{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T06:20:54Z","timestamp":1779344454750,"version":"3.51.4"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T00:00:00Z","timestamp":1616544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To comprehensively evaluate and compare the therapeutic effects of various hypoglycemic agents in NAFLD patients with or without diabetes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>All literature from the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and Clinical Trials was searched, and the language was limited to English. Two reviewers independently assessed study eligibility, continuous data extraction, and independent assessment of bias risk. Our primary outcomes were alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride levels, while our secondary outcomes were high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels, body weight, BMI, and fasting glucose and glycosylated hemoglobin (HbA1c) levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The review identified 20 eligible trials that met the inclusion criteria. We found that, compared to other drugs, thiazolidinediones, especially pioglitazone, had a greater effect on the levels of ALT (-8.01 (95% CI -14.3 to 2.02)) and AST (-5.0 (95% CI -9.21 to -1,22)) and other biological indicators, but they were also associated with an increased risk of weight gain (3.62 (95% CI 2.25 to 4.99) and increased BMI (0.59 (95% Cl -0.13 to 1.29). GLP1 RAs and metformin also had better therapeutic effects than other drugs as measured by the levels of ALT (liraglutide: -9.36 (95% Cl -18 to -0.34), metformin: -2.84 (95% CI -11.09 to 5.28)) and AST (liraglutide: -5.14 (95% CI -10.69 to 0.37), metformin: -2.39 (95% CI -7.55, 2.49)) and other biological indicators.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Despite the significant risk of weight gain, thiazolidinediones, especially pioglitazone, are beneficial in normalizing liver and glucose metabolism in NAFLD patients. In clinical practice, we believe that GLP1 RAs such as liraglutide and exenatide or metformin can be used in combination to offset the risk of weight gain associated with thiazolidinediones. However, long-term studies are still needed to verify the efficacy and safety of individual hypoglycemic agents.<\/jats:p><\/jats:sec><jats:sec><jats:title>Systematic Review Registration<\/jats:title><jats:p>[PROSPERO], identifier [CRD42020212025].<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2021.649018","type":"journal-article","created":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T06:04:45Z","timestamp":1616565885000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Efficacy of Various Hypoglycemic Agents in the Treatment of Patients With Nonalcoholic Liver Disease With or Without Diabetes\uff1a A Network Meta-Analysis"],"prefix":"10.3389","volume":"12","author":[{"given":"Jingxuan","family":"Lian","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianfang","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/nrgastro.2017.109","article-title":"Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention","volume":"15","author":"Younossi","year":"2018","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0140908","article-title":"The Prevalence of Non-Alcoholic Fatty Liver Disease in Children and Adolescents: A Systematic Review and Meta-Analysis","volume":"10","author":"Anderson","year":"2015","journal-title":"PloS One"},{"key":"B3","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.06.025","article-title":"Predicting the future burden of NAFLD and NASH","volume":"69","author":"Mahady","year":"2018","journal-title":"J Hepatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(18)30154-2","article-title":"Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies","volume":"7","author":"Stefan","year":"2019","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(17)30292-9","article-title":"Metabolically healthy obesity: the low-hanging fruit in obesity treatment","volume":"6","author":"Stefan","year":"2018","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-012615-044224","article-title":"Nonalcoholic Fatty Liver Disease: Pathogenesis and Disease Spectrum","volume":"11","author":"Hardy","year":"2016","journal-title":"Annu Rev Pathol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(13)70170-0","article-title":"Inhibition of 11\u03b2-HSD1 with RO5093151 for non-alcoholic fatty liver disease: a multicentre, randomised, double-blind, placebo-controlled trial","volume":"2","author":"Stefan","year":"2014","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.d5928","article-title":"The Cochrane Collaboration\u2019s tool for assessing risk of bias in randomised trials","volume":"343","author":"Higgins","year":"2011","journal-title":"BMJ"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2010.03.016","article-title":"Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial","volume":"64","author":"Sal","year":"2011","journal-title":"J Clin Epidemiol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.2337\/dc17-0518","article-title":"Comparison of Ipragliflozin and Pioglitazone Effects on Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes: A Randomized, 24-Week, Open-Label, Active-Controlled Trial","volume":"40","author":"Ito","year":"2017","journal-title":"Diabetes Care"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.2337\/dc19-0167","article-title":"Role of Vitamin E for Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes: A Randomized Controlled Trial","volume":"42","author":"Bril","year":"2019","journal-title":"Diabetes Care"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1097\/MEG.0000000000001369","article-title":"Treatment options for nonalcoholic fatty liver disease: a double-blinded randomized placebo-controlled trial","volume":"31","author":"Anushiravani","year":"2019","journal-title":"Eur J Gastroenterol Hepatol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)00803-X","article-title":"Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study","volume":"387","author":"Armstrong","year":"2016","journal-title":"Lancet"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2016.04.021","article-title":"Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial","volume":"65","author":"Cui","year":"2016","journal-title":"J Hepatol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.7326\/M15-1774","article-title":"Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial","volume":"165","author":"Cusi","year":"2016","journal-title":"Ann Intern Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-018-4675-2","article-title":"Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study","volume":"61","author":"Eriksson","year":"2018","journal-title":"Diabetologia"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1590\/s0004-27302013000900005","article-title":"Exenatide improves type 2 diabetes concomitant with non-alcoholic fatty liver disease","volume":"57","author":"Fan","year":"2013","journal-title":"Arq Bras Endocrinol Metabol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1111\/jdi.12888","article-title":"Effects of liraglutide, metformin and gliclazide on body composition in patients with both type 2 diabetes and non-alcoholic fatty liver disease: A randomized trial","volume":"10","author":"Feng","year":"2019","journal-title":"J Diabetes Investig"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.5812\/hepatmon.6099","article-title":"Effects of metformin, pioglitazone, and silymarin treatment on non-alcoholic Fatty liver disease: a randomized controlled pilot study","volume":"12","author":"Hajiaghamohammadi","year":"2012","journal-title":"Hepat Mon"},{"key":"B21","doi-asserted-by":"publisher","first-page":"259","DOI":"10.3390\/jcm9010259","article-title":"Ipragliflozin Additively Ameliorates Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Controlled with Metformin and Pioglitazone: A 24-Week Randomized Controlled Trial","volume":"9","author":"Han","year":"2020","journal-title":"J Clin Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1080\/00365520902845268","article-title":"Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial","volume":"44","author":"Haukeland","year":"2009","journal-title":"Scand J Gastroenterol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v23.i1.141","article-title":"Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebo-controlled trial","volume":"23","author":"Joy","year":"2017","journal-title":"World J Gastroenterol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24558","article-title":"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","volume":"54","author":"Torres","year":"2011","journal-title":"Hepatology"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa060326","article-title":"A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis","volume":"355","author":"Belfort","year":"2006","journal-title":"N Engl J Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0134172","article-title":"Efficacy of insulin-sensitizing agents in nonalcoholic fatty liver disease","volume":"10","author":"Omer","year":"2015","journal-title":"PloS One"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0134172","article-title":"Efficacy of Berberine in Patients with Non-Alcoholic Fatty Liver Disease","volume":"10","author":"Yan","year":"2015","journal-title":"PloS One"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.5812\/hepatmon.9270","article-title":"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","volume":"13","author":"Razavizade","year":"2013","journal-title":"Hepat Mon"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0907929","article-title":"Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis","volume":"362","author":"Sanyal","year":"2010","journal-title":"N Engl J Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/dom.13520","article-title":"Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease","volume":"21","author":"Shimizu","year":"2019","journal-title":"Diabetes Obes Metab"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-016-4100-7","article-title":"Twelve week liraglutide or sitagliptin does not affect hepatic fat in type 2 diabetes: a randomised placebo-controlled trial","volume":"59","author":"Smits","year":"2016","journal-title":"Diabetologia"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2011.01.011","article-title":"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","volume":"60","author":"Sofer","year":"2011","journal-title":"Metabolism"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20181304","article-title":"Efficacy of liraglutide in treating type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease","volume":"38","author":"Tian","year":"2018","journal-title":"Biosci Rep"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1097\/MEG.0000000000000981","article-title":"Comparison of fenofibrate and pioglitazone effects on patients with nonalcoholic fatty liver disease","volume":"29","author":"Yaghoubi","year":"2017","journal-title":"Eur J Gastroenterol Hepatol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30320","article-title":"Liraglutide, Sitagliptin, and Insulin Glargine Added to Metformin: The Effect on Body Weight and Intrahepatic Lipid in Patients With Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease","volume":"69","author":"Yan","year":"2019","journal-title":"Hepatology"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinre.2020.01.007","article-title":"Effect of liraglutide therapy on serum fetuin A in patients with type 2 diabetes and non-alcoholic fatty liver disease","volume":"44","author":"Zhang","year":"2020","journal-title":"Clin Res Hepatol Gastroenterol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2008.01.009","article-title":"Non-alcoholic fatty liver disease: the mist gradually clears","author":"de Alwis","year":"2008","journal-title":"J Hepatol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2008.10.010","article-title":"Epidemiology of non-alcoholic fatty liver disease in China","volume":"50","author":"Fan","year":"2009","journal-title":"J Hepatol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(19)30039-1","article-title":"Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: a systematic review and meta-analysis","volume":"4","author":"Li","year":"2019","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.03.039","article-title":"A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement","volume":"73","author":"Eslam","year":"2020","journal-title":"J Hepatol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1111\/dom.14304","article-title":"Pioglitazone and bariatric surgery are the most effective treatments for non-alcoholic steatohepatitis: A hierarchical network meta-analysis","author":"Panunzi","year":"2020","journal-title":"Diabetes Obes Metab"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27999","article-title":"Comparative effectiveness of pharmacological interventions for nonalcoholic steatohepatitis: A systematic review and network meta-analysis","volume":"62","author":"Singh","year":"2015","journal-title":"Hepatology"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(20)30110-8","article-title":"Causes, consequences, and treatment of metabolically unhealthy fat distribution","volume":"8","author":"Stefan","year":"2020","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1111\/apt.12149","article-title":"Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program","volume":"37","author":"Armstrong","year":"2013","journal-title":"Aliment Pharmacol Ther"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3350\/cmh.2020.0137","article-title":"Beneficial effect of anti-diabetic drugs for nonalcoholic fatty liver disease","volume":"26","author":"Kim","year":"2020","journal-title":"Clin Mol Hepatol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2036.2010.04467.x","article-title":"Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis","volume":"32","author":"Rakoski","year":"2010","journal-title":"Aliment Pharmacol Ther"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.11.004","article-title":"EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease","volume":"64","year":"2016","journal-title":"J Hepatol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29367","article-title":"The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases","volume":"67","author":"Chalasani","year":"2018","journal-title":"Hepatology"},{"key":"B49","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.diabres.2015.04.008","article-title":"Effect of sitagliptin on intrahepatic lipid content and body fat in patients with type 2 diabetes","volume":"109","author":"Kato","year":"2015","journal-title":"Diabetes Res Clin Pract"},{"key":"B50","article-title":"Efficacy and safety of sitagliptin for the treatment of nonalcoholic fatty liver disease with type 2 diabetes mellitus","volume":"61","author":"Fukuhara","year":"2014","journal-title":"Hepatogastroenterology"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.649018\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T06:04:47Z","timestamp":1616565887000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.649018\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,24]]},"references-count":50,"alternative-id":["10.3389\/fendo.2021.649018"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2021.649018","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,24]]},"article-number":"649018"}}