Mazdutide (IBI362, LY3305677)

Comprehensive Research Analysis - Dual GLP-1/Glucagon Receptor Agonist for Weight Loss & Type 2 Diabetes

Classification: Dual GLP-1R/GCGR Agonist, Oxyntomodulin Analog, Incretin Mimetic Amino Acid Sequence: Oxyntomodulin-based structure with modifications (proprietary) Chemical Formula: C₂₀₇H₃₁₇N₄₅O₆₅ Molecular Weight: 4,476 Da (~4.5 kDa) Research Status: Phase 3 Clinical Trials (US); APPROVED in China (June 2025) China NMPA Status: APPROVED - Chronic Weight Management & T2DM (June 2025) WADA Status: Likely under monitoring (similar to other GLP-1 agonists)

1. Executive Summary

Mazdutide (also known as IBI362 or LY3305677) is a long-acting synthetic oxyntomodulin analog and dual agonist of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR). It represents the world's first dual GCG/GLP-1 receptor agonist approved for weight loss (China, June 2025).

Dual Mechanism Advantage: Mazdutide simultaneously activates GLP-1 receptor (enhanced insulin secretion, decreased glucagon) and glucagon receptor (increased energy expenditure, improved lipid metabolism). GCG receptors expressed mainly in liver enable inhibition of hepatic fat synthesis and promotion of hepatic lipolysis.

Exceptional Clinical Efficacy:

Unique Safety Profile: No gastrointestinal adverse events led to treatment discontinuation, contrasting sharply with 10-30% discontinuation rates observed with other dual agonists.

Goal Relevance:

  • I want to lose weight and improve my body composition.
  • I'm looking for help managing my type 2 diabetes.
  • I need to enhance my metabolism and burn more fat.
  • I'm interested in reducing liver fat and improving liver health.
  • I want to control my appetite and feel fuller for longer.
  • I'm seeking a treatment that doesn't cause gastrointestinal issues.

2. Chemical Structure & Composition

Molecular Weight: 4,476 Da (~4.5 kDa) Formula: C₂₀₇H₃₁₇N₄₅O₆₅ CAS Number: 2259884-03-0

Structural Basis: Oxyntomodulin (OXM)

Oxyntomodulin Structure:

Glucagon Sequence (29 amino acids): HSQGTFTSDYSKYLDSRRAQDFVQWLMNT

Oxyntomodulin: Glucagon sequence + 8 C-terminal extension (KRNRNNIA)

Mazdutide Modifications: Mazdutide subjected to several molecular modifications including fatty-acyl moiety to prolong half-life up to several days, allowing once-weekly administration.

Proprietary Structure: Complete amino acid sequence with all modifications is proprietary to Eli Lilly/Innovent. Public information confirms OXM basis with C20 fatty acid conjugation (similar to tirzepatide/retatrutide protraction strategy).

3. Mechanism of Action

Dual Receptor Agonism

Receptor Binding Profile:

  • GCGR (Glucagon Receptor):
    • Human GCGR: Ki = 17.7 nM
    • Mouse GCGR: Ki = 15.9 nM
  • GLP-1R (GLP-1 Receptor):
    • Human GLP-1R: Ki = 28.6 nM
    • Mouse GLP-1R: Ki = 25.1 nM

Functional Activity: Stimulates insulin secretion from mouse islets with EC₅₀ = 5.2 nM.

GLP-1 Receptor Pathway

Well-Established Effects:

  1. Enhanced insulin secretion: Glucose-dependent insulinotropic action
  2. Decreased glucagon levels: Suppresses inappropriate glucagon secretion
  3. Appetite suppression: Central anorexigenic effects
  4. Slowed gastric emptying: Promotes satiety

Glucagon Receptor Pathway (Unique Advantage)

Energy Expenditure Enhancement: Mazdutide may enhance energy expenditure via activation of GCGR pathway.

Hepatic Metabolic Effects:

Superior Liver Fat Reduction: Dual glucagon and GLP-1 receptor agonist mazdutide outbalanced GLP-1 receptor agonist semaglutide monotherapy in improving mice liver fat accumulation.

Comprehensive Metabolic Benefits

Triple Action:

  1. Weight Loss: Via appetite suppression + increased energy expenditure
  2. Glycemic Control: Enhanced insulin secretion + reduced glucagon
  3. Metabolic Health: Reduced visceral fat, comprehensive metabolic benefits

Clinical Validation: Mazdutide shown to simultaneously reduce body weight, blood glucose levels, and other comorbidities associated with obesity in patients with T2DM.

