Efficacy and safety of anti-obesity drugs in metabolic dysfunction-associated steatotic liver disease: An updated review

Abstract

Obesity is a major driver of metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). As the global prevalence of obesity continues to rise, the burden of MASLD/MASH is increasing, posing significant challenges to healthcare systems. The use of anti-obesity medications (AOMs) in this population is complex due to altered hepatic metabolism, safety concerns, and potential hepatotoxicity. Recent advances in pharmacologic agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), dual GLP-1/glucose-gastric inhibitory polypeptide (GIP) agonists, and triple GLP-1/GIP/glucagon agonists, have shown promising metabolic effects in the general population. Among these, GLP-1 RAs (e.g., liraglutide and semaglutide) consistently demonstrate hepatic benefits, including reductions in hepatic steatosis, improvements in liver enzyme profiles, and attenuation of fibrosis progression. Tirzepatide, a dual GLP-1/GIP agonist, has shown superior weight loss effects compared to GLP-1 receptor agonist monotherapy, with emerging but still limited data on hepatic outcomes in MASLD/MASH. Retatrutide, a triple agonist, has produced the most pronounced metabolic effects to date, although its impact on liver histology remains underexplored. Other AOMs, such as bupropion-naltrexone and phentermine-topiramate, require cautious use due to potential hepatotoxicity. Importantly, advanced MASLD may alter drug pharmacokinetics, underscoring the need for individualized therapy and close monitoring. This review provides an updated synthesis of the efficacy and safety of current and emerging AOMs in patients with MASLD/MASH and highlights the urgent need for further research to define optimal pharmacological strategies in this high-risk population.

Keywords: Obesity; Metabolic dysfunction-associated steatotic liver disease; Metabolic dysfunction-associated steatohepatitis; Glucagon-like peptide-1 receptor agonists; Tirzepatide; Retatrutide; Anti-obesity medications

Core Tip: Obesity is a leading modifiable risk factor for chronic liver disease, particularly metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis. Glucagon-like peptide-1 receptor agonists and emerging dual and triple incretin agonists offer promising metabolic and hepatic benefits. However, their use in advanced liver disease raises concerns due to altered pharmacokinetics and limited safety data. This review synthesizes current evidence on the efficacy and safety of anti-obesity medications in individuals with metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis and underscores the need for personalized treatment strategies and robust clinical trials.