Mazdutide: Research & Studies
Scientific evidence, clinical trials, and research findings
📌TL;DR
- •6 clinical studies cited
- •Overall evidence level: high
- •7 research gaps identified
Research Studies
Safety and efficacy of a GLP-1 and glucagon receptor dual agonist mazdutide (IBI362) 9 mg and 10 mg in Chinese adults with overweight or obesity
Ji L, Gao L, Jiang H, et al. (2022) • eClinicalMedicine (The Lancet)
Phase 1b multiple-ascending-dose study showing 9 mg mazdutide achieved -11.7% body weight reduction at 12 weeks vs -1.8% placebo in Chinese adults with overweight or obesity.
Key Findings
- Mean body weight reduction of -11.7% at 12 weeks (9 mg group)
- Placebo group showed -1.8% weight change
- GI adverse events were most common but mostly mild-moderate
- No dose-limiting safety signals identified
Limitations: 12-week durationChinese population onlyOpen-label dose escalation phase
Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial
Ji L, Jiang H, An P, et al. (2024) • Diabetes Care
Phase 2 RCT demonstrating significant HbA1c reduction and weight loss with mazdutide in Chinese T2D patients. HbA1c reduced by -2.15% (6 mg) vs -0.14% (placebo) at 24 weeks.
Key Findings
- HbA1c reduction of -1.57% (4 mg) and -2.15% (6 mg) vs -0.14% placebo
- Dose-dependent weight loss alongside glycemic improvement
- Most adverse events were GI and mild-moderate
- Favorable tolerability profile supporting Phase III advancement
Limitations: 24-week durationChinese population onlyLimited dose range tested
A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity
Ji L, Gao L, Jiang H, et al. (2023) • Nature Communications
Phase 2 RCT evaluating mazdutide at multiple doses for obesity in Chinese adults. Demonstrated dose-dependent weight loss with acceptable safety profile.
Key Findings
- Significant dose-dependent weight loss
- Acceptable safety and tolerability profile
- GI adverse events were most common
- Supported dose selection for Phase III trials
Limitations: Phase 2 sample sizeChinese population only
Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight
Ji L, Jiang H, et al. (2025) • New England Journal of Medicine
Pivotal Phase III trial (GLORY) in Chinese adults showing mazdutide achieved up to 20.1% body weight reduction. Published in NEJM, supporting Chinese regulatory approval.
Key Findings
- 4 mg group: -10.09% weight loss at week 48
- 6 mg group: -12.55% weight loss at week 48
- 9 mg group: up to -20.1% weight loss at week 60
- 73.9-82.0% achieved >=5% weight loss (4-6 mg)
Limitations: Chinese populationNo active comparator arm in this trial
Efficacy and safety of Mazdutide on weight loss among diabetic and non-diabetic patients: a systematic review and meta-analysis of randomized controlled trials
Abdelgalil MS, Bahbah EI, et al. (2024) • Frontiers in Endocrinology
Systematic review and meta-analysis pooling mazdutide RCT data. Confirmed significant weight loss and glycemic improvement with quantified risk ratios for GI adverse events.
Key Findings
- Confirmed significant weight loss across studies
- Quantified GI adverse event risk ratios (nausea RR 4.22, vomiting RR 4.91)
- Decreased appetite RR 2.30 vs placebo
- No treatment discontinuations due to GI events in Phase 1b
Limitations: Limited number of trials available for poolingAll trials from Chinese populationsHeterogeneity in dosing protocols
Mazdutide versus Semaglutide for the treatment of type 2 diabetes and obesity: Rationale, design and baseline data of DREAMS-3 phase 3 trial
Ji L, et al. (2025) • Contemporary Clinical Trials
Design paper for the DREAMS-3 Phase III head-to-head trial comparing mazdutide vs semaglutide. First direct comparison of a GLP-1/glucagon dual agonist against a pure GLP-1 agonist in T2D with obesity.
Key Findings
- First head-to-head Phase III trial of dual vs single agonist
- Randomized open-label design comparing mazdutide to semaglutide
- Primary endpoint is HbA1c change
- Key secondary endpoints include body weight and metabolic parameters
Limitations: Design paper only; full results pendingOpen-label designChinese population
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🔍Research Gaps & Future Directions
- •Cardiovascular outcomes trial (MACE data) not yet completed
- •Long-term efficacy and safety beyond 60 weeks
- •Efficacy in non-Chinese populations (global Phase III needed)
- •Head-to-head comparison with tirzepatide not available
- •Effects on MASH/NAFLD not fully characterized
- •Impact on lean body mass and bone density with sustained weight loss
- •Mechanisms underlying differential effects vs pure GLP-1 agonists
Research Overview#
Mazdutide (IBI362/LY3305677) has one of the most robust clinical evidence packages among the dual GLP-1/glucagon receptor agonists, with data spanning Phase I through Phase III clinical trials. The research trajectory has progressed rapidly, from initial safety studies to pivotal efficacy trials and regulatory approval in China within approximately 5 years of first-in-human dosing.
The key clinical trial programs include the GLORY series (obesity/weight management), the Phase II diabetes program, and the DREAMS-3 head-to-head comparison with semaglutide. The research has consistently demonstrated significant weight loss and glycemic improvement with an acceptable safety profile dominated by manageable gastrointestinal adverse events.
