Pharmacological profile of lixisenatide: A new GLP-1 receptor agonist for the treatment of type 2 diabetes.
The glucagon-like peptide-1 (GLP-1) receptor represents an established therapeutic target in type 2 diabetes mellitus (T2DM). Agents that activate this receptor improve glucose tolerance alongside a low risk of hypoglycaemia, and have the potential to modify disease progression. Lixisenatide is a new potent and selective GLP-1 receptor agonist currently in development. The preclinical pharmacological profile of Lixisenatide suggests actions that are highly relevant to the long-term maintenance of glucose homeostasis. Lixisenatide protected Ins-1 cells (a rat-derived beta-cell line) from both lipid- and cytokine-induced apoptosis. More importantly, Lixisenatide also prevented lipotoxicity-induced insulin depletion in human islets and preserved insulin production, storage and pancreatic beta-cell function in vitro. Enhancement of insulin biosynthesis and pancreatic beta-cell volume could also be demonstrated in animal models of type 2 diabetes. The improvement of glucose-stimulated insulin secretion provided by Lixisenatide occurred in a strictly glucose-dependent manner. In animal models of diabetes, Lixisenatide improved basal blood glucose and HbA(1c) with a rapid onset and sustained duration of action, and prevented the deterioration of pancreatic responsiveness and glucose homeostasis. Lixisenatide also delayed gastric emptying and reduced food intake. The efficacy/safety profile of Lixisenatide is currently being studied further in an extensive ongoing Phase III clinical study programme. This article reviews the preclinical pharmacological profile of Lixisenatide.
Werner
Ulrich
U
Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany. ulrich.werner@sanofi-aventis.com
Haschke
Guido
G
Herling
Andreas W
AW
Kramer
Werner
W
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D010455:Peptides / Q000627:therapeutic use*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D000067758:Glucagon-Like Peptide-2 Receptor
D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D018027:Receptors, Glucagon; C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; C479460:lixisenatide; D000067758:Glucagon-Like Peptide-2 Receptor