Pharmacologic management of metabolic and alcohol-associated liver disease

Abstract

Metabolic dysfunction and Alcohol associated Liver Disease (MetALD) is an emerging phenotype within the steatotic liver disease spectrum, characterized by cardiometabolic risk factors coexisting with alcohol exposure, resulting in synergistic liver injury and fibrosis progression. Therapeutic development remains limited because most steatotic liver disease trials exclude patients with ongoing alcohol use. In contrast, alcohol-associated liver disease (ALD) trials have focused primarily on severe alcohol-associated hepatitis. Current management of patients with MetALD relies on an integrated approach that simultaneously controls alcohol use and cardiometabolic risk. In clinical practice, for patients with MetALD and ongoing alcohol use, therapies aimed at controlling alcohol use remain most critical, given the faster, more progressive disease course related to alcohol as compared to metabolic liver injury. Given the dynamic nature of alcohol intake and metabolic risk factors, longitudinal monitoring of disease stage with noninvasive fibrosis tests is essential. Liver-directed therapies with efficacy in metabolic dysfunction-associated steatotic liver disease (MASLD), including incretin-based agents, fibroblast growth factor 21 analogs, peroxisome proliferator-activated receptor agonists, and thyroid hormone receptor beta agonists, may benefit selected MetALD patients. Several agents may modulate both metabolic pathways and alcohol consumption through central reward mechanisms. Specific pharmacotherapies targeting alcohol use (acamprosate, naltrexone) combined with structured psychosocial interventions are effective in controlling alcohol use. Given the lack of dedicated clinical trials in MetALD patients, we synthesized data from clinical trials in MASLD and ALD. We propose adapting these data to inform the design of future clinical trials in patients with MetALD.

Keywords

MetALD / steatotic liver disease / MASLD / alcohol-associated liver disease / GLP-1 receptor agonists / FGF21 analogs / thyroid hormone receptor-β agonists / alcohol use disorder

References

[1] 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.

[2] Dunn N,Abdellatif I.Metabolic dysfunction and alcohol-associated liver disease: a narrative review.Clin Transl Gastroenterol2025;16:e00828 PMCID:PMC12101925

[3] Kalligeros M,Vassilopoulos S,Mylonakis E.Prevalence of steatotic liver disease (MASLD, MetALD, and ALD) in the United States: NHANES 2017-2020.Clin Gastroenterol Hepatol2024;22:1330-2.e4

[4] Lee BP,Terrault NA.National prevalence estimates for steatotic liver disease and subclassifications using consensus nomenclature.Hepatology2024;79:666-73 PMCID:PMC11232657

[5] Dunn N,Blaney HL.Physical activity and advanced fibrosis in MASLD, MetALD, and ALD in a nationally representative cohort: NHANES 2017-2020.Hepatol Commun2025;9:e0797 PMCID:PMC12520209

[6] Kwak M,Jiang ZG.MASLD/MetALD and mortality in individuals with any cardio-metabolic risk factor: a population-based study with 26.7 years of follow-up.Hepatology2025;81:228-37 PMCID:PMC12169893

[7] Elmustafa F,Kaur H.Met-ALD and ALD- does differentiating these impact management and clinical outcomes?.Curr Hepatol Rep2025;24:10.1007/s11901-025 PMCID:PMC12685070

[8] Hagström H,Moreno C.Interactions between the metabolic syndrome and alcohol consumption increases the risk of liver disease.United European Gastroenterol J2024;12:168-76 PMCID:PMC10954435

[9] Singal AK.Diagnosis and treatment of alcohol-associated liver disease: a review.JAMA2021;326:165-76

[10] Francque SM,Kwanten WJ.Non-alcoholic fatty liver disease and cardiovascular risk: Pathophysiological mechanisms and implications.J Hepatol2016;65:425-43

[11] Åberg F.Drinking and obesity: alcoholic liver disease/nonalcoholic fatty liver disease interactions.Semin Liver Dis2020;40:154-62

