Top

Diabetologia

Published in:

01-04-2012 | Systematic review

Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials

Authors: G. Musso, M. Cassader, F. Rosina, R. Gambino

Published in: Diabetologia | Issue 4/2012

Abstract

Aims/hypothesis

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH): NAFLD causes an increased risk of cardiovascular disease, diabetes and liver-related complications (the latter confined to NASH). The effect of proposed treatments on liver disease, glucose metabolism and cardiovascular risk in NAFLD is unknown. We reviewed the evidence for the management of liver disease and cardio-metabolic risk in NAFLD.

Methods

Publications through November 2011 were systematically reviewed by two authors. Outcomes evaluated though standard methods were: histological/radiological/biochemical features of NAFLD, variables of glucose metabolism and cardiovascular risk factors. Seventy-eight randomised trials were included (38 in NASH, 40 in NAFLD): 41% assessed post-treatment histology, 71% assessed glucose metabolism and 88% assessed cardiovascular risk factors. Lifestyle intervention, thiazolidinediones, metformin and antioxidants were most extensively evaluated.

Results

Lifestyle-induced weight loss was safe and improved cardio-metabolic risk profile; a weight loss ≥7% improved histological disease activity, but was achieved by <50% patients. Statins and polyunsaturated fatty acids improved steatosis, but their effects on liver histology are unknown. Thiazolidinediones improved histological disease activity, glucose, lipid and inflammatory variables and delayed fibrosis progression. Pioglitazone also improved blood pressure. Weight gain (up to 4.8%) was common. Antioxidants yielded mixed histological results: vitamin E improved histological disease activity when administered for 2 years, but increased insulin resistance and plasma triacylglycerols.

Conclusions/interpretation

Weight loss is safe, and improves liver histology and cardio-metabolic profile. For patients not responding to lifestyle intervention, pioglitazone improves histological disease activity, slows fibrosis progression and extensively ameliorates cardio-metabolic endpoints. Further randomised controlled trials (RCTs) of adequate size and duration will assess long-term safety and efficacy of proposed treatments on clinical outcomes.

Available only for authorised users

Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G (2010) A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 53:372–384PubMedCrossRef

Younossi ZM, Stepanova M, Afendy M et al (2011) Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 9:524–530PubMedCrossRef

Musso G, Gambino R, Cassader M, Pagano G (2011) Prognosis and non-invasive methods to assess liver disease severity in non-alcoholic fatty liver disease (NAFLD): systematic review and meta-analysis. Ann Med 43:617–649PubMedCrossRef

Ghouri N, Preiss D, Sattar N (2010) Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease: a narrative review and clinical perspective of prospective data. Hepatology 52:1156–1161PubMedCrossRef

Higgins JPT, Green S (eds) (2008) Cochrane Handbook for Systematic Reviews of Interventions, Version 5.0.0. The Cochrane Collaboration. Available at www.Cochrane-handbook.org. Accessed 26 May 2009

Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ (2003) Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology 38:413–419PubMedCrossRef

Zelber-Sagi S, Kessler A, Brazowsky E et al (2006) A double-blind randomized placebo-controlled trial of orlistat for the treatment of non-alcoholic fatty liver disease. Clin Gastroenterol Hepatol 4:639–644PubMedCrossRef

Lazo M, Solga SF, Horska A et al (2010) The effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes. Diabetes Care 33:2156–2163PubMedCrossRef

Shah K, Stufflebaum A, Hilton TN et al (2009) Diet and exercise intervention reduce intrahepatic fat content and improve insulin sensitivity in obese adult older adults. Obesity 17:2162–2168PubMedCrossRef

10.

Promrat K, Kleiner DE, Niemeier HM et al (2010) Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 51:121–129PubMedCrossRef

11.

Nobili V, Manco M, Devito R et al (2008) Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology 48:119–128PubMedCrossRef

12.

Harrison SA, Brunt EM, Fecht WJ, Neuschwander-Tetri BA (2009) Orlistat for overweight subjects with nonalcoholic steatohepatitis (NASH): a randomized prospective trial. Hepatology 49:80–86PubMedCrossRef

13.

Hayward CS, Lockwood J, Williams CD, Cole RE, Torres DM, Harrison SA (2010) Lifestyle modification and NAFLD: a prospective randomized trial. Hepatology 52(S4):622A

14.