Phase I/1b Studies#
Dose-Finding and Safety#
The Phase 1b multiple-ascending-dose study, published in eClinicalMedicine (The Lancet), evaluated mazdutide at 9 mg and 10 mg in Chinese adults with overweight or obesity. This 12-week study was critical for establishing the safety and tolerability of higher doses and for informing dose selection for Phase III development.
At 12 weeks, the 9 mg cohort achieved a mean body weight reduction of -11.7% compared to -1.8% with placebo. The study also demonstrated that gastrointestinal adverse events, while common, were predominantly mild to moderate in severity and most frequent during the dose escalation period. No dose-limiting safety signals were identified, supporting advancement to Phase III.
Phase II Studies#
Type 2 Diabetes Trial#
A randomized, double-blind, placebo-controlled Phase II trial evaluated mazdutide at doses of 3 mg, 4.5 mg, and 6 mg weekly in Chinese patients with type 2 diabetes over 24 weeks. Published in Diabetes Care, this study demonstrated dose-dependent glycemic improvement:
- HbA1c reduction of -1.57% (4 mg) and -2.15% (6 mg) versus -0.14% with placebo
- Significant body weight reduction alongside glycemic control
- Favorable tolerability with predominantly mild-moderate GI adverse events
These results were particularly noteworthy because the HbA1c reductions achieved with mazdutide were competitive with or superior to those reported for other incretin-based therapies in similar populations, suggesting the dual mechanism provides additive glycemic benefit.
Obesity Phase II Trial#
A separate Phase II randomized controlled trial, published in Nature Medicine, evaluated mazdutide at multiple doses in Chinese adults with overweight or obesity. This study confirmed dose-dependent weight loss with an acceptable safety profile and provided the dose-response data needed for Phase III trial design.
Phase III Trials#
GLORY Program (Pivotal Obesity Trial)#
The GLORY clinical trial program represents the pivotal evidence for mazdutide's obesity indication. The GLORY-2 trial, published in the New England Journal of Medicine in 2025, was a randomized, double-blind, placebo-controlled study in Chinese adults with obesity (BMI >= 28 kg/m2) or overweight (BMI >= 24 kg/m2) with at least one weight-related comorbidity.
Key Efficacy Results:
- 4 mg: -10.09% body weight reduction at week 48; 73.9% achieved >= 5% weight loss
- 6 mg: -12.55% body weight reduction at week 48; 82.0% achieved >= 5% weight loss
- 9 mg: Up to -20.1% body weight reduction at week 60
- Placebo: -0.45% body weight change
These results placed mazdutide among the most effective anti-obesity agents tested in clinical trials, with the 9 mg dose achieving weight loss comparable to or exceeding most approved therapies.
DREAMS-3 (Head-to-Head vs Semaglutide)#
The DREAMS-3 trial is a Phase III, randomized, open-label study directly comparing mazdutide with semaglutide in Chinese adults with type 2 diabetes and obesity. This represents the first head-to-head comparison of a dual GLP-1/glucagon receptor agonist against the market-leading pure GLP-1 receptor agonist.
Preliminary reports suggest mazdutide demonstrated superior glycemic control and weight loss compared to semaglutide, potentially validating the hypothesis that glucagon receptor co-agonism provides additive metabolic benefits beyond GLP-1 agonism alone. Complete results from DREAMS-3 are expected to be transformative for the field.
Systematic Review and Meta-Analysis Evidence#
A systematic review and meta-analysis published in Frontiers in Endocrinology pooled data from mazdutide randomized controlled trials. This analysis provided important quantitative context:
- Confirmed statistically significant weight loss across all mazdutide dose levels
- Quantified the increased risk of GI adverse events: nausea RR 4.22 (95% CI 2.23-7.99), vomiting RR 4.91 (95% CI 2.01-12.00), decreased appetite RR 2.30 (95% CI 1.45-3.65)
- Despite elevated GI event rates, treatment discontinuation due to adverse events was low
- Overall favorable benefit-risk profile supporting clinical use
Evidence Quality Assessment#
The evidence quality for mazdutide is high, based on:
Strengths#
- Multiple randomized, double-blind, placebo-controlled Phase II and III trials
- Published in top-tier journals (NEJM, Nature Medicine, Diabetes Care, The Lancet)
- Systematic review and meta-analysis available
- Head-to-head comparison with standard of care (semaglutide)
- Consistent dose-response relationships across studies
- Regulatory approval achieved based on clinical evidence
Limitations#
- Clinical trials conducted exclusively in Chinese populations
- No cardiovascular outcomes trial data
- Limited safety data beyond 60 weeks
- No head-to-head comparison with tirzepatide
- Limited data on special populations (elderly, renal impairment, hepatic impairment)
Research Gaps and Future Directions#
- Global Phase III trials: Studies in diverse populations outside China are needed for global regulatory submissions
- Cardiovascular outcomes: A dedicated MACE trial is essential for demonstrating cardiovascular safety and potential benefit
- MASH/liver disease: Given the glucagon receptor's hepatic effects, dedicated liver disease trials could reveal a unique therapeutic niche
- Combination therapy: Studies combining mazdutide with other weight management approaches
- Long-term maintenance: Understanding weight loss durability, weight regain patterns, and optimal long-term dosing
- Mechanism differentiation: Studies elucidating the specific contributions of glucagon receptor activation to metabolic outcomes
- Body composition: Detailed analysis of fat mass vs lean mass changes with different doses
Related Reading#
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