330
Views
0
CrossRef citations to date
0
Altmetric
Review

The role of glucagon-like peptide-1 receptor agonists in nonalcoholic fatty liver disease

, , & ORCID Icon
Pages 1063-1072 | Received 17 Jul 2023, Accepted 19 Oct 2023, Published online: 27 Oct 2023

References

  • Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American association for the study of liver diseases. Hepatology. 2018;67(1):328–357.
  • EASL, EASD, EASO. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol.2016;64(6):1388–1402.
  • Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34(3):274–285. doi: 10.1111/j.1365-2036.2011.04724.x
  • Henry L, Paik J, Younossi ZM. Review article: the epidemiologic burden of non-alcoholic fatty liver disease across the world. Aliment Pharmacol Ther. 2022;56(6):942–956. doi: 10.1111/apt.17158
  • Ng CH, Lim WH, Hui Lim GE, et al. Mortality outcomes by fibrosis stage in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2023;21(4):931–939 e935. doi: 10.1016/j.cgh.2022.04.014
  • Makri E, Goulas A, Polyzos SA. Epidemiology, pathogenesis, diagnosis and emerging treatment of nonalcoholic fatty liver disease. Arch Med Res. 2021;52(1):25–37. doi: 10.1016/j.arcmed.2020.11.010
  • Polyzos SA, Kechagias S, Tsochatzis EA. Review article: non-alcoholic fatty liver disease and cardiovascular diseases: associations and treatment considerations. Aliment Pharmacol Ther. 2021;54(8):1013–1025. doi: 10.1111/apt.16575
  • Polyzos SA, Kountouras J, Mantzoros CS. Obesity and nonalcoholic fatty liver disease: from pathophysiology to therapeutics. Metabolism. 2019;92:82–97. doi: 10.1016/j.metabol.2018.11.014
  • Mintziori G, Polyzos SA. Emerging and future therapies for nonalcoholic steatohepatitis in adults. Expert Opin Pharmacother. 2016;17(14):1937–1946. doi: 10.1080/14656566.2016.1225727
  • Athyros VG, Polyzos SA, Kountouras J, et al. Non-alcoholic fatty liver disease treatment in patients with type 2 diabetes mellitus; New kids on the block. Curr Vasc Pharmacol. 2020;18(2):172–181. doi: 10.2174/1570161117666190405164313
  • Bernsmeier C, Meyer-Gerspach AC, Blaser LS, et al. Glucose-induced glucagon-like peptide 1 secretion is deficient in patients with non-alcoholic fatty liver disease. PLoS One. 2014;9(1):e87488. doi: 10.1371/journal.pone.0087488
  • Barritt A, Marshman E, Noureddin M. Review article: role of glucagon-like peptide-1 receptor agonists in non-alcoholic steatohepatitis, obesity and diabetes—what hepatologists need to know. Aliment Pharmacol Ther. 2022;55(8):944–959. doi: 10.1111/apt.16794
  • Upadhyay J, Polyzos SA, Perakakis N, et al. Pharmacotherapy of type 2 diabetes: an update. Metabolism. 2018;78:13–42. doi: 10.1016/j.metabol.2017.08.010
  • Gastaldelli A, Cusi K. From NASH to diabetes and from diabetes to NASH: mechanisms and treatment options. JHEP Rep. 2019;1(4):312–328. doi: 10.1016/j.jhepr.2019.07.002
  • Trevaskis JL, Griffin PS, Wittmer C, et al. Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice. Am J Physiol Gastrointest Liver Physiol. 2012;302(8):G762–772. doi: 10.1152/ajpgi.00476.2011
  • Fang X, Du Z, Duan C, et al. Beinaglutide shows significantly beneficial effects in diabetes/obesity-induced nonalcoholic steatohepatitis in ob/ob mouse model. Life Sci. 2021;270:118966. doi: 10.1016/j.lfs.2020.118966
  • Park HW, Lee JH. Calcium channel blockers as potential therapeutics for obesity-associated autophagy defects and fatty liver pathologies. Autophagy. 2014;10(12):2385–2386. doi: 10.4161/15548627.2014.984268
  • Tølbøl KS, Kristiansen MN, Hansen HH, et al. Metabolic and hepatic effects of liraglutide, obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis. World J Gastroenterol. 2018;24(2):179–194. doi: 10.3748/wjg.v24.i2.179
  • Daniels SJ, Leeming DJ, Detlefsen S, et al. Biochemical and histological characterisation of an experimental rodent model of non-alcoholic steatohepatitis - effects of a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist and a glucagon-like peptide-1 analogue. Biomed Pharmacother. 2019;111:926–933. doi: 10.1016/j.biopha.2018.12.130
  • Duparc T, Briand F, Trenteseaux C, et al. Liraglutide improves hepatic steatosis and metabolic dysfunctions in a 3-week dietary mouse model of nonalcoholic steatohepatitis. J Diabetes Res. 2019;317(4):G508–G517. doi: 10.1152/ajpgi.00139.2019
  • Luo Y, Yang P, Li Z, et al. Liraglutide improves non-alcoholic fatty liver disease in diabetic mice by modulating inflammatory signaling pathways. Drug Des Devel Ther. 2019;13: 4065–4074. 10.2147/DDDT.S224688.
