GLP-1, GIP/GLP-1, and GCGR/GLP-1 receptor agonists: Novel therapeutic agents for metabolic dysfunction-associated steatohepatitis

World J Gastroenterol. 2024 Dec 28;30(48):5205-5211. doi: 10.3748/wjg.v30.i48.5205.

Abstract

The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is estimated at 32.4%, reflecting its growing clinical significance. MASLD, which includes MASLD and metabolic dysfunction-associated steatohepatitis (MASH) has been linked to increased metabolic, cardiovascular, and malignant morbidity. Progression into fibrotic stages of MASLD is also strongly associated with liver-related mortality. The past few years have seen a heightened focus on creating innovative therapeutic strategies for MASH management. GLP-1 receptor agonists (RA) have also emerged as a potential treatment option. Studies on GLP-1 agonists, such as liraglutide and semaglutide, have demonstrated efficacy in MASH management, albeit with limited histological improvement of fibrosis. However, recent investigations into GLP-1/GIP RA (tirzepatide) and Glucagon/GLP-1 RA (survodutide) have shown even more encouraging results, with higher rates of MASH resolution and fibrosis improvement. The tolerability of these medications due to their gastrointestinal side effects remains a major concern. Future research should focus on optimizing drug regimens, identifying patients most likely to benefit, and balancing efficacy with tolerability. The evolving landscape of MASH therapeutics suggests a bright future, with the potential for combination therapies to further enhance patient outcomes.

Keywords: Glucagon-like peptide-1 receptor agonists; Liver fibrosis; Metabolic dysfunction-associated steatohepatitis; Metabolic dysfunction-associated steatotic liver disease; Semaglutide; Survodutide; Tirzepatide.

Publication types

  • Review

MeSH terms

  • Fatty Liver / drug therapy
  • Fatty Liver / metabolism
  • Gastric Inhibitory Polypeptide / agonists
  • Gastric Inhibitory Polypeptide / metabolism
  • Gastric Inhibitory Polypeptide / therapeutic use
  • Glucagon-Like Peptide 1* / agonists
  • Glucagon-Like Peptide 1* / metabolism
  • Glucagon-Like Peptide-1 Receptor Agonists
  • Glucagon-Like Peptide-1 Receptor* / agonists
  • Glucagon-Like Peptide-1 Receptor* / metabolism
  • Glucagon-Like Peptide-2 Receptor
  • Glucagon-Like Peptides / adverse effects
  • Glucagon-Like Peptides / analogs & derivatives
  • Glucagon-Like Peptides / therapeutic use
  • Humans
  • Incretins / therapeutic use
  • Liraglutide / pharmacology
  • Liraglutide / therapeutic use
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Non-alcoholic Fatty Liver Disease / drug therapy
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Receptors, Gastrointestinal Hormone* / agonists
  • Receptors, Gastrointestinal Hormone* / metabolism
  • Treatment Outcome

Substances

  • Glucagon-Like Peptide-1 Receptor
  • Receptors, Gastrointestinal Hormone
  • Glucagon-Like Peptide 1
  • gastric inhibitory polypeptide receptor
  • Glucagon-Like Peptides
  • Liraglutide
  • tirzepatide
  • Gastric Inhibitory Polypeptide
  • GLP1R protein, human
  • Incretins
  • semaglutide
  • Glucagon-Like Peptide-1 Receptor Agonists
  • Glucagon-Like Peptide-2 Receptor