Gastroenterology
Volume 135, Issue 4 , Pages 1176-1184 , October 2008

Randomized, Placebo-Controlled Trial of Pioglitazone in Nondiabetic Subjects With Nonalcoholic Steatohepatitis

  • Guruprasad P. Aithal

      Affiliations

    • University Hospitals NHS Trust, Nottingham, United Kingdom
    • Corresponding Author InformationAddress reprint requests to: Guruprasad P. Aithal, MD, PhD, Consultant Hepatobiliary Physician, D Floor, South Block, Queen's Medical Centre University Hospital, Derby Road, Nottingham NG72UH, United Kingdom. fax: +44 (0)115-9709012
    • ,
  • James A. Thomas

      Affiliations

    • University Hospitals NHS Trust, Nottingham, United Kingdom
    • ,
  • Philip V. Kaye

      Affiliations

    • University Hospitals NHS Trust, Nottingham, United Kingdom
    • ,
  • Adam Lawson

      Affiliations

    • University Hospitals NHS Trust, Nottingham, United Kingdom
    • ,
  • Stephen D. Ryder

      Affiliations

    • University Hospitals NHS Trust, Nottingham, United Kingdom
    • ,
  • Ian Spendlove

      Affiliations

    • University of Nottingham, Nottingham, United Kingdom
    • ,
  • Andrew S. Austin

      Affiliations

    • Derby City General Hospital, Derby, United Kingdom
    • ,
  • Jan G. Freeman

      Affiliations

    • Derby City General Hospital, Derby, United Kingdom
    • ,
  • Linda Morgan

      Affiliations

    • University of Nottingham, Nottingham, United Kingdom
    • ,
  • Jonathan Webber

      Affiliations

    • University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom

Received 12 May 2008 ,Accepted 19 June 2008.

References 

  1. Ekstedt M, Franzén LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–873
  2. Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–1395
  3. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology. 1990;12:1106–1110
  4. Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120:1183–1192
  5. Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35:373–379
  6. Semple RK, Chatterjee VK, O'Rahilly S. PPARgamma and human metabolic disease. J Clin Invest. 2006;116:581–589
  7. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114:147–152
  8. Pfützner A, Hohberg C, Lübben G, et al. Pioneer study: PPARgamma activation results in overall improvement of clinical and metabolic markers associated with insulin resistance independent of long-term glucose control. Horm Metab Res. 2005;37:510–515
  9. Kon K, Ikejima K, Hirose M, et al. Pioglitazone prevents early-phase hepatic fibrogenesis caused by carbon tetrachloride. Biochem Biophys Res Commun. 2002;291:55–61
  10. Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–2307
  11. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003;37:1202–1219
  12. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetalogia. 1985;28:412–419
  13. Marchesini G, Brizi M, Bianchi G, et al. Metformin in non-alcoholic steatohepatitis. Lancet. 2001;358:893–894
  14. Promrat K, Lutchman G, Uwaifo GI, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004;39:188–196
  15. Brunt EM, Janney CG, Di Bisceglie AM, et al. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–2474
  16. Kleiner DE, Brunt EM, Van Natta M, et al. Nonalcoholic Steatohepatitis Clinical Research Network Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321
  17. Scheuer PJ. Liver biopsy size matters in hepatitis C: bigger is better. Hepatology. 2003;38:1356–1358
  18. Brunt EM. Nonalcoholic steatohepatitis. Semin Liv Dis. 2004;24:3–20
  19. Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–1419
  20. Wang RT, Koretz RL, Yee HF. Is weight reduction an effective therapy for nonalcoholic fatty liver? (A systematic review). Am J Med. 2003;115:554–559
  21. Hickman IJ, Jonsson JR, Prins JB, et al. Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life. Gut. 2004;53:413–419
  22. Lindor KD, Kowdley KV, Heathcote EJ, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39:770–778
  23. Dixon JB, Bhathal PS, Hughes NR, et al. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology. 2004;39:1647–1654
  24. Ratziu V, Giral P, Charlotte F, et al. Liver fibrosis in overweight patients. Gastroenterology. 2000;118:1117–1123
  25. Mofrad P, Contos MJ, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology. 2003;37:1286–1292
  26. Adams LA, Sanderson S, Lindor KD, et al. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005;42:132–138
  27. Caldwell SH, Hespenheide EE, Redick JA, et al. A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. Am J Gastroenterol. 2001;96:519–525
  28. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, et al. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology. 2003;38:1008–1017
  29. Berg AH, Combs TP, Scherer PE. ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab. 2002;13:84–89
  30. Iwaki M, Matsuda M, Maeda N, et al. Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes. 2003;52:1655–1663
  31. Pfützner A, Hohberg C, Lübben G, et al. Pioneer study: PPARgamma activation results in overall improvement of clinical and metabolic markers associated with insulin resistance independent of long-term glucose control. Horm Metab Res. 2005;37:510–515
  32. Marra F. Leptin and liver fibrosis: a matter of fat. Gastroenterology. 2002;122:1529–1532
  33. Blendis L. Hypoadiponectinemia and NASH: cause or effect?. Gastroenterology. 2006;130:1365–1367
  34. Filippidis G, Liakopoulos V, Mertens PR, et al. Resistin serum levels are increased but not correlated with insulin resistance in chronic hemodialysis patients. Blood Purif. 2005;23:421–428
  35. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, et al. Interim results of a pilot study demonstrating the early effects of the PPAR-gamma ligand rosiglitazone on insulin sensitivity, aminotransferases, hepatic steatosis and body weight in patients with non-alcoholic steatohepatitis. J Hepatol. 2003;38:434–440
  36. Balas B, Belfort R, Harrison SA, et al. Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis. J Hepatol. 2007;47:565–570
  37. NICE 2002/055 (Type 2 diabetes—management of blood pressure and blood lipids, 2002). http://www.nice.org.ukaccessed September 2007
  38. Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–121
  39. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–2471
  40. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279–1289
  41. Lincoff AM, Wolski K, Nicholls SJ, et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298:1180–1188

 Takeda Pharmaceuticals UK provided the pioglitazone and placebo tablets for this investigator-initiated study. Jonathan Webber has received funding from Takeda, Novo, Sanofi-Aventis, and Pfizer to attend meetings. Investigator conflicts of interests were disclosed to study participants.

PII: S0016-5085(08)01101-3

doi: 10.1053/j.gastro.2008.06.047

Gastroenterology
Volume 135, Issue 4 , Pages 1176-1184 , October 2008

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