  • Kojima M, Takahashi H, Kuwashiro T, et al. Glucagon-like peptide-1 receptor agonist prevented the progression of hepatocellular carcinoma in a mouse model of nonalcoholic steatohepatitis. Int J Mol Sci. 2020;21(16):5722. doi: 10.3390/ijms21165722
  • Moreira GV, Azevedo FF, Ribeiro LM, et al. Liraglutide modulates gut microbiota and reduces NAFLD in obese mice. J Nutr Biochem. 2018;62:143–154. doi: 10.1016/j.jnutbio.2018.07.009
  • Zhang N, Tao J, Gao L, et al. Liraglutide attenuates nonalcoholic fatty liver disease by modulating gut microbiota in rats administered a high-fat diet. Biomed Res Int. 2020;2020:2947549. doi: 10.1155/2020/2947549
  • Fang T, Huang S, Chen Y, et al. Glucagon like peptide-1 receptor agonists alter pancreatic and hepatic histology and regulation of endoplasmic reticulum stress in high-fat diet mouse model. Exp Clin Endocrinol Diabetes. 2021;129(9):625–633. doi: 10.1055/a-1240-4936
  • Perakakis N, Stefanakis K, Feigh M, et al. Elafibranor and liraglutide improve differentially liver health and metabolism in a mouse model of non-alcoholic steatohepatitis. Liver Int. 2021;41(8):1853–1866. doi: 10.1111/liv.14888
  • Somm E, Montandon SA, Loizides-Mangold U, et al. The GLP-1R agonist liraglutide limits hepatic lipotoxicity and inflammatory response in mice fed a methionine-choline deficient diet. Transl Res. 2021;227:75–88. doi: 10.1016/j.trsl.2020.07.008
  • Møllerhøj MB, Veidal SS, Thrane KT, et al. Hepatoprotective effects of semaglutide, lanifibranor and dietary intervention in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH. Clin Transl Sci. 2022;15(5):1167–1186. doi: 10.1111/cts.13235
  • Pontes-da-Silva RM, de Souza Marinho T, de Macedo Cardoso LE, et al. Obese mice weight loss role on nonalcoholic fatty liver disease and endoplasmic reticulum stress treated by a GLP-1 receptor agonist. Int J Obes (Lond). 2022;46(1):21–29. doi: 10.1038/s41366-021-00955-7
  • Gupta NA, Mells J, Dunham RM, et al. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology. 2010;51(5):1584–1592. doi: 10.1002/hep.23569
  • Panjwani N, Mulvihill EE, Longuet C, et al. GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE(-/-) mice. Endocrinology. 2013;154(1):127–139. doi: 10.1210/en.2012-1937
  • Tomas E, Stanojevic V, Habener JF. GLP-1-derived nonapeptide GLP-1(28-36)amide targets to mitochondria and suppresses glucose production and oxidative stress in isolated mouse hepatocytes. Regul Pept. 2011;167(2–3):177–184. doi: 10.1016/j.regpep.2011.01.003
  • Fan H, Pan Q, Xu Y, et al. Exenatide improves type 2 diabetes concomitant with non-alcoholic fatty liver disease. Arq Bras Endocrinol Metabol. 2013;57(9):702–708. doi: 10.1590/S0004-27302013000900005
  • Shao N, Kuang HY, Hao M, et al. Benefits of exenatide on obesity and non-alcoholic fatty liver disease with elevated liver enzymes in patients with type 2 diabetes. Diabetes Metab Res Rev. 2014;30(6):521–529. doi: 10.1002/dmrr.2561
  • Liu L, Yan H, Xia M, et al. Efficacy of exenatide and insulin glargine on nonalcoholic fatty liver disease in patients with type 2 diabetes. Diabetes Metab Res Rev. 2020;36(5):e3292. doi: 10.1002/dmrr.3292
  • Kuchay MS, Krishan S, Mishra SK, et al. Effect of dulaglutide on liver fat in patients with type 2 diabetes and NAFLD: randomised controlled trial (D-LIFT trial). Diabetologia. 2020;63(11):2434–2445. doi: 10.1007/s00125-020-05265-7