[12] Wong VW,Wong GL.Community-based lifestyle modification programme for non-alcoholic fatty liver disease: a randomized controlled trial.J Hepatol2013;59:536-42

[13] Keating SE,De A.Lifestyle intervention for metabolic dysfunction-associated fatty liver disease: a 24-h integrated behavior perspective.Hepatol Int2024;18:959-76 PMCID:PMC11450077

[14] Bernardino M,Rosso N.The impact of the mediterranean diet, physical activity, and nutrition education on pediatric metabolic dysfunction-associated steatotic liver disease (MASLD): a review.Nutrients2025;18:28 PMCID:PMC12787394

[15] Rinella ME,Siddiqui MS.AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease.Hepatology2023;77:1797-835 PMCID:PMC10735173

[16] Yeoh A,Singal AK.The role bariatric surgery and endobariatric therapies in nonalcoholic steatohepatitis.Clin Liver Dis2023;27:413-27

[17] Hwang J,Shin H.Bariatric intervention improves metabolic dysfunction-associated steatohepatitis in patients with obesity: a systematic review and meta-analysis.Clin Mol Hepatol2024;30:561-76 PMCID:PMC11261233

[18] Abdallah M,Provenza J,Gowda S.Safety and efficacy of dyslipidemia treatment in NAFLD patients: a meta-analysis of randomized controlled trials.Ann Hepatol2022;27:100738

[19] 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.

[20] 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.

[21] Singal AK,Dasarathy S.ACG clinical guideline: malnutrition and nutritional recommendations in liver disease.Am J Gastroenterol2025;120:950-72 PMCID:PMC12191863

[22] Gratacós-Ginès J,Sancho-Bru P,Pose E.MetALD: clinical aspects, pathophysiology and treatment.JHEP Rep2025;7:101250 PMCID:PMC11782861

[23] Patel S,Nassar S.GLP-1 receptor agonists and alcohol use disorder: a systematic review.Alcohol Alcohol2025;61:agaf069

[24] Tanguturi Yella SS, Kota Sesha Brahma Sree KS, Mahato SK. The role of glucagon-like peptide-1 receptor agonists in the treatment of alcohol use disorder: current evidence and future directions.J Clin Psychopharmacol2025;45:372-5

[25] van Bloemendaal L,Ten Kulve JS.Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans.Diabetes Obes Metab2015;17:878-86

[26] 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.

[27] Newsome PN,Engebretsen KA.Semaglutide 2.4 mg in participants with metabolic dysfunction-associated steatohepatitis: baseline characteristics and design of the phase 3 ESSENCE trial.Aliment Pharmacol Ther2024;60:1525-33 PMCID:PMC11599791

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

[29] Fisher FM.Understanding the physiology of FGF21.Annu Rev Physiol2016;78:223-41

[30] Meroni M,Tiano F,Alisi A.β-Klotho as novel therapeutic target in metabolic dysfunction-associated steatotic liver disease (MASLD): a narrative review.Biomed Pharmacother2024;180:117608

[31] Harrison SA,Knott M.FGF21 agonists: an emerging therapeutic for metabolic dysfunction-associated steatohepatitis and beyond.J Hepatol2024;81:562-76

[32] Rose JP,Sullivan AI.FGF21 reverses MASH through coordinated actions on the CNS and liver.Cell Metab2025;37:1515-29.e6 PMCID:PMC12409791

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

[34] Jeong C,Jeon N.Efficacy and safety of fibroblast growth factor-21 analogs for the treatment of metabolic dysfunction-associated steatohepatitis: a systematic review and meta-analysis.Clin Pharmacol Ther2024;116:72-81

[35] Staels B,Francque S.Treating NASH by targeting peroxisome proliferator-activated receptors.J Hepatol2023;79:1302-16