Kistler K, Brunt EM, Clark JM et al (2011) Physical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease. Am J Gastroenterol 106:460–468PubMedCrossRef

15.

Perseghin G, Lattuada G, de Cobelli F et al (2007) Habitual physical activity is associated with intrahepatic fat content in humans. Diabetes Care 30:683–688PubMedCrossRef

16.

Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R et al (2008) Role of leisure-time physical activity in non-alcoholic fatty liver disease; a population-based study. Hepatology 48:1791–1798PubMedCrossRef

17.

Rabøl R, Falk Petersen K, Dufour S, Flannery C S, Shulman GL (2011) Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. Proc Natl Acad Sci U S A 108:13705–13709PubMedCrossRef

18.

Bonekamp S, Barone BB, Clark J, Stewart KJ (2008) The effects of an exercise training intervention on hepatic steatosis. Hepatology 48(Suppl 1):806A

19.

Johnson NA, Sachinwalla T, Walton DW et al (2009) Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology 50:1105–1112PubMedCrossRef

20.

St. George A, Bauman A, Johnston A et al (2009) Independent effects of physical activity in patients with non-alcoholic fatty liver. Hepatology 50:68–76PubMedCrossRef

21.

Hallsworth K, Fattakhowa G, Hollingsworth K et al (2011) Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Gut 60:1278–1283PubMedCrossRef

22.

Frith J, Day CP, Robinson L, Elliott C, Jones DE, Newton JL (2010) Potential strategies to improve uptake of exercise interventions in non-alcoholic fatty liver disease. J Hepatol 52:112–116PubMedCrossRef

23.

Kirk E, Reeds DN, Finck BN, Mayurranjan MS, Klein S (2009) Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. Gastroenterology 136:1552–1560PubMedCrossRef

24.

Haufe S, Engeli S, Kast P et al (2011) Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects. Hepatology 53:1504–1514PubMedCrossRef

25.

de Luis DA, Aller R, Izaola O, Gonzalez Sagrato M, Conde R (2010) Effect of two different hypocaloric diets in transaminases and insulin resistance in nonalcoholic fatty liver disease and obese patients. Nutr Hosp 25:730–735PubMed

26.

Gastaldelli A, Harrison SA, Belfort-Aguilar R et al (2009) Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology 50:1087–1093PubMedCrossRef

27.

Sanyal AJ, Mofrad PS, Contos MJ et al (2004) A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2:1107–1115PubMedCrossRef

28.

Belfort R, Harrison SA, Brown K et al (2006) A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 355:2297–2307PubMedCrossRef

29.

Aithal GP, Thomas JA, Kaye PV et al (2008) Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 135:1176–1184PubMedCrossRef

30.

Ratziu V, Giral P, Jacqueminet S et al (2008) Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology 135:100–110PubMedCrossRef

31.

Idilman R, Mizrak D, Corapcioglu D et al (2008) Clinical trial: insulin-sensitizing agents may reduce consequences of insulin resistance in individuals with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 28:200–208PubMedCrossRef

32.

Sanyal AJ, Chalasani N, Kowdley KV et al (2010) Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 362:1675–1685PubMedCrossRef

33.

Omer Z, Cetinkalp S, Akyildiz M et al (2010) Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 22:18–23PubMedCrossRef

34.

Tiikkainen M, Häkkinen AM, Korsheninnikova E, Nyman T, Mäkimattila S, Yki-Järvinen H (2004) Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes 53:2169–2173PubMedCrossRef

35.

Jonker JT, Wang Y, de Haan W et al (2010) Pioglitazone decreases plasma cetp mass, associated with a decrease in hepatic triglyceride content, in patients with type 2 diabetes mellitus. Diabetes Care 33:1625–1628PubMedCrossRef

36.

Shah PK, Mudaliar S, Chang AR et al (2011) Effects of intensive insulin therapy alone and in combination with pioglitazone on body weight, composition, distribution and liver fat content in patients with type 2 diabetes. Diabetes Obes Metabol 13:505–510CrossRef

37.

Gupta AK, Bray GA, Greenway FL et al (2010) Pioglitazone, but not metformin, reduces liver fat in type-2 diabetes mellitus independent of weight changes. J Diabetes Complications 24:289–296PubMedCrossRef

38.

Torres D, Jones F, Shaw J, Williams C, Ward J, Harrison S (2011) Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis (NASH): a 12 month-randomized, prospective, open- label trial. Hepatology. doi:10.1002/hep.24558

39.

