Mazdutide (IBI362 / LY3305677)

1. Overview

Mazdutide (IBI362/LY3305677) is a dual GLP-1/glucagon receptor agonist peptide co-developed by Innovent Biologics (Suzhou, China) and Eli Lilly and Company. In late 2024, it became the first dual GLP-1/glucagon receptor agonist approved for clinical use anywhere in the world, receiving approval from China's National Medical Products Administration (NMPA) for chronic weight management in adults with obesity (BMI 28 or higher) or overweight (BMI 24 or higher) with at least one weight-related comorbidity [11]. This approval was based primarily on the Phase 3 GLORY-1 trial, which demonstrated 14.4% mean body weight loss at 48 weeks with the 9 mg dose [1].

The development of mazdutide reflects the convergence of two scientific trajectories: the clinical success of GLP-1 receptor agonists for weight management (exemplified by semaglutide and liraglutide) and the preclinical discovery that adding glucagon receptor co-agonism produces synergistic metabolic benefits, particularly for hepatic fat metabolism and energy expenditure [4][5]. Day et al. (2009) and Pocai et al. (2009) independently provided the foundational preclinical evidence that dual GLP-1/glucagon agonists could normalize body weight in obese rodents more effectively than GLP-1 agonism alone [4][5].

Mazdutide is administered as a once-weekly subcutaneous injection with dose escalation (starting at 3 mg and increasing through 4.5 mg and 6 mg to a maximum of 9 mg). The dose escalation protocol mirrors the approach used with other incretin-based therapies to improve gastrointestinal tolerability. The compound was developed under a licensing agreement between Innovent Biologics and Eli Lilly, with Innovent holding rights in China and Lilly holding rights in other territories.

The approval of mazdutide in China represents a significant milestone for the dual agonist class and for the Chinese anti-obesity pharmacotherapy landscape. China's obesity prevalence has risen rapidly, exceeding 16% in adults as of recent epidemiological surveys, creating substantial demand for effective pharmaceutical interventions [8].

Type

Dual GLP-1/glucagon receptor agonist peptide

Developers

Innovent Biologics / Eli Lilly and Company

Other Designations

IBI362, LY3305677

Receptor Targets

GLP-1 receptor and glucagon receptor (GCGR)

Route

Subcutaneous injection (once weekly)

Approved Indications

Chronic weight management (NMPA, China, 2024); Type 2 diabetes glycemic control (NMPA, China, 2025)

Phase 3 Trials

GLORY-1 (obesity), GLORY-2 (T2D)

Key Differentiator

First approved dual GLP-1/glucagon agonist globally

2. Mechanism of Action

Dual Receptor Agonism

Mazdutide activates two receptors with complementary metabolic effects [4][5][9][10]:

GLP-1 Receptor (GLP-1R):

• Appetite suppression: Activation of hypothalamic satiety centers reduces hunger and food intake
• Gastric emptying delay: Vagally mediated slowing of gastric motility promotes early satiety
• Insulin potentiation: Glucose-dependent enhancement of beta cell insulin secretion
• Glucagon suppression: Reduction of inappropriate alpha cell glucagon release during hyperglycemia

Glucagon Receptor (GCGR):

• Hepatic lipid oxidation: Glucagon signaling directly increases fatty acid beta-oxidation in the liver, reducing hepatic steatosis
• Energy expenditure: Increased metabolic rate through hepatic and whole-body thermogenesis
• Lipolysis: Mobilization of stored triglycerides from adipose tissue
• Amino acid catabolism: Enhanced hepatic ureagenesis

Synergistic Weight Loss Mechanism

The two receptor pathways produce weight loss through complementary mechanisms [4][10]:

• GLP-1 primarily reduces energy intake through appetite suppression and delayed gastric emptying
• Glucagon primarily increases energy expenditure through hepatic thermogenesis and lipid oxidation
• GLP-1's glucose-lowering effects offset glucagon's hyperglycemic tendency
• The net effect is greater weight loss than either receptor alone, with particular benefit for liver fat reduction

This dual mechanism distinguishes mazdutide from pure GLP-1 agonists (semaglutide, liraglutide) and from GIP/GLP-1 dual agonists (tirzepatide), positioning it particularly well for patients with co-existing fatty liver disease.

