Beyond glucagon-like peptide-1: The promise of polyagonists in metabolic dysfunction–associated steatotic liver disease and metabolic dysfunction–associated steatohepatitis—A systematic review of randomized trials

Background: Metabolic dysfunction–associated steatotic liver disease (MASLD), formerly termed nonalcoholic fatty liver disease, is the most prevalent hepatic manifestation of metabolic syndrome, affecting nearly 30% of the global population. Its more severe inflammatory form, metabolic dysfunction–associated steatohepatitis (MASH), affects 3%-6% of U.S. adults and carries a high risk of progression to cirrhosis and hepatocellular carcinoma. Historically, only off-label pharmacologic therapies were available for MASLD and MASH; however, recently, resmetirom and semaglutide were approved by the Food and Drug Administration for the treatment of adults with MASH. Given the shared pathophysiology with type 2 diabetes mellitus and obesity, glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have emerged as promising agents for MASLD and MASH treatment. Objectives: This review aimed to critically evaluate and synthesize existing evidence from randomized controlled trials (RCTs) assessing the efficacy and safety of drugs that affect GLP-1RA plus other incretin hormones (polyagonists) including glucose-dependent insulinotropic polypeptide (GIP) and glucagon in the treatment of MASLD and MASH. Methods: A structured literature review was conducted using PubMed, Google Scholar, and ClinicalTrials.gov through September 2025 per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search produced 49 results for author review including 37 eligible studies. Eligible studies included RCTs assessing hepatic and metabolic outcomes in adults with MASLD or MASH treated with GLP-1RAs dual- or triple-incretin agents. Nine key studies met the inclusion criteria. Results: Dual agonists such as tirzepatide, pemvidutide, survodutide, and efinopegdutide demonstrated consistent, dose-dependent reductions in relative liver fat content ranging from 43% to 72.7%. In addition to reducing liver fat, survodutide produced histologic improvements in MASH without fibrosis progression, with nearly half of participants achieving resolution of steatohepatitis. Furthermore, triple agonists targeting GLP-1, glucagon, and GIP receptors—efocipegtrutide and retatrutide—achieved even greater reductions in liver fat of 59.3% and 82.7%, respectively. Conclusion: Incretin-based polyagonists hold tremendous promise in the management of MASLD and MASH. Their ability to reduce hepatic steatosis, improve glycemic and metabolic parameters, and potentially reverse histologic injury positions them as frontrunners in a field urgently in need of effective therapies. As long-term efficacy and safety data accumulate, these agents are likely to transform the therapeutic armamentarium for metabolic liver disease. Now is the time for pharmacists to lead the way in personalized incretin therapy—helping providers make informed choices and ensuring that patients stay engaged, adherent, and successful in their treatment.