Drugs improving insulin resistance for non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis.

BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in the liver, which may progress to non-alcoholic steatohepatitis (NASH) and cirrhosis. It is suspected in persons with elevated aminotransferase levels and features of insulin resistance (or metabolic) syndrome. The pathogenesis of NAFLD is not clear and there is no universal treatment. OBJECTIVES To assess beneficial and harmful effects of drugs improving insulin resistance for NAFLD and/or NASH. SEARCH STRATEGY We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and The Chinese Biomedical Database until February 2006. SELECTION CRITERIA We included randomised clinical trials assessing the effects of drugs improving insulin resistance for patients with NAFLD or NASH. DATA COLLECTION AND ANALYSIS We evaluated the methodological quality of the randomised clinical trials by the generation of the allocation section, allocation concealment, and follow-up. Two independent observers extracted data from each trial. Dichotomous outcomes were reported as odds ratio (OR) with 95% confidence interval (CI). MAIN RESULTS Only three randomised clinical trials could be included. Two of the trials had unclear allocation concealment. None was blinded regarding outcome assessment. In two trials, metformin was associated with significantly higher normalization of serum alanine aminotransferase (OR fixed 2.83, 95% CI 1.27 to 6.31 versus diet and OR fixed 7.75, 95% CI 2.37 to 25.35 versus vitamin E) and improvement of liver echographic response (OR fixed 5.25, 95% CI 1.09 to 25.21). An improvement of fatty infiltration was observed in a limited number of patients undergoing liver biopsy. In the single pioglitazone trial, a statistically significant improvement of NASH histology was demonstrated. AUTHORS' CONCLUSIONS At present, there is insufficient data to either support or refute the use of drugs improving insulin resistance for patients with NAFLD, although current limited information suggests a favourable role of drugs improving insulin resistance. It is advisable to carry out large randomised trials on this topic employing clinically relevant outcome measures and adequate methodology, including blinded outcome assessment.

[1]  J. Mössner,et al.  Nichtalkoholische Fettleber und Steatohepatitis , 2007, Der Internist.

[2]  F. Pérez-Aguilar.  [Etiopathogenesis of non-alcoholic steatohepatitis]. , 2005, Gastroenterologia y hepatologia.

[3]  Dennis D. Kim,et al.  Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. , 2005, Diabetes care.

[4]  G. Marchesini,et al.  A Randomized Controlled Trial of Metformin versus Vitamin E or Prescriptive Diet in Nonalcoholic Fatty Liver Disease , 2005, The American Journal of Gastroenterology.

[5]  R. Deutsch,et al.  A phase 2 clinical trial of metformin as a treatment for non‐diabetic paediatric non‐alcoholic steatohepatitis , 2005, Alimentary pharmacology & therapeutics.

[6]  C. Alessandri,et al.  Insulin resistance, the metabolic syndrome, and nonalcoholic fatty liver disease. , 2005, The Journal of clinical endocrinology and metabolism.

[7]  J. Clore,et al.  A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. , 2004, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[8]  J. Schwimmer,et al.  Nonalcoholic fatty liver disease in the pediatric population. , 2004, Clinics in liver disease.

[9]  G. Farr,et al.  Metformin in the treatment of non‐alcoholic steatohepatitis: a pilot open label trial , 2004, Alimentary pharmacology & therapeutics.

[10]  J. Dixon,et al.  Nonalcoholic fatty liver disease: Improvement in liver histological analysis with weight loss , 2004, Hepatology.

[11]  G. Marchesini,et al.  Splanchnic haemodynamics in non-alcoholic fatty liver disease: effect of a dietary/pharmacological treatment. A pilot study. , 2004, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[12]  L. Burgart,et al.  Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: Results of a randomized trial , 2004, Hepatology.

[13]  A. Işık,et al.  Metformin in the treatment of patients with non‐alcoholic steatohepatitis , 2004, Alimentary pharmacology & therapeutics.

[14]  R. Stockbrugger,et al.  Non-alcoholic steatohepatitis: review of a growing medical problem. , 2004, European journal of internal medicine.

[15]  J. Hoofnagle,et al.  A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis , 2004, Hepatology.

[16]  M. Iida,et al.  A Case of Obese Type 2 Diabetes Mellitus Associated with Nonalcoholic Steatohepatitis (NASH) Treated with a Combined Therapy of Glimepiride and Insulin , 2003 .

[17]  Pamela Royle,et al.  LITERATURE SEARCHING FOR RANDOMIZED CONTROLLED TRIALS USED IN COCHRANE REVIEWS: RAPID VERSUS EXHAUSTIVE SEARCHES , 2003, International Journal of Technology Assessment in Health Care.

[18]  S. Itoh,et al.  CASE REPORT: Combined Treatment with Ursodeoxycholic Acid and Pioglitazone in a Patient with Nash Associated with Type 2 Diabetes and Psoriasis , 2003, Digestive Diseases and Sciences.

[19]  M. Jensen,et al.  Effects of pioglitazone versus diet and exercise on metabolic health and fat distribution in upper body obesity. , 2003, Diabetes care.

[20]  B. Neuschwander‐Tetri,et al.  Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR‐γ ligand rosiglitazone , 2003, Hepatology.

[21]  M. Jensen,et al.  Effect of pioglitazone on biochemical indices of non-alcoholic fatty liver disease in upper body obesity. , 2003, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[22]  C. Alessandri,et al.  Non‐alcoholic fatty liver syndrome: A hepatic consequence of common metabolic diseases , 2003, Journal of gastroenterology and hepatology.

