Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus.

Abstract

Lixisenatide, under development by sanofi-aventis, is a novel human glucagon-like peptide-1 receptor (GLP-1R) agonist for the treatment of type 2 diabetes mellitus (T2DM; non-insulin dependent diabetes). The structure of lixisenatide, based on exendin-4(1-39) modified C-terminally with six Lys residues, is able to withstand physiological degradation by dipeptidyl peptidase IV. In vitro, lixisenatide bound to human GLP-1R with a greater affinity than native human GLP-1 (7-36 amide). In various in vitro and in vivo models of T2DM, lixisenatide improved glycemic measures and demonstrated promising pancreatic beta-cell-preserving actions. In patients with T2DM, subcutaneously administered lixisenatide displayed linear pharmacokinetics. In two phase II clinical trials, lixisenatide improved glucose tolerance, resulted in weight loss and lowered HbA1C, thereby causing significantly more patients to achieve target HbA1C levels compared with placebo. Lixisenatide exhibited well-established GLP-1-related gastrointestinal side effects, with mild nausea occurring most frequently; a low frequency of hypoglycemia was also reported. The results of phase III trials are awaited for confirmation of the anticipated effects of lixisenatide on glycemic measures and weight; favorable results would place lixisenatide for consideration among other GLP-1R agonists in the treatment armamentarium for T2DM.

• Authors: Mikkel Christensen, Filip K Knop, Jens J Holst, Tina Vilsboll
• Journal: IDrugs : the investigational drugs journal (IDrugs) Vol. 12 Issue 8 Pg. 503-13 (Aug 2009) ISSN: 2040-3410 [Electronic] England
• PMID: 19629885 (Publication Type: Journal Article, Review)

Chemical References

• Carrier Proteins
• GLP1R protein, human
• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents
• Peptides
• Receptors, Glucagon
• lixisenatide

Topics

• Animals
• Carrier Proteins (pharmacokinetics, pharmacology, therapeutic use)
• Clinical Trials as Topic
• Diabetes Mellitus, Type 2 (drug therapy)
• Drug Evaluation, Preclinical
• Glucagon-Like Peptide-1 Receptor
• Humans
• Hypoglycemic Agents (pharmacokinetics, pharmacology, therapeutic use)
• Injections, Subcutaneous
• Peptides (pharmacokinetics, pharmacology, therapeutic use)
• Receptors, Glucagon (agonists)