[36] Results from the 52-week phase 2b VOYAGE trial of VK2809 in patients with biopsy-confirmed non-alcoholic steatohepatitis and fibrosis: a randomized, placebo-controlled trial.Gastroenterol Hepatol2024;20:13-4 PMCID:PMC11784560

[37] Kamata S,Ishii I.Current clinical trial status and future prospects of PPAR-targeted drugs for treating nonalcoholic fatty liver disease.Biomolecules2023;13:1264 PMCID:PMC10452531

[38] Goyal O,Goyal P.Saroglitazar in patients with non-alcoholic fatty liver disease and diabetic dyslipidemia: a prospective, observational, real world study.Sci Rep2020;10:21117 PMCID:PMC7713236

[39] Siddiqui MS,Sheikh F.Saroglitazar, a dual PPAR α/γ agonist, improves atherogenic dyslipidemia in patients with non-cirrhotic nonalcoholic fatty liver disease: a pooled analysis.Clin Gastroenterol Hepatol2023;21:2597-605.e2

[40] Takahashi H,Kawanaka M.Ipragliflozin improves the hepatic outcomes of patients with diabetes with NAFLD.Hepatol Commun2022;6:120-32 PMCID:PMC8710792

[41] Jin Z,Zheng C,Weng H.Effects of sodium-glucose co-transporter 2 inhibitors on liver fibrosis in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: an updated meta-analysis of randomized controlled trials.J Diabetes Complications2023;37:108558

[42] Soares De Oliveira L, Ritter MJ. Thyroid hormone and the liver.Hepatol Commun2025;9:e0596 PMCID:PMC11661762

[43] Venetsanaki V,Polyzos SA.Farnesoid X nuclear receptor agonists for the treatment of nonalcoholic steatohepatitis.Eur J Pharmacol2019;863:172661

[44] Loomba R, Noureddin M, Kowdley KV, et al.; for the ATLAS Investigators. Combination therapies including cilofexor and firsocostat for bridging fibrosis and cirrhosis attributable to NASH. Hepatology. 2021;73:625-43.

[45] Sanyal AJ,Lawitz EJ.Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial.Nat Med2023;29:392-400 PMCID:PMC9941046

[46] Ratziu V,Loustaud-Ratti V.Hepatic and renal improvements with FXR agonist vonafexor in individuals with suspected fibrotic NASH.J Hepatol2023;78:479-92

[47] Esler WP.Pharmacologic inhibition of lipogenesis for the treatment of NAFLD.J Hepatol2024;80:362-77 PMCID:PMC10842769

[48] 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

[49] Calle RA,Carvajal-Gonzalez S.ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials.Nat Med2021;27:1836-48

[50] Vujkovic M, Ramdas S, Lorenz KM, et al.; Regeneron Genetics Center, Geisinger-Regeneron DiscovEHR Collaboration, EPoS Consortium, VA Million Veteran Program. A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation. Nat Genet. 2022;54:761-71. PMCID:PMC10024253

[51] Stickel F,Buch S.Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers.Hepatology2020;72:88-102

[52] Schwantes-An TH, Darlay R, Mathurin P, et al.; GenomALC Consortium. Genome-wide association study and meta-analysis on alcohol-associated liver cirrhosis identifies genetic risk factors. Hepatology. 2021;73:1920-31.

[53] 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.

[54] Sanyal AJ, Bedossa P, Fraessdorf M, et al.; 1404-0043 Trial Investigators. A phase 2 randomized trial of survodutide in MASH and fibrosis. N Engl J Med. 2024;391:311-9.

[55] Groenewegen B,Crossette E.Consecutive fecal microbiota transplantation for metabolic dysfunction-associated steatotic liver disease: a randomized controlled trial.Gut Microbes2025;17:2541035 PMCID:PMC12323438

[56] Bajaj JS.Alcohol, liver disease and the gut microbiota.Nat Rev Gastroenterol Hepatol2019;16:235-46

[57] Witkiewitz K,Leggio L.Advances in the science and treatment of alcohol use disorder.Sci Adv2019;5:eaax4043 PMCID:PMC6760932

[58] Anton RF, O’Malley SS, Ciraulo DA, et al.; COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006;295:2003-17.

