Pharmacologic approach to metabolic dysfunction and related diseases: focus on liver aspects

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects nearly 1.5 billion adults worldwide. It is closely associated with type 2 diabetes mellitus and obesity. Longer duration of MASLD increases risk of progression to metabolic dysfunction-associated steatohepatitis (MASH, the progressive form of MASLD that requires pharmacological therapy), cirrhosis and hepatocellular carcinoma, as well as development of cardiovascular complications. Despite the need for MASH pharmacologic intervention, several studies on new investigational compounds have failed, with only Resmetirom and Semaglutide recently conditionally approved by the Food and Drug Administration (FDA). The role of incretins may be more critical in the early phase of MASH development, but integration with drugs that directly target the liver may represent the winning strategy. The armamentarium of drugs for MASH is rapidly expanding, and several promising drugs are under investigation in phase 2 of development. Integrating fibrosis stage-specific combination therapies targeting different steps of the complex pathogenic mechanism of MASLD/MASH may lead to successful treatment rates larger than the currently obtained 25%-30%. The effects of both FDA-approved compounds (Resmetirom and Semaglutide) on clinical outcomes remain to be shown and will not be available before the conclusion of the respective outcome studies in 2027 and 2028.

Keywords

Resmetirom semaglutide / incretins / MASLD / MASH

References

[1] Vernon G,Younossi ZM.Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.Aliment Pharmacol Ther2011;34:274-85

[2] GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.Lancet2020;396:1204-22 PMCID:PMC7567026

[3] Riazi K,Charette JH.The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis.Lancet Gastroenterol Hepatol2022;7:851-61

[4] GBD 2017 Cirrhosis Collaborators. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet Gastroenterol Hepatol2020;5:245-66 PMCID:PMC7026710

[5] Lazarus JV,Mark HE.A call for doubling the diagnostic rate of at-risk metabolic dysfunction-associated steatohepatitis.Lancet Reg Health Eur2025;54:101320 PMCID:PMC12266185

[6] Rinella ME, Lazarus JV, Ratziu V, et al; NAFLD Nomenclature consensus group. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023;79:1542-56.

[7] Younossi ZM,Paik JM,Van Dongen C.The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review.Hepatology2023;77:1335-47 PMCID:PMC10026948

[8] Valenti L,Pajvani U.Non alcoholic fatty liver disease: cause or consequence of type 2 diabetes?.Liver Intern2016; 36:1563-79

[9] Dongiovanni P,Meloni M.The role of insulin resistance in nonalcoholic steatohepatitis and liver disease development-a potential therapeutic target?.Expert Rev Gastroenterol Hepatol2016;10:229-42

[10] Mia C,Abdelmalek MF.The liver in diabetes and metabolic syndrome.Clin Liv Dis2025;29:407-29

[11] Najjar SM.Hepatic insulin clearance: mechanism and physiology.Physiology2019;34:198-215 PMCID:PMC6734066

[12] Gastaldelli A,Pettiti M.Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects.Gastroenterology2007;133:496-506

[13] Park G,Wellen KE.The interaction between the gut microbiota and dietary carbohydrates in nonalcoholic fatty liver disease.Exp Mol Med2021;53:809-22 PMCID:PMC8178320

[14] Mouries J,Silvestri A.Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development.J Hepatol2019;71:1216-28 PMCID:PMC6880766

[15] Puengel T.Pharmacotherapeutic options for metabolic dysfunction-associated steatotic liver disease: where are we today?.Expert Opin Pharmacother2024;25:1249-63

[16] Administration U. S. FOOD & DRUG. FDA approves first treatment for patients with liver scarring due to fatty liver disease. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease. [Last accessed on 22 Dec 2025].

[17] Wegovy approved for MASH.Nat Biotechnol2025;43:1404

[18] Yale JF,Catarig AM,Menzen M.Real-world safety profile of once-weekly semaglutide in people with type 2 diabetes: analysis of pooled data from the SemaglUtide Real-world Evidence (SURE) programme.Diabetes Obes Metab2024;26:4429-40

[19] Mantovani A,Beatrice G,Lonardo A.Glucagon-like peptide-1 receptor agonists for treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: an updated meta-analysis of randomized controlled trials.Metabolites2021;11:73 PMCID:PMC7911747

[20] Harrison SA, Bedossa P, Guy CD, et al; MAESTRO-NASH Investigators. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390:497-509.

