Non-alcoholic fatty liver disease: Modern approaches to therapy and possibilities of using tirzepatide

Introduction. The review covers the epidemiology, pathogenesis, clinic, diagnosis, and treatment of polysyndromic nonalcoholic fatty liver disease (NAFLD) associated with obesity, type 2 diabetes, and cardiovascular pathology.

Aim. To assess the key pathogenetic links of cardio-reno-hepato-metabolic syndrome in patients, as well as the therapeutic efficacy of dual-incretin drugs, such as tirzepatid and its domestic analogue sejaro.

Materials and methods. The search for literature sources was carried out in the PubMed and Google Scholar databases. The selection of publications was carried out on the principle of open free access, on the analysis of abstracts and assessment of relevance.

Results. 60 articles were selected for the review: 5 Russian-language and 55 foreign sources. Most publications reflect an increase in the global burden of NAFLD due to an increase in the incidence of type 2 diabetes and obesity, in the pharmacological correction of which double agonists of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), such as tirzepatid and its analogue sejaro, which are effective for weight loss, fibrosis regression and resolution of Nonalcoholic Steatohepatitis (NASH), as well as for the complex treatment of chronic metabolic diseases outside of traditional diabetes care.

Conclusions. Based on a large number of clinical trials, the review evaluated the possibilities of outpatient drug therapy for NAFLD, focused on the use of GLP-1 and GIP agonists, as well as available pharmacological drugs with a dual mechanism of action of GLP-1/GIP – tirzepatide and its domestic analogue sejaro. At the same time, sejaro shows distinct effects on pathogenic metabolic dysregulation, inflammation and fibrosis.

1. Dezan MGF, Oliveira CP, Cotrim HP. Metabolic dysfunction-associated steatotic liver disease: update. Arq Gastroenterol. 2025;62:e24117. https://doi.org/10.1590/S0004-2803.24612025-117.

2. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol. 2024;81(3):492–542. https://doi.org/10.1016/j.jhep.2024.04.031.

3. Petta S, Kim K, Targher G, Romeo S, Sookoian S, Zheng MH et al. Focus on semaglutide 2.4 mg/week for the treatment of metabolic dysfunctionassociated steatohepatitis. Liver Int. 2025;45(11):e70407. https://doi.org/10.1111/liv.70407.

4. Choi S, Jung JS, Seo YS, Song S, Ham J, Chung H et al. Convergent metabolic pathways in MASH therapeutics: an AMPK-centric analysis. J Cell Mol Med. 2026;30(2):e71023. https://doi.org/10.1111/jcmm.71023.

5. Amini-Salehi E, Letafatkar N, Norouzi N, Joukar F, Habibi A, Javid M et al. Global Prevalence of Nonalcoholic Fatty Liver Disease: An Updated Review Meta-Analysis comprising a Population of 78 million from 38 Countries. Arch Med Res. 2024;55(6):103043. https://doi.org/10.1016/j.arcmed.2024.103043.

6. Khalifa O, Arredouani A. GLP-1 RAs for treating metabolic dysfunctionassociated steatosis liver disease: from GLP-1 discovery to FDA approval: a comprehensive narrative review. Pharmaceuticals. 2026;19(3):408. https://doi.org/10.3390/ph19030408.

7. Yanai H, Adachi H, Hakoshima M, Iida S, Katsuyama H. Metabolicdysfunction-associated steatotic liver disease – its pathophysiology, association with atherosclerosis and cardiovascular disease, and treatments. Int J Mol Sci. 2023;24(20):15473. https://doi.org/10.3390/ijms242015473.

8. Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023;77(4):1335–1347. https://doi.org/10.1097/HEP.0000000000000004.

9. Martinez-Dominguez SJ, Garcia-Mateo S, Gargallo-Puyuelo CJ, Gallego-Llera B, Callau P, Mendi C et al. Inflammatory bowel disease is an independent risk factor for metabolic dysfunction-associated steatotic liver disease in lean individuals. Inflamm Bowel Dis. 2024;30(8):1274–1283. https://doi.org/10.1093/ibd/izad175.

10. Chuang MH, Chen JY, Wang HY, Jiang ZH, Wu VC. Clinical outcomes of tirzepatide or GLP-1 receptor agonists in individuals with type 2 diabetes. JAMA Netw Open. 2024;7(8):e2427258. https://doi.org/10.1001/jamanetworkopen.2024.27258.

11. Younossi ZM, Golabi P, Paik J, Owrangi S, Yilmaz Y, El-Kassas M et al. Prevalence of metabolic dysfunction-associated steatotic liver disease in the Middle East and North Africa. Liver Int. 2024;44(5):1061–1070. https://doi.org/10.1111/liv.15852.

