A Placebo-Controlled Trial of Pioglitazone in Subjects with NonAlcoholic Steatohepatitis
Abstract & Commentary
By Malcolm Robinson, MD, FACP, FACG, Emeritus Clinical Professor of Medicine, University of Oklahoma College of Medicine, Oklahoma City. Dr. Robinson reports no financial relationship to this field of study.
Synopsis: Until now, there has been no proven therapy for nonalcoholic steatohepatitis. Pioglitazone, known to improve insulin resistance, was shown to result in metabolic and histologic improvement in this common and potentially highly morbid malady.
Source: Renate Belfort, et al. The New England Journal of Medicine. 2006;355:2297-2307
Although often unrecognized, nonalcoholic steatohepatitis (NASH) is an increasingly common chronic liver disease that can progress to cirrhosis and hepatoma. Typical features associated with NASH include obesity, fatty liver disease, and type 2 diabetes mellitus. Proposed treatments have included orlistat, vitamin E, ursodeoxycholic acid, and lipid lowering agents. Although uncontrolled trials of medications that reduce glucose have been promising, none of the therapeutic regimens have been subjected to controlled randomized trials. Pioglitazone reduces glucose levels and ameliorates insulin resistance in fat, liver and in muscles. It also improves lipid metabolism in type 2 diabetes. In NASH, there are low plasma adiponectin levels and poor adiponectin receptor expression in the liver. Pioglitazone and other drugs of its class (thiazolidinediones) increase adiponectin levels, have anti-inflammatory effects, stimulate fatty acid oxidation, and inhibit hepatic fatty acid synthesis. All of these effects suggest potential efficacy in NASH. This study included 55 patients with NASH confirmed by complete evaluation including liver biopsies who also had impaired glucose tolerance or type 2 diabetes mellitus. Significant alcohol consumption was an exclusion as was fasting blood sugar levels above 240 mg per deciliter. Compliance was assessed during a 4 week placebo run-in period. Hepatic fat was measured with magnetic resonance spectroscopy, and whole body fat was assessed using dual-energy X-ray absorptiometry. Baseline glucose clearance was measured isotopically, and hepatic insulin sensitivity was computed. During a 6 month subsequent study, weight-reducing diet plus placebo was compared to the same diet plus pioglitazone 45 mg daily. Results indicated that the pioglitazone recipients had significant improvements vs placebo in hepatic histology along with improved glycemic control and normalized hepatic aminotransferase levels. Pioglitazone decreased hepatic fat by 54% vs 0% for placebo plus diet. Systemic inflammation was also lessened by pioglitazone as mirrored by plasma TNF-a and TGF-beta levels. However, fibrosis scores were not altered by pioglitazone.
Commentary
NASH is an increasingly common form of liver disease, and it is likely to increase further with the "fattening" of western populations. Although not recognized in the past as a major progenitor of hepatic cirrhosis, NASH is now thought to account for a large percentage of idiopathic liver fibrosis. This study strongly suggests that drugs such as pioglitazone may interfere with the pathophysiology of nonalcoholic steatohepatitis. However, as the authors themselves point out, actual clinical studies are needed to document the long term benefits of such treatment in terms of morbidity and mortality. Such studies will undoubtedly be initiated in the near future. Meanwhile, even in the absence of definitive clinical corroboration of these metabolic and histologic data, many physicians may opt to initiate such therapy in patients with documented NASH.
Until now, there has been no proven therapy for nonalcoholic steatohepatitis. Pioglitazone, known to improve insulin resistance, was shown to result in metabolic and histologic improvement in this common and potentially highly morbid malady.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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