pioglitazone) produced metabolic and histologic improvements in patients with nonalcoholic steatohepatitis, the most severe form of fatty liver disease, researchers here found.

In a small study, patients taking Actos for six months had improved insulin sensitivity, a reversal of the metabolic milieu leading to steatosis, and easing of cytokine-mediated systemic inflammation, reported Kenneth Cusi, M.D., of the University of Texas here, and colleagues in the Nov. 30 issue of the New England Journal of Medicine.

Actos, approved for type 2 diabetes, also increased hepatic insulin sensitivity and glucose clearance, as well as bringing about significant reductions in plasma free fatty acids, hepatic fat, glucose, and insulin levels in oral glucose-tolerance tests, they said.

In addition, the histologic features of steatohepatitis (steatosis, ballooning necrosis, and centrilobular inflammation) were reduced in treated patients compared with controls. But fibrosis did not differ significantly between the groups.

Thiazolidinediones may reverse many of the abnormalities associated with nonalcoholic steatohepatitis, a chronic liver condition that may progress to cirrhosis, the researchers said.

In their study, 55 patients with impaired glucose tolerance or type 2 diabetes and nonalcoholic steatohepatitis confirmed by liver biopsy were randomly assigned to six months of treatment with a hypocaloric diet (a reduction of 500 kcal per day in relation to the calculated daily intake required to maintain body weight) plus Actos (45 mg daily) or a hypocaloric diet plus placebo.

Participants were recruited from 2002 to 2004 from the University of Texas Health Science Center, the South Texas Veterans Health Care system, and the Brooke Army Medical Center in San Antonio. Diet plus Actos compared with diet plus placebo led to:

• improved glycemic control and glucose tolerance (P

Weight loss also failed to show a significant benefit, according to Dr. Cusi. In a subgroup of 12 patients who lost a mean of 3.2 0.5 kg of body weight, there were no significant improvements in steatosis, ballooning necrosis, or fibrosis, findings consistent with the varying results from a recent meta-analysis.

Greater weight loss might have decreased hepatic steatosis, the investigators said, but they did not encourage drastic weight loss because of difficulty in compliance and reports that it might worsen inflammation and even fibrosis.

Although Actos did not significantly reduce fibrosis compared with placebo, the issue is complicated not only by the short duration of the study and the small number of subjects, but also by the known variations in assessment of hepatic fibrosis by percutaneous biopsy, Dr.Cusi's team said.

Recently, the researchers wrote, Actos has been reported to prevent, in a dose-dependent manner, the activation of hepatic stellate cells (mediators of fibrosis) in an animal model of hepatic fibrosis.

Because fibrosis may progress in up to one-third of patients with nonalcoholic steatohepatitis, with obese type 2 diabetics at the greatest risk, larger and longer clinical trials are needed to determine the long-term efficacy and safety of Actos and to gain a better understanding of the mechanisms involved during thiazolidinedione therapy, the researchers concluded.

In an accompanying editorial, Arthur McCullough, M.D., of the Cleveland Clinic, said that a review of the literature suggests that nonalcoholic steatohepatitis has a prevalence of about 5% to 6% and is expected to increase with the epidemic of obesity and type 2 diabetes.

Although the trial reported here provides an additional rationale for the use of thiazolidinediones in this disease, she noted that the authors correctly identified their work as a "proof-of-concept" study. The sample was small, the results may not be generalizable, and the study period was extremely short for this disease, Dr. McCullough wrote.

Future studies, he said "need to be at least one to two years in duration, have a sample size based on histologic improvement as a primary outcome, and search for reliable, well-defined, noninvasive markers of histologic severity and treatment response."

The thiazolidinediones have many benefits, he said. They reduce both insulin resistance and inflammation. However, "they are not yet ready for routine use" for nonalcoholic steatohepatitis.

A recent preliminary study showed that Avandia (rosiglitazone) had little or no benefit, for example. In addition, although usually well tolerated, he noted, the thiazolidinediones are associated with considerable weight gain, and complications have been reported in two pilot studies.

Until the results of large, controlled studies of at least one to two years' duration are available, he wrote, "dietary modification, exercise, and treatment of coexisting conditions should be the preferred strategy for managing nonalcoholic steatohepatitis."

This study was supported by grants from the National Center for Research Resources to the Frederic C. Bartter General Clinical Research Center and its Imaging Core, and by Takeda Pharmaceuticals, and the Veterans Affairs Medical Research Fund. Dr. Cusi reported being a member of the speakers bureau of Eli Lilly, maker of Actos. Co-author Steven Schenker, M.D., reported being a consultant to Eli Lilly, and Ralph DeFronzo, M.D., reported being a consultant to and a member of the advisory board and speakers bureau of Takeda Pharmaceuticals.

Dr. McCullough reported being an investigator in the Nonalcoholic Steatohepatitis Clinical Research Network sponsored by the National Institutes of Health. NIH received grant support from Takeda Pharmaceuticals to help fund this research. He also reported serving on the advisory board of Pfizer and Intercept Pharmaceuticals.