Multi-agonist peptides targeting combinations of GLP-1, GIP, and glucagon receptors are emerging as powerful therapies for diabetes and obesity, with tirzepatide already achieving up to 22.5% weight loss.
Up to 22.5% weight lossTirzepatide achieved this level of weight loss in non-diabetic individuals with obesity — comparable to some bariatric surgery outcomes.
What the researchers found
The review traces the development of three major classes of gut hormone multi-agonists: dual GLP-1/glucagon receptor agonists (first discovered 2009), dual GLP-1/GIP receptor agonists (first described 2013), and triple GLP-1/GIP/glucagon receptor agonists (first designed 2015).
Tirzepatide, a dual GLP-1/GIP agonist approved by the FDA for type 2 diabetes, outperformed both basal insulin and selective GLP-1 receptor agonists in HbA1c reduction. In non-diabetic individuals with obesity, tirzepatide achieved up to 22.5% weight loss — results comparable to certain bariatric surgeries.
Why it matters
With obesity and type 2 diabetes rates climbing worldwide, multi-agonist peptide drugs represent a paradigm shift in treatment. By targeting multiple hormone pathways simultaneously, these drugs achieve greater efficacy than single-target therapies. The success of tirzepatide has validated this approach, and triple agonists in development could push results even further.
How the study worked
This is a narrative review article that synthesizes published research on gut hormone multi-agonists. The authors surveyed the literature on the discovery, development, mechanisms of action, and clinical trial results for dual and triple receptor agonists targeting GLP-1, GIP, and glucagon receptors.
What this study cannot tell us
As a review article, this paper does not present new experimental data. The long-term safety and efficacy of newer multi-agonists, particularly triple agonists, are still being established in clinical trials. The review may not capture the most recent trial results given the rapid pace of development in this field.
How to read the evidence
This is a narrative review article that synthesizes existing research rather than presenting new experimental or clinical data. It provides a useful overview but relies on the strength of its cited primary studies.
When this study was published
Published in 2024, this review captures the state of the field shortly after tirzepatide's FDA approval, though the multi-agonist landscape is evolving rapidly with new trial data.
The bigger picture
This review captures a pivotal moment in metabolic medicine. The progression from single GLP-1 agonists to dual and triple agonists mirrors a broader trend toward combination therapies that leverage biological synergies. With tirzepatide already delivering surgical-level weight loss results, and triple agonists like retatrutide in clinical trials, multi-agonist peptides are poised to reshape how obesity and diabetes are treated globally.
Questions still open
- Will triple GLP-1/GIP/glucagon agonists deliver meaningfully better outcomes than dual agonists like tirzepatide?
- What are the long-term cardiovascular and safety profiles of multi-agonist peptide therapies?
- How will multi-agonist peptides compare to or complement bariatric surgery in clinical practice?
Common questions
What makes multi-agonist peptides better than single-target GLP-1 drugs?
Is tirzepatide's weight loss really comparable to bariatric surgery?
Read the original research
Gut hormone multi-agonists for the treatment of type 2 diabetes and obesity: advances and challenges.
The Journal of endocrinology, 262(3)
Citation
Huang, Xianxian; Liu, Jing; Peng, Guangquan; Lu, Mingyue; Zhou, Zhongbo; Jiang, Neng; Yan, Zhiming. (2024). Gut hormone multi-agonists for the treatment of type 2 diabetes and obesity: advances and challenges.. The Journal of endocrinology, 262(3). https://doi.org/10.1530/JOE-23-0404