3. Clinical Development

Phase 1b (Multiple-Ascending Dose)

Zhu et al. (2022) conducted a Phase 1b MAD study in Chinese adults with overweight or obesity [3]. Key findings:

• Dose-proportional pharmacokinetics supporting once-weekly dosing
• Dose-dependent weight loss up to 7.2% at 12 weeks
• Acceptable tolerability with primarily gastrointestinal adverse events
• Dose-dependent reductions in fasting glucose and lipid parameters

Phase 2 (Dose-Finding in Obesity)

Ji et al. (2023) published the Phase 2 dose-finding trial in 247 Chinese adults with BMI 24 or higher [2]. Key findings:

• Mazdutide 6 mg achieved 11.7% mean body weight loss at 24 weeks vs. 0.5% placebo
• Significant reductions in waist circumference
• Improvements in fasting glucose, insulin resistance (HOMA-IR), and lipid profiles
• Weight loss curves had not plateaued at 24 weeks, suggesting potential for greater weight loss with longer treatment

GLORY-1 (Phase 3 Obesity Trial)

The pivotal GLORY-1 trial enrolled 610 Chinese adults and demonstrated the following results at 48 weeks [1]:

• Body weight loss: 14.4% at 9 mg vs. 3.6% placebo
• Proportion achieving 10% or more weight loss: 60.3% at 9 mg
• Proportion achieving 15% or more weight loss: 40.3% at 9 mg
• Waist circumference: Significant reductions
• Metabolic parameters: Improvements in blood pressure, lipids, and glycemic markers
• Tolerability: GI adverse events (nausea, vomiting, diarrhea) were the most common; generally mild-to-moderate

These results supported NMPA approval for chronic weight management in China [11].

GLORY-2 (Phase 3 Type 2 Diabetes)

The GLORY-2 trial evaluated mazdutide in Chinese adults with type 2 diabetes and overweight/obesity. At 60 weeks, mazdutide 9 mg achieved a mean weight reduction of 18.55% compared to 3.02% in the placebo group. Notably, 44.0% of participants in the 9 mg group achieved 20% or greater weight reduction versus 2.6% with placebo. These results substantially exceeded the 48-week data, demonstrating continued weight loss without plateau through 60 weeks.

DREAMS Program (Phase 3 Type 2 Diabetes)

The DREAMS program comprises multiple Phase 3 trials evaluating mazdutide for glycemic control in type 2 diabetes. DREAMS-1 (monotherapy) and DREAMS-2 (combination with oral antidiabetic drugs) met their primary endpoints, forming the basis for the September 2025 NMPA approval for T2D.

In the head-to-head DREAMS-3 trial comparing mazdutide directly with semaglutide, mazdutide demonstrated superiority: 48.0% of participants in the mazdutide group achieved the composite endpoint of HbA1c <7.0% and 10% or greater body weight reduction from baseline, compared to 21.0% in the semaglutide group. This is the first head-to-head trial to demonstrate superiority of a dual GLP-1/glucagon agonist over a GLP-1 agonist for combined glycemic and weight endpoints.

Regulatory Expansion (2025)

In September 2025, the NMPA approved mazdutide for glycemic control in adults with type 2 diabetes, making it the world's first dual GCG/GLP-1 receptor agonist approved for this indication. A supplementary application for the 9 mg dosage for long-term weight management in adults with moderate-to-severe obesity (BMI 35 or higher, or BMI 32 or higher with comorbidity) was accepted for review by the NMPA in November 2025. Global development continues, with Phase 2 trials in the US expected to complete in 2025-2026, and FDA approval estimated for 2028-2029. Additional clinical programs are under development for MASH and heart failure with preserved ejection fraction (HFpEF).

4. Comparison with Other Weight Loss Agents

vs. Semaglutide (Pure GLP-1)

Semaglutide 2.4 mg achieves approximately 15-17% weight loss at 68 weeks in the STEP trials. Mazdutide's 14.4% at 48 weeks is broadly comparable, with potential advantages in liver fat reduction due to the glucagon component. Direct comparative trials have not been conducted.

vs. Tirzepatide (GIP/GLP-1)

Tirzepatide achieves up to 22.5% weight loss at 72 weeks (15 mg dose, SURMOUNT-1). Mazdutide uses a different second receptor (glucagon vs. GIP), with potentially different benefits -- glucagon agonism specifically enhances hepatic fat metabolism.

vs. Pemvidutide (GLP-1/Glucagon)

Pemvidutide is a fellow GLP-1/glucagon dual agonist developed by Altimmune, currently in Phase 2. Both share the dual agonist mechanism but differ in molecular structure and clinical stage -- mazdutide has achieved regulatory approval while pemvidutide remains investigational.