Lutchamn G, Modi A, Kleiner DE et al (2007) The effects of discontinuing pioglitazone in patients with non-alcoholic steatohepatitis. Hepatology 46:424–429CrossRef

40.

Ratziu V, Charlotte F, Bernhardt C et al (2010) Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the FLIRT-2 extension trial. Hepatology 51:445–453PubMedCrossRef

41.

Zhou G, Myers R, Li Y et al (2001) Role of AMP-activated protein kinase in mechanisms of metformin action. J Clin Invest 108:1167–1174PubMed

42.

Uygun A, Kadayifci A, Isik AT et al (2004) Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 19:537–544PubMedCrossRef

43.

Haukeland JW, Konopski Z, Beate Eggesbø H et al (2009) Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 44:853–860PubMedCrossRef

44.

Shields WW, Thompson KE, Grice GA, Harrison SA, Coyle WJ (2009) The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a pilot trial. Ther Adv Gastroenterology 2:157–163CrossRef

45.

Bugianesi E, Gentilcore E, Manini R et al (2005) A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 100:1082–1090PubMedCrossRef

46.

Nar A, Gedik O (2009) The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Acta Diabetol 46:113–118PubMedCrossRef

47.

Garinis GA, Fruci B, Mazza A et al (2010) Metformin versus dietary treatment in nonalcoholic hepatic steatosis: a randomized study. Int J Obes (Lond). doi:10.1038/ijo.2010.40

48.

Tock L, Dâmaso AR, de Piano A et al (2010) Long-term effects of metformin and lifestyle modification on nonalcoholic fatty liver disease obese adolescents. J Obes. doi:10.1155/2010/831901

49.

Lavine JE, Schwimmer JB, van Natta ML et al (2011) Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 305:1659–1668PubMedCrossRef

50.

Sofer E, Boaz M, Matas Z, Mashavi M, Shargorodsky M (2011) Treatment with insulin sensitizer metformin improves arterial properties, metabolic parameters, and liver function in patients with nonalcoholic fatty liver disease: a randomized, placebo-controlled trial. Metabolism 60:1278–1284PubMedCrossRef

51.

Cohen DE, Anania FA, Chalasani N (2006) An assessment of statin safety by hepatologists. Am J Cardiol 97(8A):77C–81CPubMedCrossRef

52.

Sattar N, Preiss D, Murray HM et al (2010) Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 375:735–742PubMedCrossRef

53.

Athyros VG, Mikhailidis DP, Didangelos TP et al (2006) Effect of multifactorial treatment on non-alcoholic fatty liver disease in metabolic syndrome: a randomised study. Curr Med Res Opin 22:873–883PubMedCrossRef

54.

Foster T, Budoff MJ, Saab S, Ahmadi N, Gordon C, Guerci AD (2011) Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial. Am J Gastroenterol 106:71–77PubMedCrossRef

55.

Athyros VG, Tziomalos K, Gossios TD et al (2010) Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 376:1916–1922PubMedCrossRef

56.

Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA (2009) A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial. J Clin Gastroenterol 43:990–994PubMedCrossRef

57.

Wouters K, van Gorp PJ, Bieghs V et al (2008) Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of NASH. Hepatology 48:474–486PubMedCrossRef

58.

Yasutake K, Nakamuta M, Shima Y et al (2009) Nutritional investigation of non-obese patients with non-alcoholic fatty liver disease: the significance of dietary cholesterol. Scand J Gastroenterol 44:471–477PubMedCrossRef

59.

Enjoji M, Nakamuta M (2010) Is the control of dietary cholesterol intake sufficiently effective to ameliorate nonalcoholic fatty liver disease? World J Gastroenterol 16:800–803PubMed

60.

Zheng S, Hoos L, Cook J et al (2008) Ezetimibe improves high fat and cholesterol diet-induced non-alcoholic fatty liver disease in mice. Eur J Pharmacol 584:118–124PubMedCrossRef

61.

Nozaki Y, Fujita K, Yoneda M et al (2009) Long-term combination therapy of ezetimibe and acarbose for non-alcoholic fatty liver disease. J Hepatol 51:548–556PubMedCrossRef

62.

Deushi M, Nomura M, Kawakami A et al (2007) Ezetimibe improves liver steatosis and insulin resistance in obese rat model of metabolic syndrome. FEBS Lett 581:5664–5670PubMedCrossRef

63.