12. Konyn P, Ahmed A, Kim D. Causes and risk profiles of mortality among individuals with nonalcoholic fatty liver disease. Clin Mol Hepatol. 2023;29(Suppl.):S43–S57. https://doi.org/10.3350/cmh.2022.0351.

13. Targher G, Valenti L, Byrne CD. Metabolic dysfunction-associated steatotic liver disease. N Engl J Med. 2025;393(7):683–698. https://doi.org/10.1056/NEJMra2412865.

14. Younossi ZM, Kalligeros M, Henry L. Epidemiology of metabolic dysfunctionassociated steatotic liver disease. Clin Mol Hepatol. 2025;31(Suppl.):S32–S50. https://doi.org/10.3350/cmh.2024.0431.

15. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J Hepatol. 2020;73(1):202–209. https://doi.org/10.1016/j.jhep.2020.03.039.

16. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797–1835. https://doi.org/10.1097/HEP.0000000000000323.

17. Miao L, Targher G, Byrne CD, Cao YY, Zheng MH. Current status and future trends of the global burden of MASLD. Trends Endocrinol Metab. 2024;35(8):697–707. https://doi.org/10.1016/j.tem.2024.02.007.

18. Targher G, Byrne CD, Tilg H. MASLD: a systemic metabolic disorder with cardiovascular and malignant complications. Gut. 2024;73(4):691–702. https://doi.org/10.1136/gutjnl-2023-330595.

19. Peverelle M, Mbelle M, Joshi D. New names, new drugs, better outcomes in steatotic liver disease. Br J Hosp Med. 2025;86(8):1–18. https://doi.org/10.12968/hmed.2024.0655.

20. Stefan AG, Mitrea A, Clenciu D, Vladu IM, Roşu MM, Protasiewicz-Timofticiuc DC et al. MASH in type 2 diabetes: pathophysiology, diagnosis, and therapeutic management – a narrative review. Medicina. 2026;62(2):325. https://doi.org/10.3390/medicina62020325.

21. Lazebnik LB. Metabolicly associated fatty liver disease. Practical recommendations of the Scientific Society of Gastroenterologists of Russia. Part 1. Experimental and Clinical Gastroenterology. 2024;(10):5–10. (In Russ.) https://doi.org/10.31146/1682-8658-ecg-230-10-5-10.

22. Acierno C, Caturano A, Pafundi PC, Nevola R, Adinolfi LE, Sasso FC. Nonalcoholic fatty liver disease and type 2 diabetes: pathophysiological mechanisms shared between the two faces of the same coin. Explor Med. 2020;1:287–306. https://doi.org/10.37349/emed.2020.00019.

23. Devasia AG, Ramasamy A, Leo CH. Current therapeutic landscape for metabolic dysfunction-associated steatohepatitis. Int J Mol Sci. 2025;26(4):1778. https://doi.org/10.3390/ijms26041778.

24. Patel AH, Peddu D, Amin S, Elsaid MI, Minacapelli CD, Chandler TM et al. Nonalcoholic fatty liver disease in lean/nonobese and obese individuals: a comprehensive review on prevalence, pathogenesis, clinical outcomes, and treatment. J Clin Transl Hepatol. 2023;11(2):502–515. https://doi.org/10.14218/JCTH.2022.00204.

25. Cotter TG, Rinella M. Nonalcoholic fatty liver disease 2020: the state of the disease. Gastroenterology. 2020;158(7):1851–1864. https://doi.org/10.1053/j.gastro.2020.01.052.

26. Tanase DM, Gosav EM, Costea CF, Ciocoiu M, Lacatusu CM, Maranduca MA et al. The intricate relationship between type 2 diabetes mellitus (T2DM), insulin resistance (IR), and nonalcoholic fatty liver disease (NAFLD). J Diabetes Res. 2020;2020:3920196. https://doi.org/10.1155/2020/3920196.

27. Hashim MMA, Khan M, Ashraf M, Mohsin S, Zahoor K, Niazi J et al. Pathological evolution and internal medicine management of nonalcoholic fatty liver disease (NAFLD) in the era of metabolic dysfunctionassociated steatotic liver disease (MASLD). Cureus. 2025;17(6):e86963. https://doi.org/10.7759/cureus.86963.

28. Moncho F, Benlloch S, Górriz JL. The impact of metabolic dysfunctionassociated steatotic liver disease (MASH) on the high risk of cardiovascular disease in CKD: interconnections and management. Clin Kidney J. 2025;18(9):260. https:/doi.org/10.1093/ckj/sfaf260.

