25.14: Glucagon-like Receptor Agonists

Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.

GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by the dipeptidyl peptidase-4 (DPP-4) enzyme limits its therapeutic use. Two strategies have been implemented to exploit GLP-1 therapeutically: developing DPP-4-resistant peptide agonists of the GLP-1 receptor, and creating small-molecule DPP-4 inhibitors. An example of the former is exenatide (Byetta), a synthetic exendin-4 variant, which shares physiological and pharmacological properties with GLP-1 but is not metabolized by DPP-4, prolonging its effectiveness. Exenatide is used alone or in combination with other drugs for managing type 2 diabetes patients who fail to meet glycemic targets.

GLP-1 analogs resistant to enzymatic degradation and renal clearance, such as dulaglutide (Trulicity), liraglutide (Victoza) and lixisenatide (Adlyxin), have been developed to overcome the limitations of native peptide GLP-1. Another approach involves DPP-4 inhibitors like alogliptin (Nesina), linagliptin (Tradjenta), saxagliptin (Onglyza), sitagliptin (Januvia), and vildagliptin (Galvus), which extend the action of endogenously released GLP-1 and GIP. GLP-1 therapy also suppresses glucagon secretion, delays gastric emptying, inhibits feeding, and makes type 2 diabetes patients feel less hungry. The exact mechanism behind this reduced hunger sensation remains unclear.

Oral glucose intake triggers gut hormones like GLP-1 and GIP called incretins, which stimulate insulin secretion.

Both GLPs and glucagon originate from the preproglucagon. Proglucagon is processed into a large peptide including glucagon or GLP-1 and GLP-2, by intestinal L cells and specific hindbrain neurons.

However, GLP-1 is degraded by DPP-4 and endopeptidases and excreted renally, making it therapeutically unsuitable.

To circumvent this, metabolically stable GLP-1 analogs, including dulaglutide, liraglutide, and lixisenatide, have been developed.

These drugs help improve glycemic control in type 2 diabetes patients, either alone or combined with other drugs. Furthermore, they induce weight loss and are administered daily or weekly in an extended-release form.

Exenatide is a synthetic exendin-4 peptide variant. It is an analog of GLP-1 but is not metabolized by DPP-4, extending its action.

Another approach involves using the DPP-4 inhibitors that maximize the incretins' therapeutic efficacy.