Peptide Profile
Mazdutide
What Is Mazdutide?
Mazdutide (also known by its development codes IBI362 and LY3305677) is a GLP-1/glucagon dual receptor agonist — an engineered peptide that simultaneously activates two key metabolic receptors involved in appetite regulation, energy expenditure, and glucose control. Originally developed by Mazdutide Innovent Biologics in China, this mazdutide peptide became the world’s first GLP-1 glucagon dual agonist to receive regulatory approval for obesity when China’s National Medical Products Administration (NMPA) granted marketing authorisation in July 2025.
The compound is based on the structure of oxyntomodulin, a naturally occurring gut hormone that activates both GLP-1 and glucagon receptors. By engineering a synthetic analogue with improved pharmacokinetic properties — including a half-life of approximately 130 hours (~5.4 days) — researchers created a once-weekly subcutaneous injection suitable for chronic weight management. Eli Lilly licensed the ex-China development rights in a 2022 deal worth over $200 million upfront, signalling substantial pharmaceutical industry interest in this dual-agonist approach.
Mazdutide sits within a rapidly expanding class of multi-receptor agonists alongside compounds like tirzepatide (GLP-1/GIP dual agonist) and retatrutide (GLP-1/GIP/glucagon triple agonist). What distinguishes mazdutide is its specific combination of GLP-1 and glucagon receptor activation — a pairing that research suggests may offer unique advantages for both appetite and weight management and hepatic fat reduction.
Compound Profile
Mechanism of Action
As a GLP-1 glucagon dual agonist, mazdutide engages two distinct receptor pathways that contribute to its metabolic effects through complementary mechanisms.
GLP-1 Receptor Activation
The GLP-1 receptor agonist component of mazdutide mirrors the well-characterised effects of established compounds like semaglutide and liraglutide. Activation of the GLP-1 receptor in the brain’s hypothalamus and brainstem reduces appetite and increases satiety signalling. In the pancreas, GLP-1 receptor activation enhances glucose-dependent insulin secretion and suppresses glucagon release, contributing to improved glycaemic control. The mazdutide GLP-1 component also slows gastric emptying, which may further extend post-meal satiety.
Glucagon Receptor Activation
The mazdutide glucagon receptor component is what fundamentally differentiates this compound from pure GLP-1 receptor agonists. Glucagon receptor activation in the liver promotes glycogenolysis and gluconeogenesis, but its metabolic effects extend well beyond glucose production. Research indicates that glucagon receptor activation increases hepatic lipid oxidation and energy expenditure — essentially encouraging the body to burn more energy at rest. This thermogenic effect adds a caloric expenditure dimension to weight loss that pure GLP-1 RAs lack.
Additionally, glucagon receptor signalling appears to directly promote hepatic fat mobilisation, which may explain the emerging data on liver fat reduction with mazdutide. Preclinical and clinical evidence suggests that the glucagon component drives fatty acid oxidation in the liver, reducing hepatic steatosis through a mechanism distinct from simple caloric restriction.
The dual-receptor approach creates what researchers describe as a synergistic metabolic effect: GLP-1 receptor activation reduces caloric intake through appetite suppression, while glucagon receptor activation increases caloric expenditure through enhanced thermogenesis and lipid oxidation. This complementary pairing may explain why clinical data shows weight loss with mazdutide alongside favourable metabolic outcomes for metabolic health and insulin sensitivity.
Clinical Evidence
The mazdutide clinical programme includes two major Phase 3 trial series — GLORY (obesity/overweight) and DREAMS (type 2 diabetes) — alongside earlier Phase 1 and Phase 2 studies. Combined, these trials form a substantial evidence base that supported Chinese regulatory approval and underpin ongoing global development.
Phase 1 and Phase 2 Foundations
Early clinical development began with a Phase 1b randomised controlled trial in Chinese patients with type 2 diabetes, which established the safety and pharmacokinetic profile of the compound (then designated IBI362). This study demonstrated dose-dependent reductions in HbA1c and body weight, providing proof-of-concept for dual GLP-1/glucagon receptor activation in humans.