Chan DC, Watts GF, Gan SK, Ooi EM (2010) Barrett PH Effect of ezetimibe on hepatic fat, inflammatory markers and apolipoprotein B-100 kinetics in insulin-resistant obese subjects on a weight loss diet. Diabetes Care 33:1134–1139PubMedCrossRef

64.

Takeshita Y, Takamura T, Kita Y et al (2011) Efficacy of ezetimibe for the treatment of non-alcoholic fatty liver disease: a randomized controlled trial. J Hep 54:S346CrossRef

65.

Nobili V, Bedogni G, Alisi A et al (2011) Docosahexaenoic acid supplementation decreases liver fat content in children with non-alcoholic fatty liver disease: double-blind randomised controlled clinical trial. Arch Dis Child 96:350–353PubMedCrossRef

66.

Spadaro L, Magliocco O, Spampinato D et al (2008) Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease. Dig Liv Dis 40:194–199CrossRef

67.

Zhu FS, Liu S, Chen XM, Huang ZG, Zhang DW (2008) Effects of n-3 polyunsaturated fatty acids from seal oils on nonalcoholic fatty liver disease associated with hyperlipidemia. World J Gastroenterol 14:6395–6400PubMedCrossRef

68.

Cussons AJ, Watts GF, Mori TA, Stuckey BGA (2009) Omega-3 fatty acid supplementation decreases liver fat content in polycystic ovary syndrome: a randomized controlled trial employing proton magnetic resonance spectroscopy. J Clin Endocrinol Metab 94:3842–3848PubMedCrossRef

69.

Caldwell SH, Argo CK, Henry TD et al (2011) Dissociated histological and metabolic effects of omega-3 (3,000 mg/d) vs. placebo with both exercise and diet in a double-blind randomized controlled trial of NASH. J Hep 54:S8CrossRef

70.

Merat S, Malekzadeh R, Sohrabi MR et al (2003) Probucol in the treatment of non-alcoholic steatohepatitis: a double-blind randomized controlled study. J Hepatology 38:414–418CrossRef

71.

Seo YS, Kim JH, Jo NY et al (2008) PPAR agonists treatment is effective in a nonalcoholic fatty liver disease animal model by modulating fatty-acid metabolic enzymes. J Gastroenterol Hepatol 23:102–109PubMed

72.

Basaranoglu M, Acbay O, Sonsuz A (1999) A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol 31:384PubMedCrossRef

73.

Conjeevaram HS, McKenna BJ, Kang H et al (2009) A randomized placebo-controlled study of PPAR-alpha agonist fenofibrate in patients with nonalcoholic steatohepatitis (NASH). Hepatology 50(S4):774A

74.

Korenblat K, Fabbrini E, Mohammed BS et al (2009) Effects of fenofibrate and long-acting nicotinic acid on intrahepatic triglyceride content and adipose tissue insulin sensitivity in obese human subjects. J Hep 50:S25CrossRef

75.

Fabbrini E, Mohammed BS, Korenblat KM et al (2010) Effect of fenofibrate and niacin on intrahepatic triglyceride content, very low-density lipoprotein kinetics, and insulin action in obese subjects with nonalcoholic fatty liver disease. J Clin Endocrinol Metab 95:2727–2735PubMedCrossRef

76.

Georgescu EF, Ionescu R, Georgescu M et al (2009) Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis. World J Gastroenterol 15:942–954PubMedCrossRef

77.

Fogari R, Mugellini A, Zoppi A et al (2011) Losartan alone or in combination with simvastatin improved visceral adipose tissue and inflammation in hypertensive normocholesterolemic patients with nonalcoholic hepatic steatosis. Eur J Gastroenterol Hepatol. doi:10.1097/MEG.0b013e32834ba188

78.

Després JP, Ross R, Boka G, Alméras N, Lemieux I (2009) Effect of rimonabant on the high-triglyceride/ low-HDL-cholesterol dyslipidemia, intraabdominal adiposity, and liver fat. The ADAGIO-Lipids Trial. Arterioscler Thromb Vasc Biol 29:416–423PubMedCrossRef

79.

Buranawui W, Thung-u-thaisri P, Pramoolsinsap C et al (2010) Pentoxifylline for treatment of non-alcoholic fatty liver disease(NAFLD): a randomized, placebo-controlled study. Gastroenterology A330:s2161

80.

