Glucagon Goes from Diabetes Villain to Obesity Treatment Partner in Multi-Receptor Peptide Drugs
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.
Quick Facts
What This Study 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.
Key Numbers
How They Did This
IUPHAR-commissioned narrative review of preclinical evidence for glucagon receptor agonism mechanisms and clinical data on emerging dual and triple agonist peptide therapeutics.
Why This Research 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.
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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- Energy expenditure Glucagon receptor agonism uniquely boosts energy burning—the key limitation of current GLP-1-only drugs for obesity
- Evidence Grade:
- Authoritative IUPHAR review integrating preclinical mechanisms and early clinical evidence. Comprehensive but many drugs are still in early clinical development.
- Study Age:
- Published in 2025.
- Original Title:
- IUPHAR review: From foe to friend: Repurposing glucagon to treat obesity and type 2 diabetes.
- Published In:
- Pharmacological research, 223, 108077 (2026)
- Authors:
- Elmendorf, Andrew J, Yousefian, Mostafa, Kim, Il-Man, Hardaway, J Andrew, Habegger, Kirk, Flak, Jonathan N
- Database ID:
- RPEP-15144
Evidence Hierarchy
Frequently Asked Questions
How is glucagon becoming a weight loss treatment?
Glucagon raises blood sugar when given alone, but when combined with GLP-1 (and sometimes GIP) in a single molecule, the appetite-suppressing effects counterbalance the sugar rise while glucagon uniquely boosts calorie burning.
What is retatrutide?
Retatrutide is a triple agonist peptide drug that activates GLP-1, GIP, and glucagon receptors simultaneously. In early trials, it produced the largest weight loss of any drug tested for obesity.
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Cite This Study
https://rethinkpeptides.com/research/RPEP-15144APA
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
MLA
Elmendorf, Andrew J, et al. "IUPHAR review: From foe to friend: Repurposing glucagon to treat obesity and type 2 diabetes.." Pharmacological research, 2026. https://doi.org/10.1016/j.phrs.2025.108077
RethinkPeptides
RethinkPeptides Research Database. "IUPHAR review: From foe to friend: Repurposing glucagon to t..." RPEP-15144. Retrieved from https://rethinkpeptides.com/research/elmendorf-2026-iuphar-review-from-foe
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.