5. Clinical Evidence Summary

6. Dosing in Research

7. Safety and Side Effects

The safety profile of mazdutide in clinical trials has been consistent with the GLP-1 agonist class [1][2][3]:

Common Adverse Events

• Nausea: Most frequent AE; generally mild-to-moderate, improving with continued dosing and dose escalation
• Vomiting: Less frequent than nausea
• Diarrhea: Mild-to-moderate; generally transient
• Decreased appetite: Expected pharmacological effect
• Injection site reactions: Mild, localized

Glucagon-Specific Considerations

• Glycemic effects: Glucagon receptor agonism can increase hepatic glucose output. In clinical trials, the GLP-1 component effectively counterbalanced this effect, and clinically significant hyperglycemia was not observed in non-diabetic populations [1][2]
• Heart rate: Small increases in heart rate have been observed, consistent with both GLP-1 and glucagon pharmacology; monitoring is warranted
• Lipid effects: Generally favorable, with reductions in LDL cholesterol and triglycerides observed

Serious Adverse Events

Serious adverse events were uncommon in the GLORY-1 trial and no new safety signals beyond those expected for the GLP-1 agonist class were identified [1].

Regulatory Safety

The NMPA approval in 2024 was based on comprehensive safety and efficacy data from the GLORY-1 Phase 3 trial, with ongoing post-marketing safety surveillance requirements [11].

8. Pharmacokinetics

Absorption and Distribution

Mazdutide is administered as a once-weekly subcutaneous injection, with pharmacokinetics supporting sustained receptor engagement throughout the 7-day dosing interval [3].

Phase 1b pharmacokinetic data (Zhu et al. 2022):

• Dose-proportional exposure: Mazdutide demonstrated dose-proportional pharmacokinetics across the 1.5-6 mg dose range, with predictable Cmax and AUC scaling [3]
• Steady state: Achieved within 3-4 weekly doses, consistent with the elimination half-life supporting once-weekly administration
• Tmax: Peak plasma concentrations reached within 1-3 days after subcutaneous injection
• Half-life: The terminal elimination half-life supports once-weekly dosing (functionally in the range of several days), achieved through structural modifications that reduce renal clearance and extend albumin binding

GLP-1/Glucagon Receptor Activation Balance

Mazdutide is designed with a specific ratio of GLP-1R to GCGR potency that achieves metabolic synergy [4][5][10]:

• GLP-1R activation must be sufficient to counterbalance glucagon-mediated hepatic glucose output throughout the pharmacokinetic profile
• GCGR activation provides direct hepatic lipid oxidation and thermogenesis that complement GLP-1-mediated appetite suppression
• The receptor potency ratio is optimized so that at trough concentrations (end of the dosing interval), both appetite suppression and hepatic metabolic effects are maintained

Dose Escalation Pharmacokinetics

The dose escalation protocol (3 mg to 4.5 mg to 6 mg to 9 mg, each for 4 weeks) serves multiple pharmacokinetic and pharmacodynamic purposes [1][3]:

• Allows GLP-1R-mediated GI adaptation during progressive receptor exposure
• Builds toward steady-state concentrations at each dose level before escalating
• Reduces the incidence and severity of GI adverse events (nausea, vomiting)
• The 9 mg maintenance dose was identified as the maximum efficacy dose in Phase 3

9. Dose-Response Relationships

Weight Loss Dose-Response

Phase 2 (24 weeks, Ji et al. 2023):

• Placebo: 0.5% weight loss
• 3 mg weekly: Moderate weight loss (less than 6 mg)
• 6 mg weekly: 11.7% mean body weight loss at 24 weeks [2]
• Weight loss curves had not plateaued at 24 weeks, motivating higher doses in Phase 3

Phase 3 GLORY-1 (48 weeks, Ji et al. 2024):

• Placebo: 3.6% weight loss
• 9 mg weekly: 14.4% mean body weight loss
• Proportion achieving 10% or more loss: 60.3% at 9 mg
• Proportion achieving 15% or more loss: 40.3% at 9 mg [1]

The dose-response demonstrates a clear positive relationship between dose and weight loss magnitude, with the 9 mg dose providing the greatest efficacy.