Lee YM, Sutedja D, Wai CT et al (2008) A randomized controlled pilot study of pentoxifylline in patients with non-alcoholic steatohepatitis (NASH). Hepatol Int 2:196–201PubMedCrossRef

81.

Rinella ME, Koppe S, Brunt EM, Elias M, Gottstein J, Green RM (2010) Pentoxifylline improves ALT and histology in patients with NASH: a double-blind placebo controlled trial. Gastroenterology 136 (Supplement) Digestive Disease Week (CD-ROM)

82.

Zein CO, Yerian LM, Gogate P et al (2011) Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology. doi:10.1002/hep.24544

83.

Santos VN, Lanzoni VP, Szejnfeld D, Shigueoka D, Parise ER (2003) A randomized double-blind study of the short-time treatment of obese patients with non-alcoholic fatty liver disease with ursodeoxycholic acid. Braz J Med Biol Res 36:723–729PubMedCrossRef

84.

Mendez-Sanchez N, Gonzalez V, Chavez-Tapia N, Ramos M, Uribe M (2004) Weight reduction and ursodeoxycholic acid in subjects with non-alcoholic fatty liver disease. A double-blind, placebo-controlled trial. Ann Hepatol 3:108–112PubMed

85.

Ersoz G, Gunsar F, Karasu Z, Akay S, Batur Y, Akarca US (2005) Management of fatty liver disease with vitamin E and C compared to ursodeocycholic acid treatment. Turk J Gastroenterol 16:124–128PubMed

86.

Ratziu V, de Ledinghen V, Oberti F et al (2011) A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol 54:1011–1019PubMedCrossRef

87.

Leuschner UFH, Lindenthal B, Herrmann G et al (2010) High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology 52:472–479PubMedCrossRef

88.

Lindor KD, Kowdley KV, Heathcote EJ et al (2004) Ursodeoxycholic acid for the treatment of non-alcoholic steatohepatitis: results of a randomized trial. Hepatology 39:770–778PubMedCrossRef

89.

Dufour JF, Oneta CM, Gonvers JJ et al (2006) Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin E in non-alcoholic steatohepatitis. Clin Gastroenterol Hepatol 4:1537–1543PubMedCrossRef

90.

Musso G, Gambino R, Cassader M (2010) Emerging molecular targets for the treatment of nonalcoholic fatty liver disease. Ann Rev Med 61:375–392PubMedCrossRef

91.

Knop FK (2010) Bile-induced secretion of glucagon-like peptide-1: pathophysiological implications in type 2 diabetes? Am J Physiol Endocrinol Metab 299:E10–E13PubMedCrossRef

92.

Sanyal AJ, Mudaliar S, Henry RR et al (2010) A new therapy for non-alcoholic fatty liver disease and diabetes? Int-747-the first FXR hepatic therapeutic study. Hepatology 50:389A

93.

Rui M, Wang C, Fang J et al (2001) The clinical comparison of reduced glutathione and DaiNingPlan in the treatment of non-alcoholic steatohepatitis. Chin Gen Pract 4:269–270

94.

Harrison SA, Torgerson S, Ward J et al (2003) Vitamin E and vitamin C treatment improves fibrosis in patients with non-alcoholic steatohepatitis. Am J Gastroenterol 98:2485–2490PubMedCrossRef

95.

Abdelmalek MF, Sanderson SO, Angulo P et al (2009) Betaine for nonalcoholic fatty liver disease: results of a randomized placebo-controlled trial. Hepatology 50:1818–1826PubMedCrossRef

96.

Pamuk GE, Sonsuz A (2003) N-acetylcysteine in the treatment of nonalcoholic steatohepatitis. J Gastroenterol Hepatol 18:1220–1221PubMedCrossRef

97.

Miglio F, Rovati LC, Santoro A, Senikar I (2000) Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel group, placebo-controlled prospective clinical study. Arzneimittelforschung 50:722–727PubMed

98.

Vilar Gomez E, Rodriguez de Miranda A, Gra Oramas B et al (2009) Clinical trial: Viusid(R) in combination with diet and exercise in patients with nonalcoholic fatty liver disease. Aliment Pharmacol Ther 30:999–1009PubMedCrossRef

99.

Loguercio C, Federico A, Trappoliere M et al (2007) The effect of a silybin–vitamin E–phospholipid complex on nonalcoholic fatty liver disease. Dig Dis Sci 52:2387–2395PubMedCrossRef

100.