4. Pharmacokinetics

Half-Life

Extended Duration:

Absorption

Slow Absorption Profile:

Bioavailability

Specific absolute bioavailability data not published. All clinical trials use subcutaneous route with demonstrated therapeutic efficacy.

Pharmacokinetic Variability

Moderate PK Variability: Mazdutide demonstrated moderate pharmacokinetic variability across study populations.

Protraction Mechanism

Fatty-Acyl Modification: Peptide incorporates fatty-acyl moiety to prolong half-life, enabling once-weekly administration (similar strategy to tirzepatide/semaglutide).

5. Dosing Protocols

Phase 3 Clinical Dosing (GLORY Trial)

Approved China Doses:

  • 4 mg once weekly (subcutaneous)
  • 6 mg once weekly (subcutaneous)
  • Duration: 48 weeks

Escalation Schedule (typical): Gradual dose escalation over 20 weeks to final maintenance dose (specific escalation regimen not fully published for commercial use).

High-Dose Phase 1 Protocol

Up to 16mg Dosing: Two dose escalation regimens used to reach 16mg target dose over 20 weeks:

Phase 1b Protocol (9-10mg)

9mg Cohort:

  • Weeks 1-4: 3 mg
  • Weeks 5-8: 6 mg
  • Weeks 9-12: 9 mg (maintenance)

10mg Cohort:

  • Weeks 1-4: 2.5 mg
  • Weeks 5-8: 5 mg
  • Weeks 9-12: 7.5 mg
  • Weeks 13-16: 10 mg (maintenance)

Phase 2 Dosing

Obesity/Overweight Trial:

  • Once-weekly doses: 3 mg, 4.5 mg, 6 mg
  • Duration: 24 weeks

Type 2 Diabetes Trial:

  • Doses: 3 mg, 4.5 mg, 6 mg
  • Comparator: 1.5mg dulaglutide (open-label)
  • Duration: 20 weeks

Administration

Route: Subcutaneous injection Frequency: Once weekly (same day each week) Sites: Abdomen, thigh, upper arm (rotate) Timing: Without regard to meals

6. Clinical Research & Evidence

Phase 3 GLORY Trial (Obesity/Overweight)

NEJM Publication - Chinese Adults:

  • N: Adults with obesity or overweight
  • Duration: 48 weeks
  • Doses: 4mg, 6mg, placebo (once weekly)

Results (Week 48):

High-Dose Phase 1 Trial

Up to 16mg - 20 Week Study:

Phase 1b Trial (9-10mg)

Chinese Adults with Overweight/Obesity:

Phase 2 Trials

Obesity/Overweight (Nature Communications): 24-week treatment up to 6mg demonstrated clinically meaningful weight loss.

Type 2 Diabetes (Diabetes Care):

  • 20-week study with 3mg, 4.5mg, 6mg vs dulaglutide/placebo
  • Demonstrated glycemic control improvements + weight loss

Comparative Studies

Mazdutide vs Semaglutide: Dual glucagon and GLP-1 receptor agonist mazdutide outbalanced GLP-1 receptor agonist semaglutide monotherapy in improving mice liver fat accumulation.

DREAMS-3 Head-to-Head Trial: Mazdutide shows superiority in glycemic control with weight loss over semaglutide.

Cognitive Function (Preclinical)

Diabetes-Associated Cognitive Dysfunction: Mazdutide mitigates diabetes-associated cognitive dysfunction via multi-omics mechanisms.

Adolescent Case Report

Frontiers Publication: Dose-escalated mazdutide demonstrated efficacy and safety in adolescent with obesity, T2DM, and hyperuricemia.

7. Safety Profile

Overall Safety Assessment

Exceptional Tolerability:

Critical Distinction: NO gastrointestinal adverse events led to treatment discontinuation, in sharp contrast to 10-30% adverse event-related discontinuation rates with other dual agonists.

Common Adverse Events

Gastrointestinal (Most Frequent):

  • Upper respiratory tract infection
  • Diarrhea
  • Decreased appetite
  • Nausea
  • Urinary tract infection
  • Abdominal distension
  • Vomiting

Severity: GI adverse events mostly mild to moderate, tend to be transient.

Dose-Response Relationship

Favorable Tolerability Pattern: No dose-dependent increase in incidence of diarrhea, nausea, or vomiting.

Superior to Comparators: All mazdutide dose groups had lower incidence of nausea compared with dulaglutide.