29. Hernandez-Ceballos W, Cordova-Gallardo J, Mendez-Sanchez N. Gut microbiota in metabolic-associated fatty liver disease and in other chronic metabolic diseases. J Clin Transl Hepatol. 2021;9(2):227–238. https://doi.org/10.14218/JCTH.2020.00131.

30. Hao X, Song H, Su X, Li J, Ye Y, Wang C et al. Prophylactic effects of nutrition, dietary strategies, exercise, lifestyle and environment on nonalcoholic fatty liver disease. Ann Med. 2025;57(1):2464223. https://doi.org/10.1080/07853890.2025.2464223.

31. Devarbhavi H, Asrani SK, Arab JP, Nartey YA, Pose E, Kamath PS. Global burden of liver disease: 2023 update. J Hepatol. 2023;79(2):516–537. https://doi.org/10.1016/j.jhep.2023.03.017.

32. Handelsman Y, Anderson JE, Bakris GL, Ballantyne CM, Bhatt DL, Bloomgarden ZT et al. DCRM 2.0: multispecialty practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases. Metabolism. 2024;159:155931. https://doi.org/10.1016/j.metabol.2024.155931.

33. Long MT, Noureddin M, Lim JK. AGA Clinical Practice Update: diagnosis and management of nonalcoholic fatty liver disease in lean individuals: expert review. Gastroenterology. 2022;163(3):764–774. https://doi.org/10.1053/j.gastro.2022.06.023.

34. Djeagou A, Gunukula K, Sermani A, Vaspari SK. Emerging perspectives in the diagnosis and management of metabolic dysfunction-associated steatotic liver disease (MASLD): a narrative review. Cureus. 2025;17(10):e95288. https://doi.org/10.7759/cureus.95288.

35. Mahady SE, George J. Predicting the future burden of NAFLD and NASH. J Hepatol. 2018;69(4):774–775. https://doi.org/10.1016/j.jhep.2018.06.025.

36. Zafer M, Tavaglione F, Romero-Gomez M, Loomba R. Review article: GLP-1 receptor agonists and glucagon/GIP/GLP-1 receptor dual or triple agonists – mechanism of action and emerging therapeutic landscape in MASLD. Aliment Pharmacol Ther. 2025;61(12):1872–1888. https://doi.org/10.1111/apt.70196.

37. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205–216. https://doi.org/10.1056/NEJMoa2206038.

38. Mega A, Turri C, Marzi L, Dauriz M, Sacco R, Floreani A, Stasi C. New treatment options for MASLD patients with type 2 diabetes. Life. 2026;16(2):254. https://doi.org/10.3390/life16020254.

39. da Silva Lima N, Cabaleiro A, Novoa E, Riobello C, Knerr PJ, He Y et al. GLP-1 and GIP agonism has no direct actions in human hepatocytes or hepatic stellate cells. Cell Mol Life Sci. 2024;81(1):468. https://doi.org/10.1007/s00018-024-05507-6.

40. Targher G, Mantovani A, Byrne CD. Mechanisms and possible hepatoprotective effects of glucagon-like peptide-1 receptor agonists and other incretin receptor agonists in non-alcoholic fatty liver disease. Lancet Gastroenterol Hepatol. 2023;8(2):179–191. https://doi.org/10.1016/S24681253(22)00338-7.

41. Kosiborod MN, Abildstrom SZ, Borlaug BA, Butler J, Rasmussen S, Davies M et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med. 2023;389(12):1069–1084. https://doi.org/10.1056/NEJMoa2306963.

42. Borges RDS, Abreu ES, Berton GG, de Paula LH, Conegundes AF, Martins JMB et al. Efficacy and safety of GLP-1 receptor agonists in MASH with fibrosis: a systematic review and meta-analysis. JHEP Rep. 2026;8:101708. https://doi.org/10.1016/j.jhepr.2025.101708.

43. Mantovani A, Morandin R, Fiorio V, Lando MG, Stefan N, Tilg H et al. Glucagon-like peptide-1 receptor agonists improve MASH and liver fibrosis: a meta-analysis of randomised controlled trials. Liver Int. 2025;45(9):e70256. https://doi.org/10.1111/liv.70256.

44. Alkhatib M, Almasri N, Alshwayyat S, Almahariq H, Hammadeh BM, Taimeh Z et al. The multifaceted effects of semaglutide: exploring its broad therapeutic applications. Future Sci OA. 2025;11(1):2483607. https://doi.org/10.1080/20565623.2025.2483607.