Hashemi SJ, Hajiani E, Sardabi EH (2009) A placebo-controlled trial of silymarin in patients with nonalcoholic fatty liver disease. Hepat Mon 9:265–270

101.

Neuschwander-Tetri BA, Sanyal AJ, Chalasani NP et al (2010) Changes in ALT and vitamin E levels and histological response in patients with NASH treated with vitamin E in the PIVENS trial. Hepatology 52:620ACrossRef

102.

Malaguarnera M, Gargante MP, Russo C et al (2010) l-Carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis. A randomized and controlled clinical trial. Am J Gastroenterol. doi:10.1038/ajg.2009.719

103.

Musso G, Gambino R, Cassader M (2011) Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes. Ann Rev Med 62:361–380PubMedCrossRef

104.

Solga SF, Buckley G, Clark JM, Horska A, Diehl AM (2008) The effect of a probiotic on hepatic steatosis. J Clin Gastroenterol 42:1117–1119PubMedCrossRef

105.

Wong VWS, Wong GLH, Wong CH, Chan HLY (2011) Treatment of non-alcoholic steatohepatitis with probiotics—a proof-of-concept study with serial gut microbiota analysis by ultra-deep sequencing. J Hepatol 54:349CrossRef

106.

Aller R, de Luis DA, Izaola O et al (2011) Effect of a probiotic on liver aminotransferases in nonalcoholic fatty liver disease patients: a double blind randomized clinical trial. Eur Rev Med Pharmacol Sci 15:1090–1095PubMed

107.

Zing X, Saxena NK, Lin S et al (2006) Exedin-4, a glucagon-like protein1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 43:173–181CrossRef

108.

Buse JB, Klonoff DC, Nielsen LL (2007) Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials. Clin Ther 29:139–153PubMedCrossRef

109.

Jendle J, Nauck MA, Matthews DR et al (2009) Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue. Diabetes Obes Metab 11:1163–1172PubMedCrossRef

110.

Ratziu V, Sheikh MY, Sanyal AJ et al (2011) A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis. Hepatology. doi:10.1002/hep.24747

111.

Arase Y, Suzuki F, Ikeda K et al (2009) Multivariate analysis of risk factors for the development of type 2 diabetes in nonalcoholic fatty liver disease. J Gastroenterol 44:1064–1070PubMedCrossRef

112.

Ristow M, Zarse K, Oberbach A et al (2009) Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A 106:8665–8670PubMedCrossRef

113.

Yfanti C, Akerström T, Nielsen S et al (2010) Antioxidant supplementation does not alter endurance training adaptation. Med Sci Sports Exerc 42:1388–1395PubMed

114.

Yfanti C, Nielsen AR, Akerström T et al (2011) Effect of antioxidant supplementation on insulin sensitivity in response to endurance exercise training. Am J Physiol Endocrinol Metab 300:E761–E770PubMedCrossRef

115.

Miller ER, Pastor-Barriuso R et al (2005) Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142:37–46PubMed

116.

Le KA, Ith M, Kreis R et al (2009) Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes. Am J Clin Nutr 89:1760–1765PubMedCrossRef

117.

Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R et al (2007) Long term nutritional intake and the risk for nonalcoholic fatty liver disease (NAFLD): a population based study. J Hepatol 47:711–717PubMedCrossRef

118.

Assy N, Nasser G, Kamayse I et al (2008) Soft drink consumption linked with fatty liver in the absence of traditional risk factors. Can J Gastroenterol 22:811–816PubMed

119.

Ouyang X, Cirillo P, Sautin Y et al (2008) Fructose consumption as a risk factor for nonalcoholic fatty liver disease. J Hepatol 48:993–999PubMedCrossRef

120.

Abdelmalek MF, Suzuki A, Guy C et al (2010) Increased fructose consumption is associated with fibrosis severity in patients with NAFLD. Hepatology 51:1961–1971PubMedCrossRef

121.

Dunn W, Xu R, Schimmer JB (2008) Modest wine drinking and decreased prevalence of suspected non-alcoholic fatty liver disease. Hepatology 47:1947–1954PubMedCrossRef

122.

Cotrim HP, Freitas LA, Alves E et al (2009) Effects of light-to-moderate alcohol consumption on steatosis and steatohepatitis in severely obese patients. Eur J Gastroenterol Hepatol 21:969–972PubMedCrossRef

123.

