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Previous Volume 355:2297-2307 November 30, 2006 Number 22 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Editorial by McCullough, A. J. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background No pharmacologic therapy has conclusively proved to be effective for the treatment of nonalcoholic steatohepatitis, which is characterized by insulin resistance, steatosis, and necroinflammation with or without centrilobular fibrosis. Pioglitazone is a thiazolidinedione that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus.

Methods We randomly assigned 55 patients with impaired glucose tolerance or type 2 diabetes and liver biopsy–confirmed nonalcoholic steatohepatitis to 6 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 pioglitazone (45 mg daily) or a hypocaloric diet plus placebo. Before and after treatment, we assessed hepatic histologic features, hepatic fat content by means of magnetic resonance spectroscopy, and glucose turnover during an oral glucose tolerance test ([¹⁴C]glucose given with the oral glucose load and [³H]glucose given by intravenous infusion).

Results Diet plus pioglitazone, as compared with diet plus placebo, improved glycemic control and glucose tolerance (P<0.001), normalized liver aminotransferase levels as it decreased plasma aspartate aminotransferase levels (by 40% vs. 21%, P=0.04), decreased alanine aminotransferase levels (by 58% vs. 34%, P<0.001), decreased hepatic fat content (by 54% vs. 0%, P<0.001), and increased hepatic insulin sensitivity (by 48% vs. 14%, P=0.008). Administration of pioglitazone, as compared with placebo, was associated with improvement in histologic findings with regard to steatosis (P=0.003), ballooning necrosis (P=0.02), and inflammation (P=0.008). Subjects in the pioglitazone group had a greater reduction in necroinflammation (85% vs. 38%, P=0.001), but the reduction in fibrosis did not differ significantly from that in the placebo group (P=0.08). Fatigue and mild lower-extremity edema developed in one subject who received pioglitazone; no other adverse events were observed.

Conclusions In this proof-of-concept study, the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis. Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone. (ClinicalTrials.gov number, NCT00227110 [ClinicalTrials.gov] .)

Source Information

From the University of Texas Health Science Center at San Antonio (R. Belfort, K.B., J.F., J.H., B.B., A.G., F.T., R. Berria, J.Z.M., S.D., R.H., R.D., G.A.B., S.S., K.C.); Brooke Army Medical Center (S.A.H., J.P., C.F.); and Audie L. Murphy Division, South Texas Veterans Health Care System (C.D., J.F., F.T., R.D., S.S., K.C.) — all in San Antonio, TX; and the Institute of Clinical Physiology, National Research Council, Pisa, Italy (A.G.).

Address reprint requests to Dr. Cusi at the University of Texas Health Science Center at San Antonio, Diabetes Division, Rm. 3.380S, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900, or at cusi{at}uthscsa.edu.

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Pioglitazone in Nonalcoholic Steatohepatitis
Targher G., Chavez-Tapia N. C., Barrientos-Gutierrez T., Uribe M., Ota T., Takamura T., Kaneko S., Harrison S. A., Schenker S., Cusi K.
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N Engl J Med 2007; 356:1067-1069, Mar 8, 2007. Correspondence

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