  • Ohki T, Isogawa A, Iwamoto M, et al. The effectiveness of liraglutide in nonalcoholic fatty liver disease patients with type 2 diabetes mellitus compared to sitagliptin and pioglitazone. ScientificWorldjournal. 2012;2012:496453. doi: 10.1100/2012/496453
  • Eguchi Y, Kitajima Y, Hyogo H, et al. Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J). Hepatol Res. 2015;45(3):269–278. doi: 10.1111/hepr.12351
  • Tang A, Rabasa-Lhoret R, Castel H, et al. Effects of insulin Glargine and liraglutide therapy on liver fat as measured by magnetic resonance in patients with type 2 diabetes: a randomized trial. Diabetes Care. 2015;38(7):1339–1346. doi: 10.2337/dc14-2548
  • Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387(10019):679–690. doi: 10.1016/S0140-6736(15)00803-X
  • Smits MM, Tonneijck L, Muskiet MH, et al. Twelve week liraglutide or sitagliptin does not affect hepatic fat in type 2 diabetes: a randomised placebo-controlled trial. Diabetologia. 2016;59(12):2588–2593. doi: 10.1007/s00125-016-4100-7
  • Feng W, Gao C, Bi Y, et al. Randomized trial comparing the effects of gliclazide, liraglutide, and metformin on diabetes with non-alcoholic fatty liver disease. J Diabetes. 2017;9(8):800–809. doi: 10.1111/1753-0407.12555
  • Petit JM, Cercueil JP, Loffroy R, et al. Effect of liraglutide therapy on liver fat content in patients with inadequately controlled type 2 diabetes: the lira-NAFLD study. J Clin Endocrinol Metab. 2017;102(2):407–415. doi: 10.1210/jc.2016-2775
  • Khoo J, Hsiang JC, Taneja R, et al. Randomized trial comparing effects of weight loss by liraglutide with lifestyle modification in non-alcoholic fatty liver disease. Liver Int. 2019;39(5):941–949. doi: 10.1111/liv.14065
  • Matikainen N, Soderlund S, Bjornson E, et al. Liraglutide treatment improves postprandial lipid metabolism and cardiometabolic risk factors in humans with adequately controlled type 2 diabetes: a single-centre randomized controlled study. Diab Obes Metab. 2019;21(1):84–94. doi: 10.1111/dom.13487
  • Yan J, Yao B, Kuang H, et al. 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. Hepatology. 2019;69(6):2414–2426. doi: 10.1002/hep.30320
  • Guo W, Tian W, Lin L, et al. Liraglutide or insulin glargine treatments improves hepatic fat in obese patients with type 2 diabetes and nonalcoholic fatty liver disease in twenty-six weeks: a randomized placebo-controlled trial. Diabet Res Clin Pract. 2020;170:108487. doi: 10.1016/j.diabres.2020.108487
  • Zhang LY, Qu XN, Sun ZY, et al. Effect of liraglutide therapy on serum fetuin a in patients with type 2 diabetes and non-alcoholic fatty liver disease. Clin Res Hepatol Gastroenterol. 2020;44(5):674–680. doi: 10.1016/j.clinre.2020.01.007
  • Flint A, Andersen G, Hockings P, et al. Randomised clinical trial: semaglutide versus placebo reduced liver steatosis but not liver stiffness in subjects with non-alcoholic fatty liver disease assessed by magnetic resonance imaging. Aliment Pharmacol Ther. 2021;54(9):1150–1161. doi: 10.1111/apt.16608
  • Newsome PN, Buchholtz K, Cusi K, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384(12):1113–1124. doi: 10.1056/NEJMoa2028395
