Glucagon-based therapies — including dual and triple receptor agonists — represent the next frontier in obesity treatment, with each added receptor target potentially amplifying weight loss.
Single → Dual → Triple agonistsThe progression from GLP-1 alone to dual (GLP-1/GIP or GLP-1/glucagon) to triple (GLP-1/GIP/glucagon) agonism reflects the evolving strategy of combining receptor targets for greater metabolic impact.
What the researchers found
This review maps the full landscape of glucagon-based obesity therapies, from single-receptor agonists to the newest triple-agonist drugs. Glucagon — traditionally seen as a blood-sugar-raising hormone — is being reframed as a metabolic multitool that boosts energy expenditure, suppresses appetite, and promotes fat burning.
The review covers single glucagon receptor agonists, dual agonists (GLP-1/glucagon like survodutide, and GLP-1/GIP like tirzepatide), and the emerging triple agonists that target GLP-1, GIP, and glucagon receptors simultaneously (like retatrutide). It also discusses combination approaches involving amylin, thyroid hormone (T3), FGF21, and peptide YY. Triple agonists show the most potent weight loss in early trials, leveraging the additive metabolic benefits of activating all three receptor pathways.
Why it matters
The obesity drug pipeline is rapidly evolving from single-target GLP-1 drugs (semaglutide) to multi-receptor agonists. Understanding why glucagon — a hormone that raises blood sugar — can paradoxically help with weight loss is key to understanding the next generation of metabolic drugs. This review provides a comprehensive map of where the field is heading, explaining why adding glucagon receptor activation to GLP-1 therapy may produce superior weight loss through increased energy expenditure.
How the study worked
Narrative review summarizing preclinical and clinical findings on glucagon-based obesity therapies, including single, dual, and triple receptor agonists, with discussion of mechanism of action, safety profiles, and ongoing clinical trials.
Who was studied
Review article (no study population)
What this study cannot tell us
This is a narrative review without systematic search methodology or meta-analysis. Many of the therapies discussed are in early clinical development, so long-term safety and efficacy data are limited. The review may not capture the most recent trial results published after its preparation.
How to read the evidence
This is a narrative review that synthesizes preclinical and clinical literature. It provides a useful overview of the field but does not present new data or use systematic methodology.
When this study was published
Published in 2024. This is a current and timely overview, though the field is moving rapidly and some drugs discussed may have updated trial data since publication.
The bigger picture
We're witnessing a rapid evolution in metabolic drug design: from single GLP-1 agonists to dual and triple agonists within just a few years. The inclusion of glucagon receptor activation is a paradigm shift — using a hormone traditionally associated with raising blood sugar for weight management. This 'more receptors, more weight loss' approach is driving the pipeline toward drugs like retatrutide (GLP-1/GIP/glucagon triple agonist) that have shown unprecedented weight loss in early trials.
Questions still open
- Will triple agonists like retatrutide maintain their weight loss advantage over dual agonists in large phase 3 trials?
- Can the blood-sugar-raising effect of glucagon receptor activation be safely managed in patients with diabetes?
- Is there a ceiling to the 'more receptors, more weight loss' approach, or will quad-agonists eventually emerge?
Common questions
Why would adding glucagon help with weight loss when glucagon raises blood sugar?
What's the difference between a dual and triple agonist weight loss drug?
Read the original research
Innovative Glucagon-based Therapies for Obesity.
Journal of the Endocrine Society, 8(12), bvae197
Citation
Enyew Belay, Kibret; Jemal, Rebil Heiru; Tuyizere, Aloys. (2024). Innovative Glucagon-based Therapies for Obesity.. Journal of the Endocrine Society, 8(12), bvae197. https://doi.org/10.1210/jendso/bvae197