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. 2017 Mar 30;3(3):CD011640.
doi: 10.1002/14651858.CD011640.pub2.

Pharmacological interventions for non-alcohol related fatty liver disease (NAFLD): an attempted network meta-analysis

Rosa Lombardi  1 , Simona Onali  1 , Douglas Thorburn  1 , Brian R Davidson  2 , Kurinchi Selvan Gurusamy  2 , Emmanuel Tsochatzis  1
Affiliations

Pharmacological interventions for non-alcohol related fatty liver disease (NAFLD): an attempted network meta-analysis

Rosa Lombardi et al. Cochrane Database Syst Rev. .

Abstract

Background: Non-alcohol related fatty liver disease (commonly called non-alcoholic fatty liver disease (NAFLD)) is liver steatosis in the absence of significant alcohol consumption, use of hepatotoxic medication, or other disorders affecting the liver such as hepatitis C virus infection, Wilson's disease, and starvation. NAFLD embraces the full spectrum of disease from pure steatosis (i.e. uncomplicated fatty liver) to non-alcoholic steatohepatitis (NASH), via NASH-cirrhosis to cirrhosis. The optimal pharmacological treatment for people with NAFLD remains uncertain.

Objectives: To assess the comparative benefits and harms of different pharmacological interventions in the treatment of NAFLD through a network meta-analysis and to generate rankings of the available pharmacological treatments according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis, and instead, assessed the comparative benefits and harms of different interventions using standard Cochrane methodology.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.com to August 2016.

Selection criteria: We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with NAFLD. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention.

Data collection and analysis: We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on an available participant analysis with Review Manager. We assessed risk of bias according to the Cochrane risk of bias tool, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE.

Main results: We identified 77 trials including 6287 participants that met the inclusion criteria of this review. Forty-one trials (3829 participants) provided information for one or more outcomes. Only one trial was at low risk of bias in all domains. All other trials were at high risk of bias in one or more domains. Overall, all the evidence was very low quality. Thirty-five trials included only participants with non-alcohol related steatohepatitis (NASH) (based on biopsy confirmation). Five trials included only participants with diabetes mellitus; 14 trials included only participants without diabetes mellitus. The follow-up in the trials ranged from one month to 24 months.We present here only the comparisons of active intervention versus no intervention in which two or more trials reported at least one of the following outcomes: mortality at maximal follow-up, serious adverse events, and health-related quality of life, the outcomes that determine whether a treatment should be used. Antioxidants versus no interventionThere was no mortality in either group (87 participants; 1 trial; very low quality evidence). None of the participants developed serious adverse events in the trial which reported the proportion of people with serious adverse events (87 participants; 1 trial; very low quality evidence). There was no evidence of difference in the number of serious adverse events between antioxidants and no intervention (rate ratio 0.89, 95% CI 0.36 to 2.19; 254 participants; 2 trials; very low quality evidence). None of the trials reported health-related quality of life. Bile acids versus no interventionThere was no evidence of difference in mortality at maximal follow-up (OR 5.11, 95% CI 0.24 to 107.34; 659 participants; 4 trials; very low quality evidence), proportion of people with serious adverse events (OR 1.56, 95% CI 0.84 to 2.88; 404 participants; 3 trials; very low quality evidence), or the number of serious adverse events (rate ratio 1.01, 95% CI 0.66 to 1.54; 404 participants; 3 trials; very low quality evidence) between bile acids and no intervention. None of the trials reported health-related quality of life. Thiazolidinediones versus no interventionThere was no mortality in either group (74 participants; 1 trial; very low quality evidence). None of the participants developed serious adverse events in the two trials which reported the proportion of people with serious adverse events (194 participants; 2 trials; very low quality evidence). There was no evidence of difference in the number of serious adverse events between thiazolidinediones and no intervention (rate ratio 0.25, 95% CI 0.06 to 1.05; 357 participants; 3 trials; very low quality evidence). None of the trials reported health-related quality of life. Source of fundingTwenty-six trials were partially- or fully-funded by pharmaceutical companies that would benefit, based on the results of the trial. Twelve trials did not receive any additional funding or were funded by parties with no vested interest in the results. The source of funding was not provided in 39 trials.

Authors' conclusions: Due to the very low quality evidence, we are very uncertain about the effectiveness of pharmacological treatments for people with NAFLD including those with steatohepatitis. Further well-designed randomised clinical trials with sufficiently large sample sizes are necessary.

PubMed Disclaimer

Conflict of interest statement

This review is independent research funded by the National Institute for Health Research (NIHR Cochrane Programme Grants, 13/89/03 ‐ Evidence‐based diagnosis and management of upper digestive, hepato‐biliary, and pancreatic disorders). The views expressed in this publication are those of the authors and not necessarily those of the National Health Service (NHS), the NIHR, or the Department of Health.

Kurinchi Gurusamy and Brian Davidson have no financial disclosures. Emmanuel Tsochatzis has participated in advisory boards for Astra Zeneca and ViiV Helthcare. Astellas funded Douglas Thorburn for his attendance at the International Liver Transplantation Society meeting in 2014. Douglas Thorburn has also received GBP 25,000 from Boston Scientific to fund a clinical research fellow in 2013. There are no other financial disclosures to report.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Trial Sequential Analysis (TSA) for adverse events (proportion) and cirrhosis for different comparisons. TSA was performed using an alpha error of 2.5% for adverse events (proportion) and 2% for cirrhosis, power of 90% (10% beta error), 20% relative risk reduction (RRR), control group proportion (Pc) observed in the trials, and the diversity observed in the meta‐analysis. The trial sequential monitoring boundaries were not drawn because the accrued sample sizes (adverse events (proportion): bile acids versus no intervention = 230 participants; adverse events (proportion): bile acids versus antioxidants = 289 participants; cirrhosis: thiazolidinediones versus no intervention = 121 participants) were only fractions of the diversity‐adjusted required information size (DARIS) (adverse events (proportion): bile acids versus no intervention = 52,522 participants; adverse events (proportion): bile acids versus no intervention = 6141 participants; cirrhosis: thiazolidinediones versus no intervention = 67,859 participants). The cumulative Z‐curve (blue line) does not cross the conventional P boundary (dotted green lines). There was a high risk of random error in all comparisons.
5
5
Trial Sequential Analysis (TSA) for adverse events (proportion) and cirrhosis for different comparisons. TSA was performed using an alpha error of 2%, 90% power (10% beta error), 20% relative risk reduction (RRR), control group proportion (Pc = 12.9%) observed in the trials, and the diversity‐observed in the meta‐analysis. The trial sequential monitoring boundaries were not drawn because the accrued sample sizes (antioxidants versus no intervention = 299 participants; sulphonylureas versus no intervention = 123 participants; thiazolidinediones versus no intervention = 272 participants) were only fractions of the diversity adjusted required information size (DARIS) (antioxidants versus no intervention = 8028 participants; sulphonylureas versus no intervention = 11,394 participants; thiazolidinediones versus no intervention = 39,680 participants). The cumulative Z‐curve (blue line) does not cross the conventional P boundary (dotted green lines). There was a high risk of random error in all comparisons.
6
6
The network plots showing the comparisons in mortality at maximal follow‐up. The size of the node (circle) provides a measure of the number of trials in which the particular treatment was included as one of the arms. The thickness of the line provides a measure of the number of direct comparisons between two nodes (treatments). Abbreviation: ACE inhibitors = angiotensin‐converting enzyme inhibitors
1.1
1.1. Analysis
Comparison 1 All studies, Outcome 1 Mortality at maximal follow‐up.
1.2
1.2. Analysis
Comparison 1 All studies, Outcome 2 Serious adverse events (proportion).
1.3
1.3. Analysis
Comparison 1 All studies, Outcome 3 Serious adverse events (number of events).
1.4
1.4. Analysis
Comparison 1 All studies, Outcome 4 Adverse events (proportion).
1.5
1.5. Analysis
Comparison 1 All studies, Outcome 5 Adverse events (number of events).
1.6
1.6. Analysis
Comparison 1 All studies, Outcome 6 Cirrhosis.
1.7
1.7. Analysis
Comparison 1 All studies, Outcome 7 Resolution of fatty liver disease.
2.1
2.1. Analysis
Comparison 2 Non‐alcohol related steatohepatitis only, Outcome 1 Serious adverse events (proportion).
2.2
2.2. Analysis
Comparison 2 Non‐alcohol related steatohepatitis only, Outcome 2 Serious adverse events (number of events).
2.3
2.3. Analysis
Comparison 2 Non‐alcohol related steatohepatitis only, Outcome 3 Adverse events (proportion).
2.4
2.4. Analysis
Comparison 2 Non‐alcohol related steatohepatitis only, Outcome 4 Adverse events (number of events).
2.5
2.5. Analysis
Comparison 2 Non‐alcohol related steatohepatitis only, Outcome 5 Cirrhosis.
2.6
2.6. Analysis
Comparison 2 Non‐alcohol related steatohepatitis only, Outcome 6 Resolution of fatty liver disease.
3.1
3.1. Analysis
Comparison 3 People with diabetes mellitus only, Outcome 1 Serious adverse events (proportion).
3.2
3.2. Analysis