  • Romero-Gomez M, Lawitz E, Shankar RR, et al. A phase 2a active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with nonalcoholic fatty liver disease. J Hepatol. 2023;79(4):888–897. doi: 10.1016/j.jhep.2023.05.013
  • Polyzos SA, Kountouras J, Zavos C, et al. The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease. Diab Obes Metab. 2010;12(5):365–383. doi: 10.1111/j.1463-1326.2009.01176.x
  • Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol. 2020;73(1):202–209. doi: 10.1016/j.jhep.2020.03.039
  • Rinella ME, Lazarus JV, Ratziu V, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023. doi: 10.1016/j.jhep.2023.06.003
  • Polyzos SA, Kang ES, Tsochatzis EA, et al. Commentary: nonalcoholic or metabolic dysfunction-associated fatty liver disease? The epidemic of the 21st century in search of the most appropriate name. Metabolism. 2020;113:154413. doi: 10.1016/j.metabol.2020.154413
  • Polyzos SA, Kountouras J, Zavos C, et al. Nonalcoholic fatty liver disease: multimodal treatment options for a pathogenetically multiple-hit disease. J Clin Gastroenterol. 2012;46(4):272–284. doi: 10.1097/MCG.0b013e31824587e0
  • Gluud LL, Knop FK, Vilsboll T. Effects of lixisenatide on elevated liver transaminases: systematic review with individual patient data meta-analysis of randomised controlled trials on patients with type 2 diabetes. BMJ Open. 2014;4(12):e005325. doi: 10.1136/bmjopen-2014-005325
  • Onoviran OF, Li D, Toombs Smith S, et al. Effects of glucagon-like peptide 1 receptor agonists on comorbidities in older patients with diabetes mellitus. Ther Adv Chronic Dis. 2019;10:2040622319862691. doi: 10.1177/2040622319862691
  • Polyzos SA, Kang ES, Boutari C, et al. Current and emerging pharmacological options for the treatment of nonalcoholic steatohepatitis. Metabolism. 2020;111S:154203. doi: 10.1016/j.metabol.2020.154203
  • Filippatos TD, Panagiotopoulou TV, Elisaf MS. Adverse effects of GLP-1 receptor agonists. Rev Diabet Stud. 2014;11(3–4):202–230. doi: 10.1900/RDS.2014.11.202
  • Sim R, Chong CW, Loganadan NK, et al. Comparative effectiveness of cardiovascular, renal and safety outcomes of second-line antidiabetic drugs use in people with type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials. Diabet Med. 2022;39(3):e14780. doi: 10.1111/dme.14780
  • Elashoff M, Matveyenko AV, Gier B, et al. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141(1):150–156. doi: 10.1053/j.gastro.2011.02.018
  • Parks M, Rosebraugh C. Weighing risks and benefits of liraglutide–the FDA’s review of a new antidiabetic therapy. N Engl J Med. 2010;362(9):774–777. doi: 10.1056/NEJMp1001578
  • Alves C, Batel-Marques F, Macedo AF. A meta-analysis of serious adverse events reported with exenatide and liraglutide: acute pancreatitis and cancer. Diabet Res Clin Pract. 2012;98(2):271–284. doi: 10.1016/j.diabres.2012.09.008
  • Chiu WY, Shih SR, Tseng CH. A review on the association between glucagon-like peptide-1 receptor agonists and thyroid cancer. Exp Diabetes Res. 2012;2012:924168. doi: 10.1155/2012/924168
  • Zhang X, Wang M, Wang X, et al. Comparison of New glucose-lowering drugs on the risk of pancreatitis in type 2 diabetes: a network meta-analysis. Endocr Pract. 2022;28(3):333–341. doi: 10.1016/j.eprac.2021.12.007