45. Alharbi AG. GLP-1 receptor agonism: a transformative approach for managing type-2 diabetes and obesity. Saudi Pharm J. 2025;33(5):34. https://doi.org/10.1007/s44446-025-00038-y.

46. Zacharia GS, Ashraf MH, Sosa F, Jacob A, Patel H. Quick glance at ‘metabolic dysfunction associated steatotic liver disease’ therapeutics: targets, trials, and trends. World J Gastrointest Pharmacol Ther. 2025;16(4):110827. https://doi.org/10.4292/wjgpt.v16.i4.110827.

47. Ghaleb J, Khouzami KK, Nassif N, Attieh P, Ajlani MFA, Sleiman JB et al. Unveiling tirzepatide’s therapeutic spectrum: a dual GIP/GLP-1 agonist targeting metabolic, neurological, and cardiovascular health. Int J Endocrinol. 2025;2025:2876156. https://doi.org/10.1155/ije/2876156.

48. Banji D, Alshahrani S, Alfarhan M, Banji OJF. Revolutionizing type 2 diabetes management: the role of the pharmacist in unlocking the potential of tirzepatide. Saudi Pharm J. 2025;33(6):51. https://doi.org/10.1007/s44446-025-00050-2.

49. Kahl S, Gancheva S, Strassburger K, Herder C, Machann J, Katsuyama H et al. Empagliflozin effectively lowers liver fat content in wellcontrolled type 2 diabetes: a randomized, double-blind, phase 4, placebo-controlled trial. Diabetes Care. 2020;43(2):298–305. https://doi.org/10.2337/dc19-0641.

50. Loomba R, Hartman ML, Lawitz EJ, Vuppalanchi R, Boursier J, Bugianesi E et al. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med. 2024;391(4):299–310. https://doi.org/10.1056/NEJMoa2401943.

51. Newsome PN, Loomba R. Therapeutic horizons in metabolic dysfunctionassociated steatohepatitis. J Clin Invest. 2025;135(13):e186425. https://doi.org/10.1172/JCI186425.

52. Drygalski K. Pharmacological treatment of MASLD: contemporary treatment and future perspectives. Int J Mol Sci. 2025;26(13):6518. https://doi.org/10.3390/ijms26136518.

53. Hartman ML, Sanyal AJ, Loomba R, Wilson JM. Nikooienejad A, Bray R et al. Effects of Novel Dual GIP and GLP-1 Receptor Agonist Tirzepatide on Biomarkers of Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes. Diabetes Care. 2020;43(6):1352–1355. https://doi.org/10.2337/dc19-1892.

54. Sanyal AJ, Kaplan LM, Frias JP, Brouwers B, Wu Q, Thomas MK et al. Triple hormone receptor agonist retatrutide for metabolic dysfunctionassociated steatotic liver disease: a randomized phase 2a trial. Nat Med. 2024;30(7):2037–2048. https://doi.org/10.1038/s41591-024-03018-2.

55. Ullah MI, Tamanna S. Obesity: clinical impact, pathophysiology, complications, and modern innovations in therapeutic strategies. Medicines. 2025;12(3):19. https://doi.org/10.3390/medicines12030019.

56. Lugovik IA, Babina AV, Arutyunyan SS, Ermolaeva DO, Saparova VB, Kobeleva TN et al. The first generic tirzepatide GP30931: physicochemical and biological similarity to the reference drug. Drug Development and Registration. 2025;14(2):54–74. (In Russ.) https://doi.org/10.33380/2305-2066-2025-14-2-2084.

57. Demidova TYu, Kislyak OA, Starodubova AV, Nikitin IG, Ushanova FO. Beyond BMI: We are discussing a new concept for the definition and diagnosis of clinical obesity. Meditsinskiy Sovet. 2025;19(6):240–252. (In Russ.) https://doi.org/10.21518/ms2025-183.

58. Demidova TYu, Izmaylova MYa. New horizons in the management of metabolic diseases: Focus on the efficacy and safety of tirzepatide. FOCUS. Endocrinology. 2025;6(3):12–23. (In Russ.) https://doi.org/10.62751/2713-0177-2025-6-3-03.

59. Xiao Z, Li X, Gong J, Zhou F. Comparative efficacy of multiple drugs for nonalcoholic fatty liver disease: a Bayesian network meta-analysis. Eur J Med Res. 2025;30(1):1164. https://doi.org/10.1186/s40001-025-03445-y.

60. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab. 2018;18:3–14. https://doi.org/10.1016/j.molmet.2018.09.009.