The Premise of the Paradox: Examining the Evidence That Motivated GIPR Agonist and Antagonist Drug Development Programs.

Emerging clinical data support the paradoxical notion that glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) agonism and antagonism can provide additive weight loss when combined with a glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonist. In this review, we examine data that motivated the initiation of these seemingly contradictory drug discovery programs. We focus on the physiologic role of GIP in humans, human genetics evidence, rodent genetic models, and preclinical rodent and non-human primate pharmacology studies. Furthermore, we highlight where early preclinical findings translated into relevant clinical efficacy in the development of tirzepatide and maridebart cafraglutide (MariTide).