  • Hidayat K, Zhou YY, Du HZ, et al. A systematic review and meta-analysis of observational studies of the association between the use of incretin-based therapies and the risk of pancreatic cancer. Pharmacoepidemiol Drug Saf. 2023;32(2):107–125. doi: 10.1002/pds.5550
  • Abd El Aziz M, Cahyadi O, Meier JJ, et al. Incretin-based glucose-lowering medications and the risk of acute pancreatitis and malignancies: a meta-analysis based on cardiovascular outcomes trials. Diab Obes Metab. 2020;22(4):699–704. doi: 10.1111/dom.13924
  • Cao C, Yang S, Zhou Z. GLP-1 receptor agonists and risk of cancer in type 2 diabetes: an updated meta-analysis of randomized controlled trials. Endocrine. 2019;66(2):157–165. doi: 10.1007/s12020-019-02055-z
  • Makri E, Kita M, Goulas A, et al. Comparative effectiveness of glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors on noninvasive indices of hepatic steatosis and fibrosis in patients with type 2 diabetes mellitus. Diabetes Metab Syndr. 2020;14(6):1913–1919. doi: 10.1016/j.dsx.2020.09.030
  • Polyzos SA, Goulis DG, Giouleme O, et al. Anti-obesity medications for the management of nonalcoholic fatty liver disease. Curr Obes Rep. 2022;11(3):166–179. doi: 10.1007/s13679-022-00474-0
  • Polyzos SA, Kountouras J, Mantzoros CS. Adipose tissue, obesity and non-alcoholic fatty liver disease. Minerva Endocrinol. 2017;42(2):92–108. doi: 10.23736/S0391-1977.16.02563-3
  • Tontikidou C, Makri ES, Evripidou K, et al. Circulating adiponectin in patients with nonalcoholic fatty liver disease-related liver fibrosis: a systematic review and a meta-analysis. J Gastroenterol Hepatol. 2022;37(10):1853–1864. doi: 10.1111/jgh.15926
  • Wei T, Ye P, Peng X, et al. Circulating adiponectin levels in various malignancies: an updated meta-analysis of 107 studies. Oncotarget. 2016;7(30):48671–48691. doi: 10.18632/oncotarget.8932
  • Polyzos SA, Mantzoros CS. Adiponectin as a target for the treatment of nonalcoholic steatohepatitis with thiazolidinediones: a systematic review. Metabolism. 2016;65(9):1297–1306. doi: 10.1016/j.metabol.2016.05.013
  • Makri ES, Makri E, Polyzos SA. Combination therapies for nonalcoholic fatty liver disease. J Pers Med. 2022;12(7):1166. doi: 10.3390/jpm12071166
  • Venetsanaki V, Karabouta Z, Polyzos SA. Farnesoid X nuclear receptor agonists for the treatment of nonalcoholic steatohepatitis. Eur J Pharmacol. 2019;863:172661. doi: 10.1016/j.ejphar.2019.172661
  • Majzoub AM, Nayfeh T, Barnard A, et al. Systematic review with network meta-analysis: comparative efficacy of pharmacologic therapies for fibrosis improvement and resolution of NASH. Aliment Pharmacol Ther. 2021;54(7):880–889. doi: 10.1111/apt.16583
  • Alkhouri N, Herring R, Kabler H, et al. Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: a randomised, open-label phase II trial. J Hepatol. 2022;77(3):607–618. doi: 10.1016/j.jhep.2022.04.003
  • Polyzos SA, Katsiki N. Semaglutide, cilofexor, and firsocostat for nonalcoholic steatohepatitis: a dance that may need more than one dancer. Hormones (Athens). 2022;21(3):513–514. doi: 10.1007/s42000-022-00379-6
  • Polyzos SA, Goulas A, Papaioannidou P. Tirzepatide for diabetes and obesity: a New window to the treatment of non-alcoholic steatohepatitis. Curr Med Chem. 2023;30(22):2476–2479. doi: 10.2174/0929867330666230106103202

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.