A pivotal Phase 2 randomised controlled trial in Chinese adults with overweight or obesity (n=610) showed that mazdutide produced clinically meaningful weight loss across multiple dose levels over 24 weeks. Mean body weight reductions ranged from approximately 5% to 11% depending on dose, with the highest doses approaching efficacy levels typically seen with established GLP-1 RAs over longer treatment periods. A parallel Phase 2 trial in type 2 diabetes demonstrated significant HbA1c reductions alongside weight loss.
GLORY Trials (Obesity/Overweight)
The mazdutide phase 3 GLORY-1 trial, published in the New England Journal of Medicine in 2025, was the pivotal study supporting obesity approval. This multicentre, randomised, double-blind trial enrolled Chinese adults with obesity or overweight (with at least one weight-related comorbidity) and evaluated mazdutide at escalating doses over 48 weeks. The trial demonstrated substantial weight reduction compared to placebo, with statistically significant differences across all dose groups.
DREAMS Trials (Type 2 Diabetes)
The DREAMS trial programme evaluated mazdutide specifically in adults with type 2 diabetes. DREAMS-1, published in Nature, demonstrated that mazdutide significantly reduced HbA1c compared to placebo in Chinese adults with T2D, achieving clinically meaningful glycaemic improvements alongside body weight reduction. DREAMS-2, also published in Nature, compared mazdutide directly to dulaglutide and showed superior efficacy on both HbA1c reduction and weight loss endpoints. A DREAMS-3 trial comparing mazdutide head-to-head with semaglutide is currently underway.
Weight Loss Data
Mazdutide weight loss data from the Phase 3 GLORY-1 trial represents the most robust evidence for this compound’s efficacy in weight management. At 48 weeks, participants receiving the highest dose of mazdutide achieved mean body weight reductions of approximately 15% from baseline — a clinically significant result that positioned the compound competitively within the incretin-based weight loss landscape.
To contextualise these findings: in the GLORY-1 trial, the placebo-subtracted weight loss at 48 weeks was substantial, with a significant proportion of participants achieving ≥10% and ≥15% body weight reduction thresholds. These response rates are clinically relevant because evidence suggests that 10-15% weight loss produces meaningful improvements in obesity-related comorbidities including cardiovascular risk factors, obstructive sleep apnoea, and joint pain.
Earlier Phase 2 data in Chinese adults with overweight or obesity showed dose-dependent weight loss over 24 weeks, with higher doses producing greater reductions. The Phase 1 high-dose trial conducted by Eli Lilly in a broader (non-Chinese) population also demonstrated meaningful weight reduction, suggesting the effects may be generalisable beyond the Chinese cohort.
It is worth noting that the magnitude of mazdutide weight loss observed in the GLORY trials — while impressive — was assessed exclusively in Chinese adults, and cross-ethnic extrapolation should be approached with caution. Global Phase 3 trials currently underway will provide critical data on efficacy in Western populations. Research in the area of fat loss and body recomposition continues to evolve with these multi-receptor agonists.
Metabolic & Glycaemic Effects
Beyond weight loss, mazdutide demonstrates significant effects on glycaemic control and broader metabolic parameters — effects that appear partly attributable to its unique dual-receptor mechanism.
HbA1c Reduction
In the DREAMS-1 Phase 3 trial, mazdutide produced clinically meaningful reductions in HbA1c in adults with type 2 diabetes. The magnitude of glycaemic improvement was substantial, meeting pre-specified non-inferiority and superiority endpoints. In DREAMS-2, mazdutide demonstrated superior HbA1c reduction compared to dulaglutide, an established GLP-1 RA widely used in clinical practice.
The Phase 2 trial in type 2 diabetes published in Diabetes Care showed dose-dependent HbA1c reductions of up to approximately 1.5 percentage points, with the highest dose groups achieving the greatest glycaemic improvements. Importantly, these reductions occurred alongside significant weight loss, suggesting synergistic benefits for patients with both diabetes and obesity.
