Mazdutide is a synthetic peptide analog independently developed by Innovent Biologics. It targets both the GLP-1 (glucagon-like peptide-1) receptor and the GCG (glucagon) receptor, distinguishing it from Novo Nordisk’s semaglutide, which targets only the GLP-1 receptor, and Eli Lilly’s tirzepatide, which targets both GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) receptors.

Cyagen has conducted preclinical pharmacodynamic validation of Mazdutide, Tirzepatide, and Retatrutide in DIO (diet-induced obesity) mouse models.

A quick comparison of their targets at a glance:

      Drug Name Target Type Mechanism of Action Developer
Mazdutide
 
 
  GLP-1R + GCGR
 		 Dual agonist: appetite suppression + increased energy expenditure Innovent Biologics
Tirzepatide GLP-1R + GIPR
 
 
Dual agonist: appetite suppression + enhanced insulin secretion
 		 Eli Lilly
Retatrutide
 
 
GLP-1R + GIPR + GCGR
 		 Triple agonist: comprehensive metabolic regulation Eli Lilly

 

Methods:

Male DIO mice (~50 g) were induced with a high-fat diet (60% HFD, Research Diets, D12492) and then randomly assigned to groups based on body weight and composition. The compounds were administered via subcutaneous injection every three days for a total of 42 days. Body weight, food intake, and random blood glucose levels were monitored throughout the study.


Figure 1: Treatment results showed that all drug groups induced weight loss in DIO mice, with Retatrutide (LY3437943) demonstrating the most pronounced effect—reducing body weight by nearly 40%.


Figure 2: Body composition analysis at multiple time points (fat mass & lean mass) revealed that all treatment groups showed a significant reduction in total fat mass as early as Day 7, with even more pronounced effects observed at Days 14 and 28. Notably, Retatrutide (LY3437943), due to its robust weight loss effect, also led to a significant reduction in lean mass by Day 14.


Figure 3: Analysis of serum lipids (TC, TG, HDL-C, LDL-C) and liver function markers (ALT, AST) showed that all treatment groups effectively reduced the elevated levels of TC, HDL-C, LDL-C, ALT, and AST induced by the high-fat diet (HFD).


Figure 4: Oral glucose tolerance test (OGTT) and fasting blood glucose results showed that all treatment groups significantly reduced blood glucose levels.


From Tirzepatide’s dual synergy to Mazdutide’s dual agonism, and now to Retatrutide’s triple agonist strategy, these next-generation metabolic regulators represent the evolving frontier of anti-obesity drug development:

  • More complex targeting: Expanding beyond GLP-1R to also activate GIPR and GCGR, engaging multiple metabolic pathways.
  • Broader mechanisms: Regulating appetite and blood glucose while boosting energy expenditure and lipid metabolism.
  • Stronger effects: Retatrutide has shown near bariatric-level weight loss in clinical studies.
  • Fiercer competition: Domestic innovation (Mazdutide) is catching up fast, challenging global pharma giants.


This is more than a race in drug innovation—it's a critical chapter in the global fight against obesity.

Cyagen's Metabolic Platform – Empowering Preclinical Development of Weight Loss and Muscle-Gain Therapies

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