Comparison 3 People with diabetes mellitus only, Outcome 2 Serious adverse events (number of events).
3.3
3.3. Analysis
Comparison 3 People with diabetes mellitus only, Outcome 3 Adverse events (proportion).
3.4
3.4. Analysis
Comparison 3 People with diabetes mellitus only, Outcome 4 Adverse events (number of events).
4.1
4.1. Analysis
Comparison 4 People without diabetes mellitus only, Outcome 1 Serious adverse events (proportion).
4.2
4.2. Analysis
Comparison 4 People without diabetes mellitus only, Outcome 2 Serious adverse events (number of events).
4.3
4.3. Analysis
Comparison 4 People without diabetes mellitus only, Outcome 3 Adverse events (proportion).
4.4
4.4. Analysis
Comparison 4 People without diabetes mellitus only, Outcome 4 Adverse events (number of events).
4.5
4.5. Analysis
Comparison 4 People without diabetes mellitus only, Outcome 5 Cirrhosis.
4.6
4.6. Analysis
Comparison 4 People without diabetes mellitus only, Outcome 6 Resolution of fatty liver disease.
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    1. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, et al. Efficacy and safety of the farnesoid x receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013;145(3):574‐82.e1. - PubMed
Nar 2009 {published data only}
    1. Nar A, Gedik O. The effect of metformin on leptin in obese patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Acta Diabetologica 2009;46(2):113‐8. - PubMed
Nelson 2009 {published data only}
    1. Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo‐controlled trial. Journal of Clinical Gastroenterology 2009;43(10):990‐4. - PubMed
Neuschwander‐Tetri 2015 {published data only}
    1. Chalasani NP, Loomba R, Terrault N, McCullough AJ, Abdelmalek MF, Kowdley KV, et al. Longitudinal changes in fib‐4 and improvement in fibrosis stage with obeticholic acid: a secondary analysis of flint trial. Hepatology (Baltimore, Md.) 2015;62:332A‐3A.
    1. Hameed B, Terrault N, Gill R, Loomba R, Chalasani N, Hoofnagle JH, et al. Separate and combined effects of obeticholic acid and weight loss in nonalcoholic steatohepatitis (NASH). Journal of Hepatology 2015;62:S271.
    1. Hameed B, Terrault N, Gill RM, Loomba R, Chalasani NP, Hoofnagle JH, et al. Clinical and metabolic effects associated with weight loss and obeticholic acid in nonalcoholic steatohepatitis (NASH). Hepatology (Baltimore, Md.) 2015;62:331A.
    1. Kowdley KV, Abdelmalek MF, McCullough A, Loomba R, Hameed B, Chalasani NP, et al. Evaluation of effects of concomitant medications for NASH and associated comorbidities on histological improvements with obeticholic acid. Gastroenterology 2016;150(4 Supple 1):S1144.
    1. Kowdley KV, Abdelmalek MF, McCullough AJ, Loomba R, Hameed B, Chalasani NP, et al. Evaluation of effects of concomitant medications for non‐alcoholic steatohepatitis and associated comorbidities on histological improvements with obeticholic acid. Journal of Hepatology 2016;1:S487‐8.
Omer 2010 {published data only}
    1. Omer Z, Cetinkalp S, Akyildiz M, Yilmaz F, Batur Y, Yilmaz C, et al. Efficacy of insulin‐sensitizing agents in nonalcoholic fatty liver disease. European Journal of Gastroenterology & Hepatology 2010;22(1):18‐23. - PubMed
Parikh 2016 {published data only}
    1. Parikh P. An open label randomized control study to compare the efficacy of vitamin E versus ursodeoxycholic acid in non‐diabetic Indian NAFLD patients. Clinical Gastroenterology and Hepatology 2015;13(7):E105‐E6. - PMC - PubMed
    1. Parikh P, Ingle M, Patel J, Bhate P, Pandey V, Sawant P. An open‐label randomized control study to compare the efficacy of vitamin E versus ursodeoxycholic acid in nondiabetic and noncirrhotic Indian NAFLD patients. Saudi Journal of Gastroenterology 2016;22(3):192‐7. - PMC - PubMed
    1. Parikh P, Sawant P, Ingle M. An open label randomized control study to compare the efficacy of vitamin E versus ursodeoxycholic acid in non diabetic Indian NAFLD patients. Hepatology International 2015;9(Suppl 1):S110‐1. - PMC - PubMed
Polyzos 2011 {published data only}
    1. Polyzos SA, Kountouras J, Zafeiriadou E, Patsiaoura K, Katsiki E, Deretzi G, et al. Effect of spironolactone and vitamin E on serum metabolic parameters and insulin resistance in patients with nonalcoholic fatty liver disease. Journal of the Renin‐Angiotensin‐Aldosterone System 2011;12(4):498‐503. - PubMed
Ratziu 2008 {published data only}
    1. Lemoine M, Serfaty L, Cervera P, Capeau J, Ratziu V. Hepatic molecular effects of rosiglitazone in human non‐alcoholic steatohepatitis suggest long‐term pro‐inflammatory damage. Hepatology Research 2014;44(12):1241‐7. - PubMed
    1. Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann‐Heurtier A, Serfaty L, et al. Rosiglitazone for nonalcoholic steatohepatitis: one‐year results of the randomized placebo‐controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial. Gastroenterology 2008;135(1):100‐10. - PubMed
Ratziu 2011 {published data only}
    1. Ratziu V, Ledinghen V, Oberti F, Mathurin P, Wartelle‐Bladou C, Renou C, et al. A multicentric, double‐blind, randomised‐controlled trial (RCT) of high dose ursodeoxycholic acid in patients with non‐alcoholic steatohepatitis (NASH). Journal of Hepatology 2009;50:S21.
    1. Ratziu V, Ledinghen V, Oberti F, Mathurin P, Wartelle‐Bladou C, Renou C, et al. A randomized controlled trial of high‐dose ursodesoxycholic acid for nonalcoholic steatohepatitis. Journal of Hepatology 2011;54(5):1011‐9. - PubMed
Ratziu 2014 {published data only}
    1. Ratziu V, Bedossa P, Francque SM, Larrey D, Aithal GP, Serfaty L, et al. Lack of efficacy of an inhibitor of pde4 in phase 1 and 2 trials of patients with nonalcoholic steatohepatitis. Clinical Gastroenterology and Hepatology 2014;12(10):1724‐U202. - PubMed
Ratziu 2016 {published data only}
    1. Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an agonist of the peroxisome proliferator‐activated receptor‐alpha and ‐delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016;150(5):1147‐59. - PubMed
Razavizade 2013 {published data only}
    1. Razavizade M, Jamali R, Arj A, Matini SM, Moraveji A, Taherkhani E. The effect of pioglitazone and metformin on liver function tests, insulin resistance, and liver fat content in nonalcoholic fatty liver disease: a randomized double blinded clinical trial. Hepatitis Monthly 2013;13(5):e9270. - PMC - PubMed
    1. Razavizadeh M, Arj A. Comparison of the therapeutic effects of pioglitazone and metformin in nonalcoholic steatohepatitis. Journal of Gastroenterology and Hepatology 2012;27:247.
Razavizadeh 2012 {published data only}
    1. Razavizadeh M, Arj A. Comparison of the therapeutic effects of vitamin E and silimarin in nonalcoholic steatohepatitis. Journal of Gastroenterology and Hepatology 2012;27:270.
Safadi 2014 {published data only}
    1. Safadi R, Konikoff FM, Mahamid M, Zelber‐Sagi S, Halpern M, Gilat T, et al. The fatty acid‐bile acid conjugate aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clinical Gastroenterology and Hepatology 2014;12(12):2085‐91. - PubMed
Santos 2003 {published data only}
    1. Santos VN, Lanzoni VP, Szejnfeld J, Shigueoka D, Parise ER. A randomized double‐blind study of the short‐time treatment of obese patients with nonalcoholic fatty liver disease with ursodeoxycholic acid. Brazilian Journal of Medical and Biological Research 2003;36(6):723‐9. - PubMed
Sanyal 2004 {published data only}
    1. Sanyal AJ, Mofrad PS, Contos MJ, Sargeant C, Luketic VA, Sterling RK, et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clinical Gastroenterology and Hepatology 2004;2(12):1107‐15. - PubMed
Sanyal 2010 {published data only}
    1. Corey K, Vuppalanchi R, Wilson L, Cummings O, Chalasani NP. Nash resolution is associated with improvements in HDL and triglycerides but not in LDL or non‐HDL‐C. Hepatology (Baltimore, Md) 2014;60:224A‐5A.
    1. Corey KE, Vuppalanchi R, Vos M, Kohli R, Molleston JP, Wilson L, et al. Improvement in liver histology is associated with reduction in dyslipidemia in children with nonalcoholic fatty liver disease. Journal of Pediatric Gastroenterology and Nutrition 2015;60(3):360‐7. - PMC - PubMed
    1. Guy CD, Suzuki A, Abdelmalek MF, Burchette JL, Diehl AM. Treatment response in the PIVENS trial is associated with decreased hedgehog pathway activity. Hepatology (Baltimore, Md.) 2015;61(1):98‐107. - PMC - PubMed
    1. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. New England Journal of Medicine 2010;362(18):1675‐85. - PMC - PubMed
Sharma 2012 {published data only}
    1. Sharma BC, Kumar A, Garg V, Reddy RS, Sakhuja P, Sarin SK. A randomized controlled trial comparing efficacy of pentoxifylline and pioglitazone on metabolic factors and liver histology in patients with non‐alcoholic steatohepatitis. Journal of Clinical and Experimental Hepatology 2012;2(4):333‐7. - PMC - PubMed
Shields 2009 {published data only}
    1. Shields WW, Thompson KE, Grice GA, Harrison SA, Coyle WJ. The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): A pilot trial. Therapeutic Advances in Gastroenterology 2009;2(3):157‐63. - PMC - PubMed
Shiffman 2015 {published data only}