Insulin Sensitivity and Metabolic Markers
Clinical data indicates that mazdutide improves several metabolic markers beyond glycaemic control. Evidence from the trial programme suggests improvements in fasting glucose, fasting insulin, and markers of insulin resistance. The glucagon receptor component may contribute to these effects through enhanced hepatic lipid oxidation, which research suggests can improve hepatic insulin sensitivity by reducing intrahepatic triglyceride content.
Lipid profile improvements have also been observed, including reductions in triglycerides and total cholesterol. While lipid effects are common across GLP-1 RA class drugs, the glucagon component of mazdutide may enhance these benefits through direct hepatic lipid mobilisation pathways.
Liver Fat & MASLD Research
One of the most scientifically compelling aspects of mazdutide relates to its potential for reducing hepatic steatosis — the hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD). The glucagon receptor agonist component provides a mechanistic rationale for enhanced liver fat reduction compared to pure GLP-1 RAs.
Glucagon signalling in the liver directly promotes fatty acid oxidation, stimulates lipid mobilisation from hepatocytes, and may reduce de novo lipogenesis. These effects, combined with the weight-loss-driven reduction in hepatic fat delivery, create a dual mechanism for addressing hepatic steatosis. Preclinical data consistently shows that GLP-1/glucagon dual agonists produce greater liver fat reduction than equivalent GLP-1-only stimulation.
Clinical evidence for mazdutide’s effects on liver fat is still emerging. Secondary endpoints and exploratory analyses from the GLORY and DREAMS programmes have suggested reductions in liver-related biomarkers, though dedicated liver imaging studies with mazdutide-specific MASLD endpoints are needed to fully characterise this effect. The broader class of GLP-1/glucagon dual agonists — including survodutide from Boehringer Ingelheim — has generated encouraging liver fat reduction data, suggesting a class-level benefit that mazdutide likely shares.
Given the enormous global burden of MASLD and the limited approved pharmacological options, the hepatic effects of the glp-1 glucagon dual agonist class represent a potentially transformative therapeutic avenue. However, more targeted clinical trials are required before definitive conclusions about mazdutide’s MASLD benefits can be drawn.
Safety & Side Effects
The mazdutide side effects profile is broadly consistent with the GLP-1 receptor agonist class, with gastrointestinal events being the most frequently reported adverse effects across all clinical trials.
Common Side Effects
Gastrointestinal adverse events — including nausea, vomiting, diarrhoea, and decreased appetite — were the most commonly reported mazdutide side effects in both the GLORY and DREAMS trials. These events were predominantly mild to moderate in severity and tended to occur during the dose-escalation phase, decreasing in frequency with continued treatment. The incidence of GI adverse events was dose-dependent, with higher doses producing more frequent events.
Discontinuation Rates
In the GLORY-1 Phase 3 trial, the rate of treatment discontinuation due to adverse events was higher in the mazdutide groups compared to placebo, though the overall discontinuation rate was manageable. The majority of discontinuations were related to gastrointestinal intolerance during early dose escalation.
Glucagon-Specific Considerations
The glucagon receptor agonist component introduces theoretical safety considerations that differ from pure GLP-1 RAs. Glucagon is known to promote hepatic glucose output, which raises questions about glycaemic balance — particularly in patients with diabetes. However, clinical data from the DREAMS trials suggests that the GLP-1 component effectively counterbalances any pro-hyperglycaemic effects of glucagon receptor activation, with net improvements in glycaemic control observed across all dose levels.
Heart rate increases have been observed with mazdutide, consistent with findings seen across GLP-1-based therapies. The long-term cardiovascular safety profile remains to be fully established through dedicated cardiovascular outcome trials. No clinically significant signals for pancreatitis, thyroid tumours, or gallbladder-related events beyond background rates have been reported, though post-marketing surveillance and longer-term studies will be important for confirming the safety profile.
Research Limitations
While the evidence base for mazdutide is substantial and growing, several important limitations should be considered when interpreting the available data.
Population specificity: All pivotal Phase 3 trials (GLORY and DREAMS) were conducted exclusively in Chinese adults. East Asian populations may respond differently to incretin-based therapies due to differences in body composition, beta-cell function, and metabolic phenotype. The Eli Lilly high-dose Phase 1 trial included a broader population, but definitive efficacy data in Western cohorts awaits the completion of ongoing global Phase 3 trials.