[59] Marek GW.MetALD: does it require a different therapeutic option?.Hepatology2024;80:1424-40 PMCID:PMC12172020

[60] Kranzler HR.Diagnosis and pharmacotherapy of alcohol use disorder: a review.JAMA2018;320:815-24 PMCID:PMC7391072

[61] McPheeters M,Riley S.Pharmacotherapy for alcohol use disorder: a systematic review and meta-analysis.JAMA2023;330:1653-65 PMCID:PMC10630900

[62] European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of alcohol-related liver disease. J Hepatol. 2018;69:154-81.

[63] Wu T,Kulai T.Safety of acamprosate in patients with alcohol-associated liver disease: a single-arm phase 2 trial.Mayo Clin Proc2025;100:954-61

[64] Leggio L,Farokhnia M.GLP-1 receptor agonists are promising but unproven treatments for alcohol and substance use disorders.Nat Med2023;29:2993-5 PMCID:PMC12320759

[65] Wang W,Berger NA,Kaelber DC.Associations of semaglutide with incidence and recurrence of alcohol use disorder in real-world population.Nat Commun2024;15:4548 PMCID:PMC11133479

[66] Quddos F,Tegge A.Semaglutide and tirzepatide reduce alcohol consumption in individuals with obesity.Sci Rep2023;13:20998 PMCID:PMC10684505

[67] Nasrollahizadeh A,Javankiani S.Repurposing GLP-1 receptor agonists for alcohol use disorder: a systematic review and meta-analysis.Diabetol Metab Syndr2026;18:29 PMCID:PMC12825243

[68] Cooley BJ,Choi EA.FGF21 analogue PF-05231023 on alcohol consumption and neuronal activity in the nucleus accumbens.Neuropsychopharmacology2026;51:519-29 PMCID:PMC12708781

[69] Desai BN,Watanabe M.Fibroblast growth factor 21 (FGF21) is robustly induced by ethanol and has a protective role in ethanol associated liver injury.Mol Metab2017;6:1395-406 PMCID:PMC5681240

[70] Flippo KH,Gillum MP.FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit.Cell Metab2022;34:317-28.e6 PMCID:PMC9093612

[71] Cronjé HT, Hu S, Gurrell R, et al. Robust human genetic evidence supporting causal effects of FGF21 on reducing alcohol consuming behaviours. medRxiv 2025;2025.11.15.25340305v1. Available from: https://www.medrxiv.org/content/10.1101/2025.11.15.25340305v1.full. [Last accessed on 12 Jun 2026].

[72] Shahi A,Rajak S.Liver-specific thyroid hormone receptor-β agonism alleviates alcoholic steatohepatitis (ASH) in mice.Biochem Biophys Res Commun2024;734:150742

[73] Matheson J.Therapeutic potential of peroxisome proliferator-activated receptor (PPAR) agonists in substance use disorders: a synthesis of preclinical and human evidence.Cells2020;9:1196 PMCID:PMC7291117

[74] Ferguson LB,Blednov YA.PPAR agonists regulate brain gene expression: relationship to their effects on ethanol consumption.Neuropharmacology2014;86:397-407 PMCID:PMC4188800

[75] Schwandt ML,Umhau JC,George DT.PPARγ activation by pioglitazone does not suppress cravings for alcohol, and is associated with a risk of myopathy in treatment seeking alcohol dependent patients: a randomized controlled proof of principle study.Psychopharmacology2020;237:2367-80 PMCID:PMC11018293

[76] Karahanian E,Fernandez K.Fenofibrate--a lipid-lowering drug--reduces voluntary alcohol drinking in rats.Alcohol2014;48:665-70

