Using Incretin and Glucagon Peptides as Targets for New Obesity Medications

This is a narrative review that synthesizes published research on proglucagon-derived peptides and their role in obesity management. The authors evaluated preclinical animal studies and early clinical development data on dual and triple receptor agonists targeting the incretin and glucagon hormone systems.

Current obesity medications have limited effectiveness because they typically target only one metabolic pathway. This review makes the case that combining multiple peptide hormone targets into a single drug could be far more effective. This multi-targeting approach has already led to breakthrough drugs like tirzepatide, and understanding the science behind these combinations is key to developing the next generation of obesity treatments.

This review was published just as the first dual-agonist drugs (like tirzepatide) were emerging in clinical trials. The multi-receptor approach it describes has since proven transformative, with tirzepatide achieving unprecedented weight loss results. The concept of triple agonists targeting GLP-1, GIP, and glucagon simultaneously represents the next frontier in peptide-based obesity pharmacotherapy.

Most evidence for dual and triple agonists at the time of this review came from animal models, which don't always predict human outcomes. The exact contribution of glucagon receptor activation to weight loss versus potential adverse metabolic effects was not fully understood. The review also acknowledges that the molecular mechanisms of action for these multi-target drugs require further elucidation.