Serious Adverse Events

Minimal Serious Events:

Treatment Discontinuation

Excellent Retention:

Special Populations

Adolescent Safety: Mazdutide well tolerated throughout treatment, no adverse events or drug-related side effects, no hypoglycemia or hypotension episodes.

8. Administration & Practical Application

Route: Subcutaneous injection Sites: Abdomen, thigh, upper arm (rotate sites) Frequency: Once weekly (same day each week) Timing: Without regard to meals

Injection Technique

Pre-filled Pen (Commercial Formulation):

  • Allow pen to reach room temperature
  • Clean injection site with alcohol swab
  • Inject slowly over 5-10 seconds
  • Rotate sites to prevent lipohypertrophy

Reconstituted Vial (If Applicable):

  • Use insulin syringes
  • Draw prescribed dose
  • Inject subcutaneously
  • Rotate injection sites

Dose Escalation

Important: Gradual dose escalation essential to improve tolerability. Typical escalation schedule over 12-20 weeks depending on target dose.

Missed Dose

  • If <4 days since missed dose: take ASAP
  • If ≥4 days: skip and resume next scheduled dose
  • Never double dose

Storage

Unopened:

  • Refrigerate 2-8°C until expiration
  • Protect from light

After First Use:

  • May store at room temperature ≤30°C
  • Follow manufacturer guidelines (typically 21-28 days)
  • Do NOT freeze

9. Storage & Stability

Lyophilized Powder (Research Chemical):

  • Store at -20°C (freezer) long-term
  • 2-8°C (refrigerator) short-term acceptable
  • Protect from light and moisture

Reconstituted Solution:

  • Refrigerate 2-8°C immediately
  • Use within 14-30 days (varies by formulation)
  • Do not freeze
  • Protect from light

Commercial Formulation (Pre-filled Pen):

  • Unopened: Refrigerate 2-8°C
  • After first use: Follow manufacturer guidance
  • Typically room temperature storage acceptable for limited period

Stability: Extended half-life (~8 days) provides stability for once-weekly dosing.

Development Partnership

Licensing Agreement:

  • Innovent: Chinese rights (secured from Lilly in 2019)
  • Eli Lilly: All markets outside China

WADA Status

No specific prohibition on WADA Prohibited List (as of 2025). Similar GLP-1 agonists (semaglutide, tirzepatide) under Monitoring Program; mazdutide likely follows similar pathway.

11. Product Cross-Reference

Core Peptides Equivalent: NOT AVAILABLE (404 error during research) - Mazdutide is approved/investigational drug, not typically available as research chemical

Epiq Aminos: Product availability extremely unlikely due to:

  • China NMPA approval (prescription drug)
  • US investigational status
  • Eli Lilly/Innovent proprietary development

Research Chemical Suppliers: Limited availability as research chemical:

Recommended Path:

  • China: Obtain via prescription from licensed healthcare provider
  • US: Participation in clinical trials (ClinicalTrials.gov)
  • Elsewhere: Await regulatory approval in respective jurisdictions

12. References & Citations

  1. Mazdutide - Wikipedia
  2. DrugBank - Mazdutide
  3. Rosenstock J, et al. Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight. NEJM. 2024.
  4. Bhattachar S, et al. Mazdutide reduces body weight: High-dose Phase 1 trial. Diabetes Obes Metab. 2025.
  5. Liu J, et al. Phase 2 trial of mazdutide in Chinese overweight/obese adults. Nat Commun. 2023.
  6. Gao L, et al. Efficacy and safety of mazdutide in Chinese T2DM patients. Diabetes Care. 2024.
  7. Gao L, et al. Safety and efficacy of mazdutide 9-10 mg. eClinicalMedicine. 2022.
  8. Shi Q, et al. Mazdutide mitigates cognitive dysfunction. eBioMedicine. 2025.
  9. Innovent NMPA Approval Announcement. June 2025.
  10. Fierce Pharma - Mazdutide China Approval Coverage
  11. MedChemExpress - Mazdutide Product Page
  12. Peptide Dosages - Mazdutide Protocol

Document Version: 1.0 Last Updated: December 23, 2025 Development Status: APPROVED in China (June 2025); Investigational in US (Phase 3) Regulatory Status: China NMPA Approved (Weight Management & T2DM); US FDA Investigational

Educational Information Only: DosingIQ provides educational information only. This is not medical advice. Consult a licensed healthcare provider before starting any supplement, peptide, or hormone protocol. Individual results may vary.