Obesity is a chronic, multifactorial, relapsing disease. Despite multicomponent lifestyle interventions, including
pharmacotherapy, maintaining bodyweight loss is challenging for many people. The pathophysiology of
obesity is complex, and currently approved
pharmacotherapies only target a few of the many pathways involved; thus, single-targeting agents have limited efficacy.
Proglucagon-derived
peptides,
glucagon, and the
incretin hormones glucagon-like peptide-1 (GLP-1) and
glucose-dependent insulinotropic
polypeptide (GIP), represent attractive targets for managing
obesity and metabolic disorders because they may have direct roles in multiple mechanisms including satiety, energy homeostasis, and lipolytic activity. Unimolecular dual and triple agonists targeting
glucagon and
incretin hormone receptors have been shown to promote bodyweight loss, lower
glucose levels, and reduce food intake in animal models of
obesity. Multiple dual receptor agonists are in clinical development for the treatment of
obesity, including
GLP-1/GIP and
GLP-1/
glucagon receptor agonists. The extent to which
glucagon contributes to treatment effects remains to be understood, but it may promote bodyweight loss by reducing food intake, while concomitant
GLP-1 receptor agonism ensures normal
glucose control. Further research is required to fully understand the molecular mechanisms of action and metabolic effects of both dual and triple receptor agonists.