GLP-1 agonists for type 2 diabetes: pharmacokinetic and toxicological considerations

Expert Opin Drug Metab Toxicol. 2013 Jan;9(1):17-29. doi: 10.1517/17425255.2013.731394. Epub 2012 Oct 24.


Introduction: Within recent years, glucagon-like peptide 1 receptor agonists (GLP-1-RA) have emerged as a new treatment option for type 2 diabetes. The GLP-1-RA are administered subcutaneously and differ substantially in pharmacokinetic profiles.

Areas covered: This review describes the pharmacokinetics and safety aspects of the currently available GLP-1 receptor agonists, liraglutide (based on the structure of native GLP-1), exenatide twice daily and exenatide once weekly (based on exendin-4) in relation to the kinetics and toxicology of native GLP-1. The review is based on electronic literature searches and legal documents in the form of assessment reports from the European Medicines Agency and the United States Food and Drug Administration.

Expert opinion: GLP-1-based therapy combines several unique mechanisms of action and have the potential to gain widespread use in the fight against diabetes and obesity. The difference in chemical structure have strong implications for key pharmacokinetic parameters such as absorption and clearance, and eventually the safety and efficacy of the individual GLP-1-RA. The main safety concerns are pancreatitis and neoplasms, for which there are no identifiable differences in risk between the available agents. Antibody formation and injection site reactions are more frequent with the exendin-4-based compounds. The efficacy with regard to Hb(A1c) reduction is superior with the longer-acting agonists, whereas the shorter-acting GLP-1-RA seems to provide greater postprandial glucose control and lower tolerability as a possible consequence of less induction of tachyphylaxis. The future place of these agents will depend on the added safety and efficacy data in the several ongoing cardiovascular outcome trials.

Publication types

  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Exenatide
  • Glucagon-Like Peptide 1 / adverse effects
  • Glucagon-Like Peptide 1 / agonists*
  • Glucagon-Like Peptide 1 / analogs & derivatives
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide 1 / pharmacokinetics
  • Glucagon-Like Peptide 1 / therapeutic use
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypoglycemic Agents / therapeutic use
  • Liraglutide
  • Pancreatitis / chemically induced
  • Pancreatitis / metabolism
  • Peptides / adverse effects
  • Peptides / pharmacokinetics
  • Peptides / therapeutic use
  • Tachyphylaxis / physiology
  • Venoms / adverse effects
  • Venoms / pharmacokinetics
  • Venoms / therapeutic use


  • Hypoglycemic Agents
  • Peptides
  • Venoms
  • Liraglutide
  • Glucagon-Like Peptide 1
  • Exenatide