A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis
Renata Belfort, M.D., Stephen A. Harrison, M.D., Kenneth Brown, M.D., Celia Darland, R.D., Joan Finch, R.N., Jean Hardies, Ph.D., Bogdan Balas, M.D., Amalia Gastaldelli, Ph.D., Fermin Tio, M.D., Joseph Pulcini, M.D., Rachele Berria, M.D., Jennie Z. Ma, Ph.D., Sunil Dwivedi, M.D., Russell Havranek, M.D., Chris Fincke, M.D., Ralph DeFronzo, M.D., George A. Bannayan, M.D., Steven Schenker, M.D., and Kenneth Cusi, M.D.
Background No pharmacologic therapy has conclusively provedto be effective for the treatment of nonalcoholic steatohepatitis,which is characterized by insulin resistance, steatosis, andnecroinflammation with or without centrilobular fibrosis. Pioglitazoneis a thiazolidinedione that ameliorates insulin resistance andimproves glucose and lipid metabolism in type 2 diabetes mellitus.
Methods We randomly assigned 55 patients with impaired glucosetolerance or type 2 diabetes and liver biopsyconfirmednonalcoholic steatohepatitis to 6 months of treatment with ahypocaloric diet (a reduction of 500 kcal per day in relationto 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]glucosegiven with the oral glucose load and [3H]glucose given by intravenousinfusion).
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 plasmaaspartate 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), andincreased hepatic insulin sensitivity (by 48% vs. 14%, P=0.008).Administration of pioglitazone, as compared with placebo, wasassociated with improvement in histologic findings with regardto steatosis (P=0.003), ballooning necrosis (P=0.02), and inflammation(P=0.008). Subjects in the pioglitazone group had a greaterreduction in necroinflammation (85% vs. 38%, P=0.001), but thereduction in fibrosis did not differ significantly from thatin the placebo group (P=0.08). Fatigue and mild lower-extremityedema developed in one subject who received pioglitazone; noother adverse events were observed.
Conclusions In this proof-of-concept study, the administrationof pioglitazone led to metabolic and histologic improvementin subjects with nonalcoholic steatohepatitis. Larger controlledtrials of longer duration are warranted to assess the long-termclinical 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.
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.
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