Peptide hormones and
proteins control
body weight and
glucose homeostasis by engaging peripheral and central metabolic signalling pathways responsible for the maintenance of
body weight and euglycaemia. The development of
obesity, often in association with
type 2 diabetes mellitus (T2DM), reflects a dysregulation of metabolic,
anorectic and orexigenic pathways in multiple organs. Notably, therapeutic attempts to normalize
body weight and glycaemia with single agents alone have generally been disappointing. The success of
bariatric surgery, together with emerging data from preclinical studies, illustrates the rationale and feasibility of using two or more agonists, or single co-agonists, for the treatment of
obesity and T2DM. Here, we review advances in the science of co-agonist
therapy, and highlight promising areas and challenges in co-agonist development. We describe mechanisms of action for combinations of
glucagon-like peptide 1,
glucagon,
gastric inhibitory polypeptide,
gastrin,
islet amyloid polypeptide and
leptin, which enhance
weight loss whilst preserving glucoregulatory efficacy in experimental models of
obesity and T2DM. Although substantial progress has been achieved in preclinical studies, the putative success and safety of co-agonist
therapy for the treatment of patients with
obesity and T2DM remains uncertain and requires extensive additional clinical validation.