Description

Product Summary – Mazdutide – (IBI362 / LY3305677)

Field	Details
Product Name	Mazdutide (IBI362; LY3305677) ⁠— a dual GLP-1 receptor (GLP-1R) and gluqagon receptor (GCGR) agonist
Category	Synthetic long-acting oxyntomodulin analog; dual incretin-gluqagon receptor agonist aimed at treating obesity and type 2 diabetes
Length / Structure	~33–34 amino acid peptide with fatty-acyl (C20 diacid) conjugated via a hydrophilic linker (AEEA). Contains the non-coded amino acid Aib at position 2
Molecular Formula	C₂₁₀H₃₂₂N₄₆O₆₇
Molecular Weight	≈ 4563.06 Da (free base)⁠
Form & Purity	Lyophilized white/off-white powder; research-use grade, typically ≥98% purity (HPLC)⁠
Storage	Store desiccated at ≤ −20 °C for long-term; reconstituted ≤ 4 °C for short term⁠
Key Mechanisms of Action	– GLP-1R activation: stimulates glucose-dependent insulin release, reduces appetite, slows gastric emptying⁠ – GCGR activation: increases energy expenditure, promotes lipolysis, enhances fatty liver metabolism⁠
Research / Clinical Use Cases	– Phase 1b (Chinese subjects with T2D): significant HbA1c reduction (−1.46% to −2.23%) and weight loss (up to −5.4%) compared to dulaglutide and placebo⁠ – Phase 3 obesity trials (GLORY-1): 4 mg and 6 mg arms met primary and secondary endpoints (≤48-week results), including sustained weight loss and cardio-metabolic improvements⁠
Common AEs / Safety Signals	– Well tolerated, mild-to-moderate GI symptoms (nausea, vomiting, diarrhea, reduced appetite) – Heart rate increases observed in all participants, but adverse events were transient—no discontinuations for safety reasons⁠
Contraindications / Warnings	– Investigational in most countries. – Regulatory approval limited (see below) – Typical precautions for incretin-based therapies apply (e.g., risk of GI side effects). – No known contraindications have been published yet.
Regulatory / Compliance	Approved in China in June 2025 for weight management⁠ NDA accepted by China’s NMPA based on efficacy and favorable safety outcomes in Phase 3 trials⁠

Mechanism of Action of Mazdutide

Receptor Level Pharmacology

Mazdutide, as an oxyntomodulin class co-agonist, triggers dual cAMP signalling on the GLP-1R and GCGR. Preclinical literature shows that oxyntomodulin-like ligands have reduced intrinsic potency as compared to the native GLP-1 or gluqagon at their respective receptors. However, they achieve synergistic metabolic effects when both receptors are co-activated, leading to increased anorectic signaling and peripheral substrate utilization. These effects have a dose-responsive reduction in body weight and improvements in the glycemic and cardiometabolic risk markers. [1]

Dual GLP-1R/GCGR Engagment

Mazdutide, as a selective, long-acting, co-agonist at GLP-1R and GCGR, coordinates the anorectic and thermogenic programs. At the hypothalamic-brainstem circuits, GLP-1R activation by mazdutide decreases energy intake and increases satiety, and slows down the gastric emptying, resulting in a reduction of post-prandial glucose excursions and caloric intake.

In islets, GLP-1R increases the glucose-dependent insulin secretion and decreases the gluqagon secretion with beta-cell stimulus secretion improvement. Whereas GCGR signaling exerts a negative energy balance by elevating the energy expenditure and lipid oxidation, and promoting fatty acid mobilization and thermogenesis. The GLP-1R counterbalances the GCGR-mediated hepatic and glucose output, preserving glycemic control.

Tolerability and Safety Considerations of Mazdutide

Phase 2–3 trials show a favorable safety profile with low discontinuation rates.
Mild to moderate GI symptoms (nausea, diarrhea, vomiting), usually early and transient.
Severe adverse events and hypoglycemia are uncommon, similar to placebo or dulaglutide.
Small, clinically insignificant increases in heart rate; no CV risk identified.

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Citations

Novikoff, A., & Müller, T. D. (2023). The molecular pharmacology of gluqagon agonists in diabetes and obesity. Peptides, 165, 171003. https://doi.org/10.1016/j.peptides.2023.171003
Drucker D. J. (2022). GLP-1 physiology informs the pharmacotherapy of obesity. Molecular metabolism, 57, 101351. https://doi.org/10.1016/j.molmet.2021.101351