Ruhl CE, Everhart JE (2005) Joint effects of body weight and alcohol on elevated serum alanine aminotransferase in the United States population. Clin Gastroenterol Hepatol 3:1260–1268PubMedCrossRef

124.

Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN (2010) The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51:1972–1978PubMedCrossRef

125.

Hamabe A, Uto H, Imamura Y et al (2011) Impact of cigarette smoking on onset of nonalcoholic fatty liver disease over a 10-year period. J Gastroenterol 46:769–778PubMedCrossRef

126.

Zein CO, Unalp A, Colvin R, Liu YC, McCullough AJ, Nonalcoholic Steatohepatitis Clinical Research Network (2011) Smoking and severity of hepatic fibrosis in nonalcoholic fatty liver disease. J Hepatol 54:753–759PubMedCrossRef

127.

Tsochatzis EA, Papatheodoridis GV (2010) Smoking is associated with histological severity in nonalcoholic steatohepatitis. Hepatology 52:1522–1523PubMedCrossRef

128.

Argo CK, Northup PG, Al-Osaimi AM et al (2009) Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol 51:371–379PubMedCrossRef

129.

Chiang DJ, Pritchard MT, Nagy LE (2011) Obesity, diabetes mellitus, and liver fibrosis. Am J Physiol Gastrointest Liver Physiol 300:G697–G702PubMedCrossRef

130.

Musso G, Gambino R, Cassader M (2011) Need for a three-focused approach to nonalcoholic fatty liver disease. Hepatology 53:1773PubMedCrossRef

131.

Preiss D, Khunti K, Sattar N (2011) Combined cardiovascular and diabetes risk assessment in primary care. Diabet Med 28:19–22PubMedCrossRef

132.

Silbernagel G, Grammer TB, Winkelmann BR, Boehm BO, März W (2011) Glycated hemoglobin predicts all-cause, cardiovascular, and cancer mortality in people without a history of diabetes undergoing coronary angiography. Diabetes Care. doi:10.2337/dc10-2010

133.

Abdul-Ghani MA, Williams K, DeFronzo RA, Stern M (2007) What is the best predictor of future type 2 diabetes? Diabetes Care 30:1544–1548PubMedCrossRef

134.

Musso G, Gambino R, Biroli G et al (2005) Hypoadiponectinemia predicts the severity of hepatic fibrosis and pancreatic beta-cell dysfunction in nondiabetic nonobese patients with nonalcoholic steatohepatitis. Am J Gastroenterol 100:2438–2446PubMedCrossRef

135.

Reddy KJ, Singh M, Bangit JR, Batsell RR (2010) The role of insulin resistance in the pathogenesis of atherosclerotic cardiovascular disease: an updated review. J Cardiovasc Med 11:633–647CrossRef

136.

Calori G, Lattuada G, Ragogna F et al (2011) Fatty liver index (FLI) and mortality: the Cremona study at the 15th year of follow up. Hepatology. doi:10.1002/hep.24356

137.

Muniyappa R, Lee S, Chen H, Quon MJ (2008) Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab 294:E15–E26PubMedCrossRef

138.

Devaraj S, Valleggi S, Siegel D, Jialal I (2010) Role of C-reactive protein in contributing to increased cardiovascular risk in metabolic syndrome. Curr Atheroscler Rep 12:110–118PubMedCrossRef

139.

Musso G, Gambino R, Cassader M, Pagano G (2010) A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology 52:79–104PubMedCrossRef

140.

Gambino R, Musso G, Cassader M (2011) Redox balance in the pathogenesis of nonalcoholic fatty liver disease: mechanisms and therapeutic opportunities. Antioxid Redox Signal 15:1325–1365PubMedCrossRef

Title: Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials
Authors: G. Musso
M. Cassader
F. Rosina
R. Gambino
Publication date: 01-04-2012
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 4/2012
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-011-2446-4

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Please log in to get access to this content

Other articles of this Issue 4/2012

Lowering of postprandial lipids in individuals with type 2 diabetes treated with alogliptin and/or pioglitazone: a randomised double-blind placebo-controlled study

How the immunoassay transformed C-peptide from a duckling into a swan

Deletion of Fas protects islet beta cells from cytotoxic effects of human islet amyloid polypeptide

Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat

Erratum to: Cancer occurrence in Danish diabetic patients: duration and insulin effects

The proteomic signature of insulin-resistant human skeletal muscle reveals increased glycolytic and decreased mitochondrial enzymes

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials