Gut hormone-based pharmacology: novel formulations and future possibilities for metabolic disease therapy

Abstract

Glucagon-like peptide-1 (GLP-1) receptor agonists are established pharmaceutical therapies for the treatment of type 2 diabetes and obesity. They mimic the action of GLP-1 to reduce glucose levels through stimulation of insulin secretion and inhibition of glucagon secretion. They also reduce body weight by inducing satiety through central actions. The GLP-1 receptor agonists used clinically are based on exendin-4 and native GLP-1 and are available as formulations for daily or weekly s.c. or oral administration. GLP-1 receptor agonism is also achieved by inhibitors of dipeptidyl peptidase-4 (DPP-4), which prevent the inactivation of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), thereby prolonging their raised levels after meal ingestion. Other developments in GLP-1 receptor agonism include the formation of small orally available agonists and compounds with the potential to pharmaceutically stimulate GLP-1 secretion from the gut. In addition, GLP-1/glucagon and GLP-1/GIP dual receptor agonists and GLP-1/GIP/glucagon triple receptor agonists have shown the potential to reduce blood glucose levels and body weight through their effects on islets and peripheral tissues, improving beta cell function and stimulating energy expenditure. This review summarises developments in gut hormone-based therapies and presents the future outlook for their use in type 2 diabetes and obesity.

Keywords: Diabetes; Double receptor agonists; GIP; GLP-1 receptor agonists; Glucagon; Obesity; Review; Triple receptor agonists.

Fig. 1

Schematic illustration of monoagonists, dual agonists and triple agonists based on GLP-1, GIP and glucagon receptor activation alone or in combination. This figure is available as part of a downloadable slideset

Fig. 2

The clinically most relevant mechanisms of action of GLP-1, glucagon and GIP. These provide the main basis for the actions of GLP-1 receptor agonists and dual and triple receptor agonists in the therapy of type 2 diabetes and obesity. This figure is available as part of a downloadable slideset

Fig. 3

Structures of formulations of GLP-1 receptor agonists [, , –21, 26]. (a) GLP-1, (b) exenatide, (c) lixisenatide, (d) efpeglenatide, (e) liraglutide, (f) semaglutide, (g) dulaglutide, (h) albiglutide. Amino acids are illustrated in circles; red circles show amino acids that are different from those in GLP-1. The red arrow in (a) illustrates the site of DPP-4 inactivation. This figure is available as part of a downloadable slideset

Fig. 4

Structures of (a) GLP-1, (b) GIP and (c) tirzepatide [19, 88, 90]. Amino acids are illustrated in circles; blue circles show amino acids that are identical to those in GLP-1; black circles show amino acids that are present in GIP and tirzepatide but not in GLP-1; red circles show amino acids that are identical in tirzepatide and exenatide (see Fig. 3b); and green circles show amino acids that are present in tirzepatide but not in GLP-1, GIP or exenatide. AiB, aminoisobutyric acid. This figure is available as part of a downloadable slideset