Duration of evidence: The longest controlled trial data available spans 48 weeks. Obesity and type 2 diabetes are chronic conditions requiring long-term treatment, and the durability of weight loss, safety over years of use, and effects on hard clinical endpoints (cardiovascular events, mortality) remain unknown.
Comparator data gaps: While DREAMS-2 compared mazdutide to dulaglutide and DREAMS-3 is comparing it to semaglutide, there are no head-to-head trials against tirzepatide, survodutide, or retatrutide. Cross-trial comparisons are inherently unreliable due to differences in patient populations, trial design, and endpoints.
Liver fat evidence: While the mechanistic rationale for hepatic benefit is strong, dedicated imaging-based studies with MASLD-specific primary endpoints have not yet been published for mazdutide specifically. Claims about liver fat reduction should be interpreted as preliminary.
Cardiovascular outcomes: No dedicated cardiovascular outcome trial has been completed for mazdutide. While the metabolic improvements observed are likely to be cardioprotective, this has not been confirmed in outcome studies.
Long-term safety: Post-marketing safety data from China is still accumulating. The theoretical risks associated with chronic glucagon receptor stimulation — including effects on hepatic glucose output, bone density, and body composition — require longer-term monitoring.
Verdict
Mazdutide represents a genuinely novel approach to metabolic disease — one of the first compounds to demonstrate that co-activating GLP-1 and glucagon receptors can produce clinically meaningful weight loss and glycaemic improvement with an acceptable safety profile. Its approval in China as the world’s first GLP-1/glucagon dual agonist for obesity marks a significant milestone in the evolution of incretin-based therapeutics.
The clinical evidence is encouraging. Phase 3 data showing approximately 15% weight loss at 48 weeks places mazdutide in competitive territory, while the DREAMS trials confirm robust efficacy in type 2 diabetes. The mechanistic advantage of glucagon receptor activation — enhanced energy expenditure and potential liver fat benefits — distinguishes it from pure GLP-1 RAs and GLP-1/GIP dual agonists like tirzepatide.
However, several caveats temper enthusiasm. The evidence base is currently limited to Chinese populations, and global Phase 3 data will be critical for establishing whether these results translate across ethnic groups. The compound faces intense competition from tirzepatide, semaglutide, retatrutide, and survodutide — each with distinct receptor profiles and varying levels of clinical evidence. Head-to-head comparisons will ultimately determine where mazdutide fits in the treatment hierarchy.
For the research community, mazdutide provides important proof-of-concept that the glp-1 glucagon dual agonist class is clinically viable. Whether the glucagon component delivers meaningful advantages over existing therapies in real-world practice remains an open question that ongoing global trials should help answer.
FAQ
What is mazdutide?
Mazdutide is a GLP-1/glucagon dual receptor agonist — an engineered peptide that activates both the GLP-1 receptor and the glucagon receptor. Based on the structure of oxyntomodulin, this mazdutide peptide was developed by Innovent Biologics and is designed as a once-weekly subcutaneous injection for obesity and type 2 diabetes. It was the first compound in its class to receive regulatory approval for weight management (China, July 2025).
How does mazdutide differ from semaglutide?
While semaglutide is a pure GLP-1 receptor agonist, mazdutide activates both GLP-1 and glucagon receptors. This dual mechanism means mazdutide may promote energy expenditure through the glucagon component in addition to the appetite suppression provided by GLP-1 receptor activation. Research suggests this could offer advantages for liver fat reduction and overall metabolic improvement compared to GLP-1-only approaches.
What weight loss does mazdutide produce?
In the GLORY-1 Phase 3 trial, mazdutide weight loss at 48 weeks reached approximately 15% from baseline at the highest dose level. Earlier Phase 2 data showed dose-dependent weight reductions of 5-11% over 24 weeks. These results are from Chinese populations, and global trial data in Western populations is pending.
What are the main mazdutide side effects?