[21] Newsome PN.Incretins (GLP-1 receptor agonists and dual/triple agonists) and the liver.J Hepatol2023;79:1557-65

[22] Sookoian S,Valenti L.Genetics of metabolic dysfunction-associated steatotic liver disease: the state of the art update.Clin Gastroenterol Hepatol2024;22:2177-87.e3 PMCID:PMC11512675

[23] Raverdy V,Chatelain E.Data-driven cluster analysis identifies distinct types of metabolic dysfunction-associated steatotic liver disease.Nat Med2024;30:3624-33 PMCID:PMC11645276

[24] Jamialahmadi O,Tavaglione F.Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease.Nat Med2024;30:3614-23 PMCID:PMC11645285

[25] Gastaldelli A.Insulin resistance and reduced metabolic flexibility: cause or consequence of NAFLD?.Clin Sci2017;131:2701-4

[26] Dongiovanni P,Pietrelli A.Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver.J Intern Med2018;283:356-70 PMCID:PMC5900872

[27] Fromenty B.Mitochondrial alterations in fatty liver diseases.J Hepatol2023;78:415-29

[28] Sanyal AJ,Ratziu V.The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials.Hepatology2019;70:1913-27

[29] Angulo P,Batts KP.Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis.Hepatology1999;30:1356-62

[30] Taylor RS,Bayliss S.Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.Gastroenterology2020;158:1611-25.e12

[31] Marino L,Ni B.Thyroid hormone action and liver disease, a complex interplay.Hepatology2025;81:651-69 PMCID:PMC11737129

[32] Harrison SA,Neff GW.Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial.Nat Med2023;29:2919-28 PMCID:PMC10667098

[33] Harrison SA,Guy CD.Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.Lancet2019;394:2012-24

[34] Silverman MG,Im K.Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis.JAMA2016;316:1289-97

[35] National Guideline Centre (UK). Non-alcoholic fatty liver disease: assessment and management. London: National Institute for Health and Care Excellence (NICE); 2016.

[36] Loomba R, Neuschwander-Tetri BA, Sanyal A, et al; NASH Clinical Research Network. Multicenter validation of association between decline in MRI-PDFF and histologic response in NASH. Hepatology. 2020;72:1219-29. PMCID:PMC8055244

[37] European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD).J Hepatol2024;81:492-542

[38] Noureddin M,Harrison SA.Expert panel recommendations: practical clinical applications for initiating and monitoring resmetirom in patients with MASH/NASH and moderate to noncirrhotic advanced fibrosis.Clin Gastroenterol Hepatol2024;22:2367-77

[39] Loomba R,Bernard D.LBP-20-VK2809, a novel liver-directed thyroid receptor beta agonist, significantly reduces liver fat with both low and high doses in patients with non-alcoholic fatty liver disease: a phase 2 randomized, placebo-controlled trial.J Hepatol2019;70:e150-1

[40] Pyke C,Kirk RK.GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody.Endocrinology2014;155:1280-90

[41] Barritt AS 4th,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 Ther2022;55:944-59 PMCID:PMC9310586

[42] Armstrong MJ,Guo K.Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis.J Hepatol2016;64:399-408 PMCID:PMC4713865

[43] Liuzzo G.Weekly Journal Scan: The ESSENCE of metabolic risk: targeting metabolic dysfunction-associated steatohepatitis with semaglutide.Eur Heart J2025;46:3505-7

[44] Armstrong MJ, Gaunt P, Aithal GP, et al; LEAN trial team. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387:679-90.

[45] Newsome PN, Buchholtz K, Cusi K, et al; NN9931-4296 Investigators. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384:1113-24.

[46] Sanyal AJ, Newsome PN, Kliers I, et al; ESSENCE Study Group. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392:2089-99.

[47] Husain M, Birkenfeld AL, Donsmark M, et al; PIONEER 6 Investigators. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381:841-51.

[48] Chen VL,Rotman Y.Resmetirom therapy for metabolic dysfunction-associated steatotic liver disease: October 2024 updates to AASLD Practice Guidance.Hepatology2025;81:312-20

[49] Loomba R, Abdelmalek MF, Armstrong MJ, et al; NN9931-4492 investigators. Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol Hepatol. 2023;8:511-22. PMCID:PMC10792518

[50] Alkhouri N,Gray M.The pleiotropic effects of glucagon-like peptide-1 receptor agonists in patients with metabolic dysfunction-associated steatohepatitis: a review for gastroenterologists.Expert Opin Investig Drugs2025;34:169-95

[51] Qin W,Ni Y.Efficacy and safety of once-weekly tirzepatide for weight management compared to placebo: an updated systematic review and meta-analysis including the latest SURMOUNT-2 trial.Endocrine2024;86:70-84 PMCID:PMC11445313

[52] Soni H.Peptide-based GLP-1/glucagon co-agonists: a double-edged sword to combat diabesity.Med Hypotheses2016;95:5-9

[53] Loomba R, Hartman ML, Lawitz EJ, et al; SYNERGY-NASH Investigators. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med. 2024;391:299-310.

