New Triple-Acting Peptide Drug Outperforms Semaglutide and Tirzepatide for Weight Loss and Atherosclerosis in Mice | Research

The takeaway

A novel stapled peptide that simultaneously activates GLP-1, GIP, and glucagon receptors outperformed semaglutide and tirzepatide in reducing weight, improving glucose tolerance, and fighting atherosclerosis in obese mice.

Outperformed both semaglutide and tirzepatide
In obese mice, the triple agonist UTG-4 showed superior weight loss, appetite suppression, glucose control, and liver health compared to the two leading approved drugs

What the researchers found

The lead candidate UTG-4, a stapled triple agonist targeting GLP-1R/GIPR/GCGR, demonstrated enhanced efficacy over semaglutide (GLP-1R monoagonist) and tirzepatide (GLP-1R/GIPR dual agonist) in obese mice across multiple endpoints: weight loss, food intake suppression, glucose tolerance, and liver health. In Apoe knockout mice (a model of atherosclerosis), UTG-4 showed remarkable anti-atherosclerotic effects. Mechanistically, UTG-4 alleviated endothelial-to-mesenchymal transition in human aortic endothelial cells — a key process driving atherosclerosis progression. The peptide achieved balanced bioactivity across all three receptor targets comparable to their native ligands, with improved pharmacokinetic properties.

Why it matters

The race to build on GLP-1 drug success is one of the biggest stories in pharmaceutical development. Triple agonists represent the next frontier — adding glucagon receptor activation to the GLP-1/GIP dual agonism of tirzepatide. If UTG-4's superiority over both semaglutide and tirzepatide translates to humans, it could become the most potent anti-obesity peptide drug yet. The atherosclerosis benefit adds a cardiovascular dimension that goes beyond weight loss alone.

How the study worked

Researchers used a solid-phase Ugi macrocyclization strategy to synthesize stapled peptides with a side-chain protractor (for long-acting duration) attached to the exocyclic lactam bridge. They tested receptor activation using bioactivity assays, assessed pharmacokinetics, and evaluated efficacy in diet-induced obese mice (comparing to semaglutide and tirzepatide) and Apoe knockout mice (atherosclerosis model). Mechanistic studies used human aortic endothelial cells to assess endothelial-to-mesenchymal transition.

What this study cannot tell us

This is a preclinical mouse study — the efficacy advantages over semaglutide and tirzepatide in mice may not translate proportionally to humans. No human safety or efficacy data exist for UTG-4. The atherosclerosis model (Apoe knockout) is a genetic model that may not perfectly replicate human disease. Specific quantitative outcomes (percent weight loss, dose levels) were not detailed in the abstract. Long-term safety of simultaneous triple receptor activation is unknown.

How to read the evidence

This is a preclinical drug development study using mouse models of obesity and atherosclerosis with appropriate comparator drugs. The head-to-head comparisons with approved therapeutics strengthen the findings, but all results are in mice and no human data exist.

When this study was published

Published in 2025 in the Journal of Medicinal Chemistry, this is very recent work at the forefront of next-generation GLP-1 therapeutic development.

The bigger picture

The GLP-1 drug revolution has progressed from monoagonists (semaglutide/liraglutide) to dual agonists (tirzepatide) and is now moving toward triple agonists. Retatrutide (Eli Lilly's triple agonist) is already in late-stage clinical trials. UTG-4 enters this landscape with a novel stapled peptide chemistry and the added benefit of atherosclerosis reduction. The cardiovascular angle is particularly significant, as many obese patients are at high risk for heart disease, and showing that a single peptide can address both metabolic and vascular pathology is a compelling therapeutic proposition.

Questions still open

Will the superiority of UTG-4 over semaglutide and tirzepatide hold in human clinical trials?
Could the glucagon receptor activation component cause problematic blood sugar elevation in diabetic patients?
How does the anti-atherosclerotic effect of UTG-4 compare to that of dedicated cardiovascular drugs like statins?

Common questions

How is UTG-4 different from existing drugs like Ozempic and Mounjaro?

Ozempic (semaglutide) activates one receptor (GLP-1R), while Mounjaro (tirzepatide) activates two (GLP-1R and GIPR). UTG-4 goes a step further by activating all three — GLP-1R, GIPR, and the glucagon receptor. In mice, this triple action produced greater weight loss, better blood sugar control, and healthier livers than either existing drug. UTG-4 is also engineered with a chemical 'staple' that stabilizes its structure for longer-lasting effects.

Can a weight loss drug also protect against heart disease?

This study suggests UTG-4 may be able to do both. Beyond its metabolic benefits, UTG-4 reduced atherosclerosis (plaque buildup in arteries) in mice and prevented harmful changes in blood vessel lining cells. If confirmed in humans, this dual benefit would be especially valuable since obesity and cardiovascular disease frequently occur together, and treating both with a single drug could simplify treatment and improve outcomes.

Read the original research

Long-Acting and Stapled GLP-1R/GIPR/GCGR Triple Agonist for the Treatment of Obesity and Atherosclerosis.

Journal of medicinal chemistry, 68(15), 16578-16592

View on PubMed ↗Publisher’s paper ↗

Citation

Zhou, Yaqi; Tu, Longfang; Wang, Xueying; Xu, Jiean; Xu, Shujing; Ning, Xiao; Xiong, Xiaochun; Zheng, Nan. (2025). Long-Acting and Stapled GLP-1R/GIPR/GCGR Triple Agonist for the Treatment of Obesity and Atherosclerosis.. Journal of medicinal chemistry, 68(15), 16578-16592. https://doi.org/10.1021/acs.jmedchem.5c01399