GEP44, a novel peptide that simultaneously activates GLP-1, Y1R, and Y2R receptors, produced 15.6% body weight reduction versus 9.7% with liraglutide in obese male rats over 28 days.
−15.6% body weight vs −9.7% liraglutideThe triple-agonist peptide GEP44 produced 60% greater weight loss than liraglutide in male obese rats over 28 days of treatment
What the researchers found
Over 28 days, GEP44 (a GLP-1R/Y1R/Y2R triple agonist) produced body weight reductions of -15.6% in males and -11.9% in females versus vehicle, compared to -9.7% (males) and -5.1% (females) with liraglutide. Cumulative food intake reductions were also significantly greater: GEP44 reduced intake by -39% in males and -30% in females versus -20% and -10% with liraglutide, respectively.
Glucose tolerance tests showed similar stimulation of glucose-induced insulin secretion between GEP44 and liraglutide, indicating comparable glycemic effects despite the superior weight loss with the triple agonist.
Why it matters
Current GLP-1 agonists achieve meaningful weight loss but many patients don't reach their goals. This study demonstrates that a single peptide targeting three complementary pathways can produce substantially greater weight loss than GLP-1 agonism alone. The multi-receptor approach — combining gut hormone and neuropeptide Y pathways — addresses the reality that obesity involves multiple dysregulated systems simultaneously.
How the study worked
Diet-induced obese male and female rats received daily injections of GEP44 (triple agonist), liraglutide, or vehicle for 28 days. Body weight, food intake, glucose tolerance (IPGTT at baseline and day 14), and metabolic blood parameters (day 28) were measured. Both sexes were studied to assess potential sex differences in response.
What this study cannot tell us
This is an animal study that may not translate directly to humans. Rats received daily injections, which differs from the weekly dosing preferred in humans. Side effects (nausea, GI issues) were not comprehensively reported, which is a major concern for GLP-1-based therapies. The 28-day duration is short — sustained effects and safety need longer-term evaluation. The mechanism of weight loss (fat vs lean mass) was not detailed.
How to read the evidence
This is a preclinical study in diet-induced obese rats published in Clinical Nutrition. The head-to-head comparison with liraglutide, inclusion of both sexes, and multiple metabolic endpoints strengthen the study, but findings remain limited to an animal model.
When this study was published
Published in 2024, this is a very recent study representing the forefront of multi-receptor peptide drug development for obesity.
The bigger picture
The evolution of obesity peptide drugs has gone from single-agonists (liraglutide) to dual-agonists (tirzepatide) to emerging triple-agonists. GEP44 represents a novel triple-agonist approach that uniquely combines GLP-1 receptor activation with neuropeptide Y receptor modulation — a different strategy than the GLP-1/GIP/glucagon triple agonists currently in clinical trials. This diversification of multi-receptor targets could yield more options for personalized obesity treatment.
Questions still open
- Will GEP44's superior weight loss over liraglutide translate to human clinical trials without proportionally worse side effects?
- How does the Y1R/Y2R component of GEP44 contribute to weight loss independently of GLP-1R activation?
- Could GEP44's unique triple-agonist mechanism offer advantages over GLP-1/GIP dual agonists like tirzepatide?
Common questions
What makes GEP44 different from current weight-loss drugs like semaglutide?
Why did GEP44 work better in males than females?
Read the original research
Reductions of food intake and body weight in diet-induced obese rats following chronic treatment with a monomeric peptide multiagonist.
Clinical nutrition (Edinburgh, Scotland), 43(7), 1782-1790
Citation
Elfers, Clinton T; Chichura, Kylie S; Ashlaw, Emily F; Chepurny, Oleg G; Holz, George G; Doyle, Robert P; Roth, Christian L. (2024). Reductions of food intake and body weight in diet-induced obese rats following chronic treatment with a monomeric peptide multiagonist.. Clinical nutrition (Edinburgh, Scotland), 43(7), 1782-1790. https://doi.org/10.1016/j.clnu.2024.05.035