    1. Shiffman M, Freilich B, Vuppalanchi R, Watt K, Burgess G, Morris M, et al. A placebo‐controlled, multicenter, double‐blind, randomised trial of emricasan in subjects with non‐alcoholic fatty liver disease (NAFLD) and raised transaminases. Journal of Hepatology 2015;62:S282.
Siddique 2015 {published data only}
    1. Siddique KU, Reddy H, Rana H, Singhal S, Parihar A, Pandey A. A comparative study of effect of insulin sensitizers and statins in nonalcoholic fatty liver disease (NAFLD). Diabetes 2015;64:A661.
Sofer 2011 {published data only}
    1. Sofer E, Boaz M, Matas Z, Mashavi M, Shargorodsky M. 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: Clinical and Experimental 2011;60(9):1278‐84. - PubMed
    1. Sofer E, Shargorodsky M. Effect of metformin treatment on circulating osteoprotegerin in patients with nonalcoholic fatty liver disease. Hepatology International 2016;10(1):169‐74. - PubMed
    1. Soifer E, Gavish D, Shargorodsky M. Does metformin treatment influence bone formation in patients with nonalcoholic fatty liver disease?. Hormone & Metabolic Research 2015;47(8):556‐9. - PubMed
Solhi 2014 {published data only}
    1. Solhi H, Ghahremani R, Kazemifar AM, Yazdi ZH. Silymarin in treatment of non‐alcoholic steatohepatitis: a randomized clinical trial. Caspian Journal of Internal Medicine 2014;5(1):9‐12. - PMC - PubMed
Song 2014 {published data only}
    1. Song XX, Jiang T, Kang K, Wen Z. Efficacy of sitagliptin combined with metformin in the initial treatment of type 2 diabetes with non‐alcoholic fatty liver. Chinese Journal of New Drugs 2014;23(2):215‐8.
Stefan 2014 {published data only}
    1. Stefan N, Ramsauer M, Jordan P, Nowotny B, Kantartzis K, Machann J, et al. Inhibition of 11 beta‐hsd1 with ro5093151 for non‐alcoholic fatty liver disease: a multicentre, randomised, double‐blind, placebo‐controlled trial. Lancet Diabetes & Endocrinology 2014;2(5):406‐16. - PubMed
Stilidi 2014 {published data only}
    1. Stilidi EI, Klyaritskay IL. Effect of ursodeoxycholic acid or ursodeoxycholic acid combined with losartan for treatment of non‐alcoholic steatohepatitis. Journal of Hepatology 2014;60(1 Suppl):S334.
Sunny 2015 {published data only}
    1. Sunny N, Bril F, Kalavalapalli S, Sanchez PP, Maximos M, Biernacki D, et al. Pioglitazone therapy improves insulin suppression of branched chain amino acids in patients with prediabetes or T2DM and NAFLD. Diabetes 2015;64:A341.
Taghvaei 2013 {published data only}
    1. Taghvaei T, Bahar A, Hosseini V, Maleki I, Kasrai M. Efficacy of silymarin on treatment of nonalcoholic steatohepatitis. Journal of Mazandaran University of Medical Sciences 2013;23(98):164‐71.
Torres 2011 {published data only}
    1. Torres D, Jones FJ, Shaw J, Williams C, Ward JA, Harrison SA. Open‐label prospective randomized 48 week clinical trial: rosiglitazone versus rosiglitazone and metformin (avandamet) versus rosiglitazone and losartan in the treatment of non‐alcoholic steatohepatitis (NASH). Journal of Hepatology 2011;54:S7‐8. - PubMed
    1. Torres DM, Jones FJ, Shaw JC, Williams CD, Ward JA, Harrison SA. Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12‐month randomized, prospective, open‐ label trial. Hepatology (Baltimore, Md.) 2011;54(5):1631‐9. - PubMed
Uygun 2004 {published data only}
    1. Uygun A, Kadayifci A, Isik AT, Ozgurtas T, Deveci S, Tuzun A, et al. Metformin in the treatment of patients with non‐alcoholic steatohepatitis. Alimentary Pharmacology & Therapeutics 2004;19(5):537‐44. - PubMed
Van Wagner 2011 {published data only}
    1. Wagner LB, Koppe SWP, Brunt EM, Gottstein J, Gardikiotes K, Green RM, et al. Pentoxifylline for the treatment of non‐alcoholic steatohepatitis: a randomized controlled trial. Annals of Hepatology 2011;10(3):277‐86. - PubMed
Wang 2015 {published data only}
    1. Wang X, Zhao B, Cheng Y, Bu L, Qu S. Sitagliptin decreases intrahepatic lipid accumulation in diabetic patients with NAFLD. Diabetes 2015;64:A620‐1.
Yaginuma 2009 {published data only}
    1. Yaginuma R, Ikejima K, Kon K, Okumura K, Yamashina S, Suzuki S, et al. Efficacy of low‐dose pioglitazone for the treatment of NAFLD patients in japan. Hepatology (Baltimore, Md.) 2009;50:793A‐4A.
Yan 2015 {published data only}
    1. Yan H, Xia M, Chang X, Bian H, Lin H, Zhang L, et al. Berberine vs. pioglitazone for treatment of nonalcoholic fatty liver disease and its associated impaired glucose metabolism. Diabetes 2014;63:A513‐4.
    1. Yan HM, Xia MF, Wang Y, Chang XX, Yao XZ, Rao SX, et al. Efficacy of berberine in patients with non‐alcoholic fatty liver disease. PLoS ONE 2015;10(8):e0134172. - PMC - PubMed

