Dual and triple receptor agonists targeting GLP-1, GIP, and glucagon receptors show promise for more effective obesity treatment by addressing multiple metabolic pathways simultaneously.
3 receptor targetsGLP-1, GIP, and glucagon receptors can be targeted simultaneously by a single drug molecule for enhanced obesity treatment
What the researchers found
Unimolecular dual and triple agonists targeting combinations of GLP-1, GIP, and glucagon receptors have demonstrated the ability to promote body weight loss, lower glucose levels, and reduce food intake in animal models of obesity. Multiple dual receptor agonists (GLP-1/GIP and GLP-1/glucagon combinations) are now in clinical development for obesity treatment.
The review highlights that glucagon may contribute to weight loss by reducing food intake, while simultaneous GLP-1 receptor activation helps maintain normal blood sugar control — addressing a key concern about using glucagon-based therapies in people with metabolic disorders.
Why it matters
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.
How the study worked
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.
What this study cannot tell us
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.
How to read the evidence
This is a narrative review paper synthesizing existing research rather than presenting new experimental data. While authored by leading experts in the field, the evidence for multi-receptor agonists was largely preclinical at the time of publication.
When this study was published
Published in 2022, this review predates many clinical trial results for dual and triple agonists. Since then, tirzepatide (a GLP-1/GIP dual agonist) has been approved and shown remarkable results, validating the approach described here.
The bigger picture
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.
Questions still open
- Can triple receptor agonists targeting GLP-1, GIP, and glucagon achieve even greater weight loss than dual agonists without unacceptable side effects?
- How does glucagon receptor activation contribute to weight loss independently of GLP-1 effects, and does it pose risks for glucose control?
- Will multi-receptor agonists prove effective for long-term weight maintenance, or will weight regain occur as with existing therapies?
Common questions
What are incretin hormones and why do they matter for obesity?
How are dual and triple agonists different from existing GLP-1 drugs?
Read the original research
The incretin/glucagon system as a target for pharmacotherapy of obesity.
Obesity reviews : an official journal of the International Association for the Study of Obesity, 23(2), e13372
Citation
Del Prato, Stefano; Gallwitz, Baptist; Holst, Jens Juul; Meier, Juris J. (2022). The incretin/glucagon system as a target for pharmacotherapy of obesity.. Obesity reviews : an official journal of the International Association for the Study of Obesity, 23(2), e13372. https://doi.org/10.1111/obr.13372