[77] Blednov YA,Black M.Peroxisome proliferator-activated receptors α and γ are linked with alcohol consumption in mice and withdrawal and dependence in humans.Alcohol Clin Exp Res2015;39:136-45 PMCID:PMC4308472

[78] Rivera-Meza M,Jerez E.Fenofibrate administration reduces alcohol and saccharin intake in rats: possible effects at peripheral and central levels.Front Behav Neurosci2017;11:133 PMCID:PMC5509805

[79] Mutlu EA,Rangwala H.Colonic microbiome is altered in alcoholism.Am J Physiol Gastrointest Liver Physiol2012;302:G966-78 PMCID:PMC3362077

[80] Wang SC,Chen SJ,Cheng CM.Alcohol addiction, gut microbiota, and alcoholism treatment: a review.Int J Mol Sci2020;21:6413 PMCID:PMC7504034

[81] Vatsalya V,Kong M.The beneficial effects of Lactobacillus GG therapy on liver and drinking assessments in patients with moderate alcohol-associated hepatitis.Am J Gastroenterol2023;118:1457-60 PMCID:PMC10524173

[82] Bajaj JS,Fagan A.A randomized clinical trial of fecal microbiota transplant for alcohol use disorder.Hepatology2021;73:1688-700

[83] Yu L,Yi H.Beneficial effects of LRP6-CRISPR on prevention of alcohol-related liver injury surpassed fecal microbiota transplant in a rat model.Gut Microbes2020;11:1015-29 PMCID:PMC7524294

[84] Arab JP,Rehm J.Metabolic dysfunction and alcohol-related liver disease (MetALD): position statement by an expert panel on alcohol-related liver disease.J Hepatol2025;82:744-56 PMCID:PMC12242919

[85] Gao B,Liangpunsakul S.Metabolic dysfunction and alcohol-associated liver disease (MetALD).eGastroenterology2025;3:e100319 PMCID:PMC12742176

[86] Tampaki M,Lekakis V.Prevalence, characteristics and outcomes of patients with metabolic and alcohol related/associated liver disease (MetALD): a systematic review and meta-analysis.Metabolism2025;163:156101

[87] Liu H,Guillot A,Tacke F.Bariatric surgery for metabolic dysfunction-associated steatotic liver disease (MASLD): current knowledge of mechanisms.Hepatology2025;Epub ahead of print:

[88] Singal AK,DiMartini A.Alcohol use disorder in alcohol-associated liver disease: two sides of the same coin.Liver Transpl2024;30:200-12 PMCID:PMC12432517

[89] Rady ED.Integrating phosphatidylethanol to enhance alcohol quantification in steatotic liver disease and clinical trials.Liver Int2026;46:e70489 PMCID:PMC12720218

[90] Harrison SA,Taub R.SAT-263 resmetirom treatment of a subgroup of patients with possible MetALD enrolled in MAESTRO-NASH, a phase 3 NASH/MASH serial liver biopsy study.J Hepatol2024;80:S141-2

[91] Sodhi M,Kezouh A.Risk of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists for weight loss.JAMA2023;330:1795-7 PMCID:PMC10557026

[92] Heymsfield SB,Montgomery P.Bimagrumab plus semaglutide alone or in combination for the treatment of obesity: a randomized phase 2 trial.Nat Med2026;32:869-82 PMCID:PMC13004672

[93] Neokosmidis G,Tziomalos K.Acetyl-CoA carboxylase inhibitors in non-alcoholic steatohepatitis: is there a benefit?.World J Gastroenterol2021;27:6522-6 PMCID:PMC8554398

[94] Niu C,Idoate-Domench DJ.Evaluating the long-term benefits of medications for alcohol use disorder in alcohol-associated cirrhosis.Liver Int2025;45:e70424

[95] Thompson R,Kaplan D.Safety of naltrexone in patients with cirrhosis.JHEP Rep2024;6:101095 PMCID:PMC11220533