References to studies excluded from this review

Abenavoli 2013 {published data only}
    1. Abenavoli L, Nazionale I, Greco M, Larussa T, Suraci E, Imeneo M, et al. Metabolic effects of diet vs diet and silybin combined with phosphatidylcholine and vitamin E in overweight patients with non‐alcoholic fatty liver disease. Digestive and Liver Disease 2013;45:S165‐6.
Abenavoli 2015 {published data only}
    1. Abenavoli L, Greco M, Nazionale I, Peta V, Milic N, Accattato F, et al. Effects of Mediterranean diet supplemented with silybin‐vitamin E‐phospholipid complex in overweight patients with non‐alcoholic fatty liver disease. Expert Review of Gastroenterology & Hepatology 2015;9(4):519‐27. - PubMed
Acquati 2007 {published data only}
    1. Acquati S, Silvani G, Bondi A, Cicognani R, Bondi G, Gagliardi L, et al. Beyond glycated haemoglobin: effectiveness of rosiglitazone in type‐2 diabetes with hypertension and non‐alcoholic fatty liver. A randomized controlled one‐year study. Atherosclerosis Supplements 2007;8(1):191.
Athyros 2011 {published data only}
    1. Athyros VG, Giouleme O, Ganotakis ES, Elisaf M, Tziomalos K, Vassiliadis T, et al. Safety and impact on cardiovascular events of long‐term multifactorial treatment in patients with metabolic syndrome and abnormal liver function tests: a post hoc analysis of the randomised attempt study. Archives of Medical Science 2011;7(5):796‐805. - PMC - PubMed
Carnelutti 2012 {published data only}
    1. Carnelutti A, Donnini D, Nadalutti G, Luca L, Cappello D, Cugini F, et al. Effect of statin therapy vs diet in hypercholesterolemic patients affected by nonalcoholic steatohepatitis (NASH). Digestive and Liver Disease 2012;44:S25‐6.
Corey 2015a {published data only}
    1. Corey KE, Vuppalanchi R, Wilson LA, Cummings OW, Chalasani N, Nash CRN. Nash resolution is associated with improvements in HDL and triglyceride levels but not improvement in LDL or non‐HDL‐C levels. Alimentary Pharmacology & Therapeutics 2015;41(3):301‐9. - PMC - PubMed
Dajani 2015 {published data only}
    1. Dajani AIM, Abu Hammour AM, Zakaria MA, Al Jaberi MR, Nounou MA, Semrin AIM. Essential phospholipids as a supportive adjunct in the management of patients with NAFLD. Arab Journal of Gastroenterology 2015;16(3‐4):99‐104. - PubMed
Faghihzadeh 2014 {published data only}
    1. Faghihzadeh F, Adibi P, Rafiei R, Hekmatdoost A. Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease. Nutrition Research 2014;34(10):837‐43. - PubMed
Fan 2010 {published data only}
    1. Fan XF, Deng YQ, Ye L, Li YD, Chen J, Lu WW, et al. Effect of xuezhikang capsule on serum tumor necrosis factor‐alpha and interleukin‐6 in patients with nonalcoholic fatty liver disease and hyperlipidemia. Chinese Journal of Integrative Medicine 2010;16(2):119‐23. - PubMed
Fan 2013 {published data only}
    1. Fan H, Pan Q, Xu Y, Yang X. Exenatide improves type 2 diabetes concomitant with non‐alcoholic fatty liver disease. Arquivos Brasileiros de Endocrinologia e Metabologia 2013;57(9):702‐8. - PubMed
Gastaldelli 2015 {published data only}
    1. Gastaldelli A, Tripathy D, Gaggini M, Musi N, DeFronzo RA. Improvement in hepatic metabolism is associated with reduced conversion to diabetes in IGT subjects treated with pioglitazone (act now study). Diabetologia 2015;58(Suppl 1):S164.
Han 2012 {published data only}
    1. Han KH, Rha SW, Kang HJ, Bae JW, Choi BJ, Choi SY, et al. Evaluation of short‐term safety and efficacy of HMG‐CoA reductase inhibitors in hypercholesterolemic patients with elevated serum alanine transaminase concentrations: PITCH study (PITavastatin versus atorvastatin to evaluate the effect on patients with hypercholesterolemia and mild to moderate hepatic damage). Journal of Clinical Lipidology 2012;6(4):340‐51. - PubMed
Han 2014a {published data only}
    1. Han Y, Shi JP, Ma AL, Xu Y, Ding XD, Fan JG. Randomized, vitamin E‐controlled trial of bicyclol plus metformin in non‐alcoholic fatty liver disease patients with impaired fasting glucose. Clinical Drug Investigation 2014;34(1):1‐7. - PubMed
Idilman 2008 {published data only}
    1. Idilman R, Mizrak D, Corapcioglu D, Bektas M, Doganay B, Sayki M, et al. Clinical trial: Insulin‐sensitizing agents may reduce consequences of insulin resistance in individuals with non‐alcoholic steatohepatitis. Alimentary Pharmacology & Therapeutics 2008;28(2):200‐8. - PubMed
Jaafari 2012 {published data only}
    1. Jaafari Haidarlo A, Rashidbeygi M, Ehsanbakhsh S. Vitamin E, pioglitazone and diet therapy for patients with nonalcoholic fatty liver disease (NAFLD): evaluation of treatment. Journal of Hepatology 2012;56(Suppl 2):S507.
Kowdley 2015 {published data only}
    1. Kowdley KV, Wilson LA, Natta ML, Pai RK, Sanyal AJ. Efficacy and safety of vitamin E for nonalcoholic steatohepatitis: Combined analysis of three controlled trials. Journal of Hepatology 2015;62:S268.
Kowdley 2015a {published data only}