[54] Ludvik B,Jódar E.Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial.Lancet2021;398:583-98

[55] Gastaldelli A,Fernández Landó L,Brouwers B.Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial.Lancet Diabetes Endocrinol2022;10:393-406

[56] Parlati L,Guillou H.New targets for NAFLD.JHEP Rep2021;3:100346 PMCID:PMC8507191

[57] Sanyal AJ,Fraessdorf M.A phase 2 randomized trial of survodutide in MASH and Fibrosis.N Engl J Med.2024;391:311-9

[58] Chiang CH,Colak SC.Glucagon-like peptide-1 receptor agonists and gastrointestinal adverse events: a systematic review and meta-analysis.Gastroenterology2025;169:1268-81

[59] Sanyal AJ,Frias JP.Triple hormone receptor agonist retetrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial.Nat Med2024;30:2037-48 PMCID:PMC11271400

[60] Lefere S,Hundertmark J.Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages^☆.J Hepatol2020;73:757-70

[61] Francque SM, Bedossa P, Ratziu V, et al; NATIVE Study Group. A randomized, controlled trial of the Pan-PPAR agonist lanifibranor in NASH. N Engl J Med. 2021;385:1547-58.

[62] Barb D,Godinez Leiva E.Pan-PPAR agonist lanifibranor improves insulin resistance and hepatic steatosis in patients with T2D and MASLD.J Hepatol2025;82:979-91

[63] Pharma Inventiva. Inventiva announces positive results from the Phase II, LEGEND, Proof-of-Concept study combining lanifibranor with empagliflozin in patients with MASH/NASH and T2D. Available from: https://inventivapharma.com/wp-content/uploads/2024/03/Inventiva-PR-Results-LEGEND-EN-03-18-2024.pdf. [Last accessed on 12 Dec 2025].

[64] Tillman EJ.FGF21: an emerging therapeutic target for non-alcoholic steatohepatitis and related metabolic diseases.Front Endocrinol2020;11:601290 PMCID:PMC7767990

[65] Kaufman A,Denney WS,Rolph T.AKR-001, an Fc-FGF21 analog, showed sustained pharmacodynamic effects on insulin sensitivity and lipid metabolism in type 2 diabetes patients.Cell Rep Med2020;1:100057 PMCID:PMC7659583

[66] Harrison SA,Freilich BL.Efruxifermin in non- alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial.Nat Med2021;27:1262-71

[67] Harrison SA,Freilich B.A randomized, double- blind, placebo-controlled phase IIa trial of efruxifermin for patients with compensated NASH cirrhosis.J HEP Rep2023;5:100563 PMCID:PMC9832280

[68] Harrison SA, Frias JP, Neff G, et al; HARMONY Study Group. Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Gastroenterol Hepatol. 2023;8:1080-93.

[69] Noureddin M,Chalasani NP.Efruxifermin in compensated liver cirrhosis caused by MASH.N Engl J Med2025;392:2413-24

[70] Loomba R,Kowdley KV.Randomized, controlled trial of the FGF21 analogue pegozafermin in NASH.NEJM2023;389:998-1008 PMCID:PMC10718287

[71] Loomba R,Rodriguez J.Efimosfermin alpha (BOS -580), a long-acting FGF21 analogue, in participants with phenotypic metabolic dysfunction-associated steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled. phase 2a trial.Lancet Gastroenterol Hepatol2025;10:734-45

[72] Loomba R,Grimmer K.Denifanstat for the treatment of metabolic dysfunction-associated steatohepatitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2b trial.Lancet Gastroenterol Hepatol2024;9:1090-100

[73] Targher G,Tilg H.MASLD: a systemic metabolic disorder with cardiovascular and malignant complications.Gut2024;73:691-702

[74] Lincoff AM, Brown-Frandsen K, Colhoun HM, et al; SELECT Trial Investigators. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389:2221-32.

[75] Hovingh GK,Heggen E.Resmetirom (MGL-3196) in patients with heterozygous familial hypercholesterolemia.J Am Coll Cardiol2022;79:1220-2

[76] Noureddin M.MASH clinical trials and drugs pipeline: an impending tsunami.Hepatology2025;82:1325-40