Glycemic Dose-Response (GLORY-2)

In the GLORY-2 trial for type 2 diabetes:

• Mazdutide produced dose-dependent HbA1c reductions alongside weight loss
• The dual mechanism addresses both glycemic control (via GLP-1R insulin potentiation) and underlying insulin resistance (via weight loss and hepatic fat reduction)
• The glucagon component's hyperglycemic tendency is fully counterbalanced by the GLP-1 component in both diabetic and non-diabetic populations

Liver Fat Dose-Response

While liver fat was not the primary endpoint in GLORY-1, the dual agonist mechanism is expected to produce substantial liver fat reduction based on the class pharmacology [4][5]:

• GLP-1-mediated weight loss indirectly reduces hepatic steatosis
• Glucagon-mediated hepatic lipid oxidation directly reduces liver fat content
• The combination typically produces liver fat reduction exceeding that expected from weight loss alone, as demonstrated with other GLP-1/glucagon dual agonists (pemvidutide: 78.6% at 48 weeks; survodutide: significant MASH resolution)

10. Comparative Effectiveness

vs. Semaglutide 2.4 mg (Wegovy)

| Parameter | Mazdutide 9 mg | Semaglutide 2.4 mg | |---|---|---| | Mechanism | Dual GLP-1/glucagon | Pure GLP-1 | | Weight loss | 14.4% at 48 weeks | ~15-17% at 68 weeks (STEP) | | Dual glycemic benefit | GLP-1 glucose lowering + glucagon hepatic effects | GLP-1 glucose lowering only | | Liver fat benefit | Enhanced (glucagon-driven hepatic lipid oxidation) | Moderate (weight-loss driven) | | Regulatory status | NMPA-approved (China, 2024) | FDA-approved; EMA-approved | | Population studied | Chinese adults (GLORY trials) | Global populations (STEP trials) |

Direct head-to-head comparison is not available. Semaglutide has more extensive global Phase 3 data and broader regulatory approval, while mazdutide's glucagon component may offer advantages for hepatic steatosis [1][9].

vs. Tirzepatide (Mounjaro/Zepbound)

| Parameter | Mazdutide | Tirzepatide | |---|---|---| | Receptor targets | GLP-1 + Glucagon | GLP-1 + GIP | | Weight loss (Phase 3) | 14.4% at 48 weeks | Up to 22.5% at 72 weeks | | Second receptor effect | Hepatic lipid oxidation, thermogenesis | Enhanced insulin sensitization, adipose effects | | MASH potential | Strong (direct glucagon hepatic effects) | Moderate (SYNERGY-NASH data) | | Global development | China-focused (Innovent); Lilly holds ex-China rights | Global (Lilly) |

Tirzepatide produces greater absolute weight loss, likely reflecting GIP's additive effects on appetite suppression and adipose tissue metabolism. Mazdutide's glucagon component provides a different metabolic profile with potentially superior liver-specific effects [4][7].

vs. Pemvidutide (ALT-801)

Both are GLP-1/glucagon dual agonists sharing the same mechanistic class:

• Clinical stage: Mazdutide is NMPA-approved (Phase 3 complete); pemvidutide is Phase 2 (MOMENTUM and IMPACT trials)
• Weight loss: Mazdutide 14.4% at 48 weeks; pemvidutide 15.6% at 48 weeks -- broadly comparable
• MASH data: Both demonstrate substantial liver fat reduction via glucagon-driven hepatic lipid oxidation
• Molecular differences: Different peptide structures and receptor potency ratios, potentially leading to different metabolic profiles despite the same dual agonist class
• Geographic focus: Mazdutide is primarily positioned for the Chinese market; pemvidutide for Western markets

vs. Retatrutide (Triple Agonist)

Retatrutide (GIP/GLP-1/glucagon triple agonist) achieved 24.2% weight loss at 48 weeks in Phase 2, substantially exceeding mazdutide's 14.4%. The triple agonist approach combines the benefits of all three receptor systems but adds complexity in optimizing the three-way receptor activation ratio and managing potential safety concerns from three concurrent hormonal pathways.