    1. Kowdley KV, Wilson LA, Natta ML, Pai RK, Sanyal AJ. Efficacy and safety of vitamin E in nonalcoholic steatohepatitis patients with and without diabetes: pooled analysis from the PIVENS and FLINT NIDDK NASH CRN trials. Hepatology (Baltimore, Md.) 2015;62:264A.
Li 2015 {published data only}
    1. Li YH, Yang LH, Sha KH, Liu TG, Zhang LG, Liu XX. Efficacy of poly‐unsaturated fatty acid therapy on patients with nonalcoholic steatohepatitis. World Journal of Gastroenterology 2015;21(22):7008‐13. - PMC - PubMed
Lo 2016 {published data only}
    1. Lo J, Lu MT, Kim EA, Nou E, Hallett TR, Park J, et al. Statin effects to reduce hepato steatosis as measured by computed tomography in patients with human immunodeficiency virus. Open Forum Infectious Diseases 2016;3(2):ofw062. - PMC - PubMed
McCormick 2015 {published data only}
    1. McCormick KG, Scorletti E, Bhatia L, Calder PC, Griffin MJ, Clough GF, et al. Impact of high dose n‐3 polyunsaturated fatty acid treatment on measures of microvascular function and vibration perception in non‐alcoholic fatty liver disease: Results from the randomised welcome trial. Diabetologia 2015;58(8):1916‐25. - PubMed
Merat 2015 {published data only}
    1. Merat S, Poustchi H, Hemming K, Jafari E, Radmard AR, Nateghi A, et al. Polypill for prevention of cardiovascular disease in an urban Iranian population with special focus on nonalcoholic steatohepatitis: a pragmatic randomized controlled trial within a cohort (polyiran ‐ liver) ‐ study protocol. Archives of Iranian Medicine 2015;18(8):515‐23. - PubMed
Oh 2016 {published data only}
    1. Oh B, Choi WS, Park SB, Cho B, Yang YJ, Lee ES, et al. Efficacy and safety of ursodeoxycholic acid composite on fatigued patients with elevated liver function and/or fatty liver: a multi‐centre, randomised, double‐blinded, placebo‐controlled trial. International Journal of Clinical Practice 2016;70(4):302‐11. - PMC - PubMed
Scorletti 2014 {published data only}
    1. Scorletti E, Bhatia L, McCormick KG, Clough GF, Nash K, Hodson L, et al. Effects of purified eicosapentaenoic and docosahexaenoic acids in nonalcoholic fatty liver disease: results from the Welcome* study. Hepatology (Baltimore, Md.) 2014;60(4):1211‐21. - PubMed
Scorletti 2015 {published data only}
    1. Scorletti E, West AL, Bhatia L, Hoile SP, McCormick KG, Burdge GC, et al. Treating liver fat and serum triglyceride levels in NAFLD, effects of pnpla3 and tm6sf2 genotypes: results from the Welcome trial. Journal of Hepatology 2015;63(6):1476‐83. - PubMed
Shiasi 2014 {published data only}
    1. Shiasi Arani K, Taghavi Ardakani A, Moazami Goudarzi R, Talari HR, Hami K, Akbari H, et al. Effect of vitamin E and metformin on fatty liver disease in obese children‐ randomized clinical trial. Iranian Journal of Public Health 2014;43(10):1417‐23. - PMC - PubMed
Sultana 2012 {published data only}
    1. Sultana SS, Amin F, Rahman A, Afsana F. A comparative study with metformin and pioglitazone versus metformin alone in nonalcoholic fatty liver disease in newly detected glucose intolerant patients. Diabetologia 2012;55:S500.
Talebi 2015 {published data only}
    1. Talebi Pour B, Jameshorani M, Salmani R, Chiti H. The effect of chlorella vulgaris vs. Artichoke on patients with non‐alcoholic fatty liver disease (NAFLD): a randomized clinical trial. Journal of Zanjan University of Medical Sciences and Health Services 2015;23(100):36‐44.
Tan 2011 {published data only}
    1. Tan HH, Low ASC, Lim KH, Wan WK, Goh BB, Wang YT, et al. A randomized, unblinded pilot trial of essential phospholipids in Chinese subjects with nonalcoholic fatty liver disease (NASH). Journal of Gastroenterology and Hepatology 2011;26:162.
Taniai 2009 {published data only}
    1. Taniai M, Hashimoto E, Tobari M, Yatsuji S, Haruta I, Tokushige K, et al. Treatment of nonalcoholic steatohepatitis with colestimide. Hepatology Research 2009;39(7):685‐93. - PubMed
Tsuchiya 2011 {published data only}
    1. Tsuchiya M. Alogliptin decreases liver fat content in patients with IGT or type Q2 DM: comparing alogliptin and voglibose. Diabetes 2011;60:A595.
Vos 2016 {published data only}
    1. Vos M, Jin R, Welsh J, Konomi J, Karpen SJ, Soler‐Rodriquez D, et al. Losartan improves hepatic inflammation in children with non‐alcoholic fatty liver disease. Gastroenterology 2016;150(4):S1036.
Wang 2013 {published data only}
    1. Wang Q, Lao J, Zou X, Huang Y. Clinical effect of metformin combined with reduced glutathione in non‐alcoholic fatty liver disease. Journal of Gastroenterology and Hepatology 2013;28:186.
Zelber‐Sagi 2006 {published data only}
    1. Zelber‐Sagi S, Kessler A, Brazowsky E, Webb M, Lurie Y, Santo M, et al. A double‐blind randomized placebo‐controlled trial of orlistat for the treatment of nonalcoholic fatty liver disease. Clinical Gastroenterology & Hepatology 2006;4(5):639‐44. - PubMed
    1. Zelber‐Sagi S, Kessler A, Brazowsky E, Webb M, Lurie Y, Santo M, et al. Randomized placebo‐controlled trial of orlistat for the treatment of patients with non alcoholic fatty liver disease (NAFLD). Hepatology (Baltimore, Md) 2004;40(4 Supl 1):237a. - PubMed

