The Paradox and Future of GLP-1/GIP Combination Therapies: Efficacy and Mechanisms.

Glucagon-like peptide-1 (GLP-1)-based obesity pharmacotherapies have revolutionized obesity treatment. In this review, we discuss the discovery of GLP-1 and evaluate the efficacy of marketed and investigational GLP-1 receptor (GLP-1R) agonists (GLP-1RAs), most notably semaglutide, as well as their potential central mechanism of action. We highlight the GLP-1R/glucose-dependent insulinotropic polypeptide receptor (GIPR) dual agonist tirzepatide and the GLP-1RA/GIPR antagonist maridebart cafraglutide, discussing how both methods of GIPR targeting can produce beneficial metabolic effects. The lack of evidence for the anorectic effects of GIPR agonism or antagonism alone in humans is noted, and the review concludes with an evaluation of other reasons for the greater efficacy of GIPR/GLP-1R dual targeting compounds over semaglutide.