The most commonly reported mazdutide side effects are gastrointestinal in nature — nausea, vomiting, diarrhoea, and decreased appetite. These are consistent with the GLP-1 receptor agonist class and tend to be most frequent during dose escalation, typically diminishing with continued treatment. Most adverse events were mild to moderate in severity.
Is mazdutide approved for use?
As of 2025, mazdutide has received regulatory approval in China for chronic weight management in adults with obesity or overweight with at least one weight-related comorbidity. It is not yet approved in the United States, European Union, or other major markets. Eli Lilly holds ex-China development rights and global Phase 3 trials are underway.
What is the difference between mazdutide and tirzepatide?
Mazdutide is a GLP-1/glucagon dual agonist, while tirzepatide is a GLP-1/GIP dual agonist. These are fundamentally different receptor combinations. Tirzepatide has shown greater peak weight loss in trials (~22% vs ~15%), but mazdutide’s glucagon component may provide distinct advantages for energy expenditure and liver fat reduction that GIP receptor activation does not offer.
Who developed mazdutide?
Mazdutide was originally developed by Mazdutide Innovent Biologics, a Chinese biopharmaceutical company. In 2022, Eli Lilly acquired the ex-China development and commercialisation rights in a licensing deal worth over $200 million upfront. Innovent retains rights within China, where the compound has already been approved and launched.
What are the GLORY and DREAMS trials?
The GLORY trials are the mazdutide phase 3 clinical programme for obesity/overweight, with GLORY-1 (published in NEJM) serving as the pivotal approval trial. The DREAMS trials are the Phase 3 programme for type 2 diabetes, with DREAMS-1 and DREAMS-2 (both published in Nature) evaluating mazdutide versus placebo and versus dulaglutide respectively. DREAMS-3 is comparing mazdutide with semaglutide.
Could mazdutide help with liver fat (MASLD/NAFLD)?
Research suggests that mazdutide’s glucagon receptor component may be beneficial for reducing liver fat, as glucagon signalling promotes hepatic fatty acid oxidation. While dedicated MASLD imaging trials for mazdutide are still pending, the broader class of GLP-1/glucagon dual agonists has shown promising liver fat reduction data. This remains an active area of investigation.
How does mazdutide compare to survodutide?
Mazdutide and survodutide (Boehringer Ingelheim) are both GLP-1/glucagon dual agonists, making them the most direct competitors in this class. Survodutide has shown greater peak weight loss in Phase 2 data (~19% vs ~15%), but mazdutide is further along in development — having achieved regulatory approval in China while survodutide remains in Phase 3. The two compounds differ in their receptor potency ratios, which may produce clinically distinct profiles.
References
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- Zhu D et al. “Mazdutide versus placebo in Chinese adults with type 2 diabetes.” Nature, 2026; 652(8108):174-180. PubMed
- Guo L et al. “Mazdutide versus dulaglutide in Chinese adults with type 2 diabetes.” Nature, 2026; 652(8108):181-188. PubMed
- Ji L et al. “A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity.” Nat Commun, 2023; 14(1):8289. PubMed
- Zhang B et al. “Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial.” Diabetes Care, 2024; 47(1):160-168. PubMed
- Jiang H et al. “A phase 1b randomised controlled trial of a glucagon-like peptide-1 and glucagon receptor dual agonist IBI362 (LY3305677) in Chinese patients with type 2 diabetes.” Nat Commun, 2022; 13(1):3613. PubMed
- Bhattachar SN et al. “Mazdutide reduces body weight in adults with overweight or obesity: A high-dose Phase 1 trial.” Diabetes Obes Metab, 2025; 27(11):6460-6469. PubMed
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- Neff GW. “Shared mechanistic pathways of glucagon signalling: Unlocking its potential for treating obesity, MASLD, and other cardio-kidney-metabolic conditions.” Diabetes Obes Metab, 2025; 27(12):6869-6883. PubMed
- Luo Y et al. “Mazdutide versus Semaglutide for the treatment of type 2 diabetes and obesity: Rationale, design and baseline data of DREAMS-3 phase 3 trial.” Contemp Clin Trials, 2026; 160:108150. PubMed