[23]  B. Neuschwander‐Tetri,et al.  Nonalcoholic steatohepatitis: Summary of an AASLD Single Topic Conference , 2003, Hepatology.

[24]  B. Neuschwander‐Tetri,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. , 2003, Journal of hepatology.

[25]  P. Linhart,et al.  Therapie der nichtalkoholischen Fettleber (NAFL) und Fettleberhepatitis (NASH) , 2003 .

[26]  G. Farrell.  Non‐alcoholic steatohepatitis: What is it, and why is it important in the Asia–Pacific region? , 2003, Journal of gastroenterology and hepatology.

[27]  K. Lindor,et al.  Treatment of non-alcoholic steatohepatitis. , 2002, Best practice & research. Clinical gastroenterology.

[28]  G. Crepaldi,et al.  Silybin-beta-cyclodextrin in the treatment of patients with diabetes mellitus and alcoholic liver disease. Efficacy study of a new preparation of an anti-oxidant agent. , 2002, Diabetes, nutrition & metabolism.

[29]  Mauro Salizzoni,et al.  Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. , 2002, Gastroenterology.

[30]  H. Lebovitz,et al.  Evaluation of liver function in type 2 diabetic patients during clinical trials: evidence that rosiglitazone does not cause hepatic dysfunction. , 2002, Diabetes care.

[31]  P. Angulo,et al.  Nonalcoholic fatty liver disease. , 2002, Revista de gastroenterologia de Mexico.

[32]  E. Christensen.  Alcoholic hepatitis - glucocorticosteriods or not? , 2002 .

[33]  Z. Younossi,et al.  Nonalcoholic fatty liver disease: An agenda for clinical research , 2002, Hepatology.

[34]  A. McCullough,et al.  Update on nonalcoholic fatty liver disease. , 2002, Journal of clinical gastroenterology.

[35]  R. Karim,et al.  NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome , 2002, Hepatology.

[36]  U. Visco-Comandini,et al.  Metformin in non-alcoholic steatohepatitis , 2002, The Lancet.

[37]  R. Koretz,et al.  Weight reduction for non‐alcoholic fatty liver , 2002 .

[38]  Christian Gluud,et al.  Reported Methodologic Quality and Discrepancies between Large and Small Randomized Trials in Meta-Analyses , 2001, Annals of Internal Medicine.

[39]  Marco Zoli,et al.  Metformin in non-alcoholic steatohepatitis , 2001, The Lancet.

[40]  K. Lindor,et al.  Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study , 2001, American Journal of Gastroenterology.

[41]  G. Marchesini,et al.  Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. , 2001, Diabetes.

[42]  K. Lindor,et al.  Severe cholestatic hepatitis from troglitazone in a patient with nonalcoholic steatohepatitis and diabetes mellitus , 2001, American Journal of Gastroenterology.

[43]  N. Tajima,et al.  Troglitazone prevents the rise in visceral adiposity and improves fatty liver associated with sulfonylurea therapy--a randomized controlled trial. , 2001, Metabolism: clinical and experimental.

[44]  J. Clore,et al.  Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. , 2001, Gastroenterology.

[45]  S. Caldwell,et al.  A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis. , 2001 .

[46]  P. Thuluvath,et al.  Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: A case‐control study , 2000, Hepatology.

[47]  G. Marchesini,et al.  Association of nonalcoholic fatty liver disease with insulin resistance. , 1999, The American journal of medicine.

[48]  B. Neuschwander‐Tetri,et al.  Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions , 1999, American Journal of Gastroenterology.

[49]  S. Caldwell,et al.  Cryptogenic cirrhosis: Clinical characterization and risk factors for underlying disease , 1999, Hepatology.

[50]  L. Ranek,et al.  Pharmacokinetics of troglitazone, a PPAR-γ agonist, in patients with hepatic insufficiency , 1998, European Journal of Clinical Pharmacology.

[51]  D. Cook,et al.  Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? , 1998, The Lancet.

[52]  C. Day,et al.  Steatohepatitis: a tale of two "hits"? , 1998, Gastroenterology.

[53]  G. Smith,et al.  Bias in meta-analysis detected by a simple, graphical test , 1997, BMJ.

[54]  D. Bosman,et al.  Contraindications to Metformin Therapy in Patients With NIDDM , 1997, Diabetes Care.

[55]  T. Sørensen,et al.  Prediction of risk of liver disease by alcohol intake, sex, and age: A prospective population study , 1996, Hepatology.

[56]  R. J. Hayes,et al.  Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. , 1995, JAMA.

[57]  B. Neuschwander‐Tetri,et al.  Nonalcoholic steatohepatitis: an expanded clinical entity. , 1994, Gastroenterology.

[58]  D L Demets,et al.  Methods for combining randomized clinical trials: strengths and limitations. , 1987, Statistics in medicine.

[59]  N. Laird,et al.  Meta-analysis in clinical trials. , 1986, Controlled clinical trials.

[60]  Neil Kaplowitz,et al.  Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis , 1981, Hepatology.

[61]  Y. Chawla,et al.  Assessment of insulin resistance and effect of metformin in nonalcoholic steatohepatitis--a preliminary report. , 2004, Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology.

[62]  G. Farrell,et al.  Etiopathogenesis of Nonalcoholic Steatohepatitis , 2001, Seminars in liver disease.

[63]  R. Taliwal,et al.  Unsuspected cirrhosis discovered during elective obesity operations. , 1998, Archives of surgery.