Glucagon receptor agonism, once avoided in diabetes treatment, is now being combined with GLP-1 and GIP agonism to create dual and triple peptide agonists that enhance weight loss through increased energy expenditure.
Energy expenditureGlucagon receptor agonism uniquely boosts energy burning—the key limitation of current GLP-1-only drugs for obesity
What the researchers found
Glucagon receptor agonism enhances weight loss through energy expenditure stimulation when combined with GLP-1R and/or GIPR agonism, with dual (survodutide, cotatutide, mazdutide) and triple (retatrutide) agonists in clinical development.
Why it matters
Current GLP-1 drugs cause weight loss mainly by reducing food intake. Adding glucagon receptor agonism could produce more durable weight loss by also burning more calories—addressing the main limitation of current therapy.
How the study worked
IUPHAR-commissioned narrative review of preclinical evidence for glucagon receptor agonism mechanisms and clinical data on emerging dual and triple agonist peptide therapeutics.
What this study cannot tell us
Most GCGR agonism evidence is preclinical in rodents. Human clinical data on dual/triple agonists are limited. Safety concerns include cardiovascular effects and hepatotoxicity.
How to read the evidence
Authoritative IUPHAR review integrating preclinical mechanisms and early clinical evidence. Comprehensive but many drugs are still in early clinical development.
When this study was published
Published in 2025.
The bigger picture
The evolution from single (GLP-1) to dual (GLP-1/GIP or GLP-1/glucagon) to triple (GLP-1/GIP/glucagon) receptor agonists represents the cutting edge of peptide drug engineering for metabolic disease.
Questions still open
- Will the energy expenditure benefits of GCGR agonism translate proportionally to humans?
- Can GCGR-related cardiovascular concerns be managed in multi-receptor agonist drugs?
- Is the triple agonist approach superior to optimized dual agonism?
Common questions
How is glucagon becoming a weight loss treatment?
What is retatrutide?
Read the original research
IUPHAR review: From foe to friend: Repurposing glucagon to treat obesity and type 2 diabetes.
Pharmacological research, 223, 108077
Citation
Elmendorf, Andrew J; Yousefian, Mostafa; Kim, Il-Man; Hardaway, J Andrew; Habegger, Kirk; Flak, Jonathan N. (2026). IUPHAR review: From foe to friend: Repurposing glucagon to treat obesity and type 2 diabetes.. Pharmacological research, 223, 108077. https://doi.org/10.1016/j.phrs.2025.108077