Tirzepatide: a new low for bodyweight and blood glucose

The normal incretin effect—an enhanced prandial insulin response—is mediated mostly by meal-stimulated release of the intestinal hormones GLP-1 and glucose-dependent insulinotropic peptide (GIP). 1 Analogues of GLP-1 that act as GLP-1 receptor agonists are established glucose-lowering agents that potentiate insulin release and suppress glucagon in a glucose-dependent manner. GLP-1 receptor agonists also facilitate weight loss via reduced food intake, by creating a feeling of fullness through delayed gastric emptying and by modulating central hunger-satiety controls. GIP probably makes a greater contribution to the normal prandial insulin response than does GLP-1, but GIP was disregarded for therapeutic purposes because its insulinotropic activity is greatly reduced in type 2 diabetes. 2 However, subsequent studies noted that the insulinotropic potency of GIP is restored in individuals with type 2 diabetes if the hyperglycaemia is first reduced by another agent such as insulin. This discovery has brought GIP back into therapeutic consideration, and a new incretin mimetic, tirzepatide, combines GIP receptor agonism with GLP-1 receptor agonism in a single chimeric peptide. 3