Additional references

Abdelmalek 2007
    1. Abdelmalek MF, Diehl AM. Nonalcoholic fatty liver disease as a complication of insulin resistance. Medical Clinics of North America 2007;91(6):1125‐49, ix. - PubMed
Abenavoli 2013a
    1. Abenavoli L, Bellentani S. Milk thistle to treat non‐alcoholic fatty liver disease: dream or reality?. Expert Review of Gastroenterology & Hepatology 2013;7(8):677‐9. - PubMed
Adams 2005
    1. Adams LA, Lymp JF, Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease: a population‐based cohort study. Gastroenterology 2005;129(1):113‐21. - PubMed
Adorini 2012
    1. Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discovery Today 2012;17(17‐18):988‐97. - PubMed
Alberti 2009
    1. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120(16):1640‐5. - PubMed
Angulo 2015
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Anstee 2012
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Ballestri 2016
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Bedogni 2005
    1. Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology (Baltimore, Md.) 2005;42(1):44‐52. - PubMed
Bedogni 2007
    1. Bedogni G, Miglioli L, Masutti F, Castiglione A, Croce LS, Tiribelli C, et al. Incidence and natural course of fatty liver in the general population: the Dionysos study. Hepatology (Baltimore, Md.) 2007;46(5):1387‐91. - PubMed
Buzetti 2017
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