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Glucagon-like peptide-1 GLP-1 is a naturally occurring 30-amino acid eptide synthesised in intestinal endocrine L cells. GLP-1 mediates glucose homeostasis through stimulation of glucose-dependent insulin secretion, biosynthesis of insulin and inhibition of glucagon secretion. These effects have potential clinical value in type 2 diabetes.

However, because native GLP-1 is rapidly degraded to its inactive form by dipeptidyl peptidase-4 (DPP-4), it has a short half-life in vivo. Strategies to overcome this therapeutic limitation include developing GLP-1 mimetics and analogues with longer half-lives and to inhibit DPP-4. Exenatide (exendin-4) is a 39-amino acid peptide originally derived from the venom of the Gila monster lizard, and shares a 53% sequence identity with human GLP-1. Exenatide has a longer circulating half-life, reflecting relative resistance to DPP-4 degradation, and is administered twice daily.

Liraglutide is a once-daily human GLP-1 analogue with high (97%) sequence identity. The specific structural modifications that characterise liraglutide result in increased self-association (allowing slow absorption from the subcutaneous depot), promote albumin binding and reduce susceptibility to DPP-4, giving liraglutide a halflife of 13 hours after once-daily administration. Preliminary studies of exenatide and liraglutide showclinically relevant reductions in glycosylated haemoglobin A1c (HbA1c) compared with placebo,without hypoglycaemia andwithweight loss of up to 3 kg.

DPP-4 inhibitors, such as vildagliptin (not available in the USA) and sitagliptin can help stabilise postprandial GLP-1 levels and thus produce desirable effects on insulin and glucagon production. The potential forweight reductionwith DPP-4 inhibitors appears limited, perhaps reflecting the limited increase in GLP-1 levels achieved with these agents.