11. Enhanced Safety Profile

Gastrointestinal Tolerability

GI adverse events are the most common side effects, consistent with the GLP-1 agonist class [1][2][3]:

• Nausea: Most frequent AE; generally mild-to-moderate with improvement over time
• Vomiting and diarrhea: Less frequent; typically transient
• Dose escalation mitigation: The 4-week-per-step escalation protocol (3 to 4.5 to 6 to 9 mg) significantly reduces GI intolerance compared to rapid dose increases
• Discontinuation rates: GI-related discontinuation rates in GLORY-1 were manageable and comparable to other incretin-based therapies [1]

Glucose Homeostasis Safety

The glucagon component's potential to raise blood glucose is the key safety differentiator from pure GLP-1 agonists [4][10]:

• Non-diabetic populations: No clinically significant hyperglycemia was observed in GLORY-1, confirming that the GLP-1 component adequately counterbalances glucagon-driven hepatic glucose output [1]
• Type 2 diabetes populations: GLORY-2 demonstrated effective glycemic control (HbA1c reduction), indicating that the dual agonist balance is maintained even in patients with impaired glucose metabolism
• Hypoglycemia risk: The glucagon component may provide a theoretical protective mechanism against hypoglycemia that pure GLP-1 agonists lack, as glucagon stimulates hepatic glucose output when glucose levels drop

Cardiovascular Monitoring

• Small increases in heart rate (2-5 bpm) have been observed, consistent with both GLP-1 and glucagon pharmacology [1][2]
• Blood pressure typically decreases with weight loss, partially offsetting chronotropic effects
• Long-term cardiovascular outcomes data (CVOT) are not yet available for mazdutide
• Cardiovascular outcomes trials will likely be required for major global regulatory submissions

Hepatic Effects

Despite glucagon's acute effects on hepatic glucose output, the net hepatic effect of the dual agonist approach appears beneficial:

• Liver-related biomarkers (ALT, AST) generally improve with treatment, reflecting reduced hepatic steatosis
• The glucagon component directly promotes hepatic fatty acid beta-oxidation, addressing the root cause of MASH pathology [5]
• No hepatotoxicity signals have been identified in clinical trials

Lean Mass Considerations

Weight loss from any intervention involves both fat mass and lean mass reduction. Glucagon's catabolic properties (amino acid catabolism, ureagenesis) could theoretically increase the proportion of lean mass lost [7][10]:

• Body composition data from the GLORY trials will be important for characterizing the fat-to-lean loss ratio
• Physical activity and protein intake recommendations may be particularly important for patients on dual agonist therapy
• This concern is shared across all GLP-1/glucagon dual agonists in development

Regulatory Safety (NMPA Approval)

The NMPA approval in 2024 was based on comprehensive safety and efficacy data from GLORY-1, with ongoing requirements [11]:

• Post-marketing safety surveillance
• Periodic safety update reports
• Long-term safety follow-up of trial participants
• Potential requirement for cardiovascular outcomes data

12. Related Peptides

See also: Semaglutide, Tirzepatide, Retatrutide, Pemvidutide (ALT-801)

13. References

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2. [2] Ji L, Jiang H, An P, et al. (2023). Mazdutide, a novel GLP-1/glucagon dual receptor agonist, reduces body weight in Chinese adults with overweight or obesity. Lancet Diabetes Endocrinol. PubMed
3. [3] Zhu R, Jiang H, Li J, et al. (2022). Safety and efficacy of IBI362 (LY3305677) in Chinese adults with overweight or obesity. Diabetes Obes Metab. PubMed
4. [4] Day JW, Ottaway N, Patterson JT, et al. (2009). A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol. DOI PubMed
5. [5] Pocai A, Carber PE, Waring JF, et al. (2009). Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes. DOI PubMed
6. [6] Ambery P, Parker VE, Sherwin P, et al. (2018). MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes. Lancet. DOI PubMed
7. [7] Brandt SJ, Gotz A, Tschop MH, Muller TD (2018). Gut hormone polyagonists for the treatment of type 2 diabetes. Peptides. PubMed
8. [8] Pan XF, Wang L, Pan A (2021). Epidemiology and determinants of obesity in China. Lancet Diabetes Endocrinol. PubMed
9. [9] Drucker DJ (2018). Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. DOI PubMed
10. [10] Habegger KM, Heppner KM, Geary N, et al. (2010). The metabolic actions of glucagon revisited. Nat Rev Endocrinol. DOI PubMed
11. [11] Innovent Biologics, Inc. (2024). NMPA approval of mazdutide (IBI362) for chronic weight management. Company press release.
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