Liraglutide: the therapeutic promise from animal models

P>Aims: To review the differences between the human glucagon-like peptide-1 (GLP-1) molecule and the analogue liraglutide, and to summarise key data from the liraglutide preclinical study programme showing the therapeutic promise of this new agent. Key findings: Liraglutide is a full agonist of the GLP-1 receptor and shares 97% of its amino acid sequence identity with human GLP-1. Unlike human GLP-1, however, liraglutide binds reversibly to serum albumin, and thus has increased resistance to enzymatic degradation and a longer half-life. In preclinical studies, liraglutide demonstrated good glycaemic control, mediated by the glucose-dependent stimulation of insulin and suppression of glucagon secretion and by delayed gastric emptying. Liraglutide also had positive effects on body weight, beta-cell preservation and mass, and cardiac function. Conclusions: The therapeutic promise of liraglutide is evident from preclinical data. Liraglutide showed the potential to provide good glycaemic control without increasing the risk of hypoglycaemia and, as with exenatide, but not dipeptidyl peptidase-4 inhibitors, to mediate weight loss. Although these benefits have subsequently been studied clinically, beta-cell mass can be directly studied only in animal models. In common with other incretin-based therapies, liraglutide showed the potential to modulate the progressive loss of beta-cell function that drives the continuing deterioration in glycaemic control in patients with type 2 diabetes. Body weight was lowered by a mechanism involving mainly lowered energy intake, but also potentially altered food preference and maintained energy expenditure despite weight loss.