Mazdutide: The GLP-1/Glucagon Agonist from China

Mazdutide and Dual Receptor Agonists

10.3% Weight Loss

In the DREAMS-3 head-to-head trial, mazdutide produced 10.3% body weight reduction at 32 weeks versus 6.0% with semaglutide in Chinese adults with type 2 diabetes and obesity.

DREAMS-3 Trial, 2025

DREAMS-3 Trial, 2025

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Mazdutide (IBI362) is a once-weekly injectable peptide that activates two receptors simultaneously: the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR). Developed by Innovent Biologics and Eli Lilly, mazdutide represents a bet that adding glucagon receptor activation to the GLP-1 agonist framework will produce greater weight loss and metabolic improvement than GLP-1 agonism alone. In 2025, China's National Medical Products Administration (NMPA) approved mazdutide for both weight management and glycemic control, making it the first dual GLP-1/glucagon agonist to receive regulatory approval anywhere in the world. In the DREAMS-3 head-to-head trial against semaglutide, mazdutide produced 10.3% body weight reduction versus 6.0% for semaglutide at 32 weeks in patients with type 2 diabetes.

The mazdutide story is also a story about where peptide drug development is happening. China's pharmaceutical industry has moved from generic manufacturing to novel biologics development, and mazdutide is among the most prominent examples of a first-in-class peptide drug emerging from a Chinese pipeline. Innovent Biologics, founded in 2011, has built a portfolio spanning monoclonal antibodies, bispecifics, and peptide therapeutics. The Eli Lilly partnership, which provides access to Lilly's GLP-1 agonist expertise and global commercial infrastructure, bridges the Chinese and Western pharmaceutical ecosystems in a way that few peptide programs have achieved.

How Mazdutide Works: Dual Receptor Agonism

GLP-1 receptor agonists like semaglutide work primarily by suppressing appetite through central nervous system signaling and slowing gastric emptying. These mechanisms reduce food intake. Mazdutide adds a second mechanism: glucagon receptor activation, which increases energy expenditure through hepatic lipid oxidation and thermogenesis.

The rationale is additive pharmacology. GLP-1R activation reduces caloric intake. GCGR activation increases caloric output. Together, these mechanisms attack energy balance from both directions. Glucagon has historically been avoided as a drug target because it raises blood glucose, the opposite of what diabetes patients need. Mazdutide resolves this conflict by calibrating the ratio of GLP-1R to GCGR activity so that the glucose-lowering effects of GLP-1 agonism offset the glucose-raising effects of glucagon agonism, producing net glucose reduction along with enhanced weight loss.

The glucagon component also produces effects that GLP-1 alone cannot achieve. Glucagon receptor activation increases resting energy expenditure, meaning patients burn more calories even without exercise or dietary changes. In clinical trials, this manifests as greater weight loss at comparable caloric intake. Glucagon also directly stimulates hepatic amino acid catabolism, which may contribute to the reduction in circulating amino acid levels observed in some metabolic disease states.

This dual mechanism also explains mazdutide's pronounced effect on liver fat. Glucagon receptor activation directly stimulates hepatic beta-oxidation, the process by which the liver breaks down stored fat for energy. A 2023 Phase 2 study published in Nature Communications reported that in subjects with baseline liver fat content above 5%, mazdutide reduced liver fat by 73.3% after 24 weeks.^[1] This is a striking finding because non-alcoholic fatty liver disease (NAFLD) and its progressive form MASH (metabolic dysfunction-associated steatohepatitis) affect approximately 30% of the global population and have limited approved treatments.

The molecular structure of mazdutide is a modified peptide backbone with fatty acid acylation for albumin binding, extending its half-life to support once-weekly dosing. The ratio of GLP-1R to GCGR activity was optimized during preclinical development to maximize weight loss and liver fat reduction while maintaining glucose control. This ratio is the key design parameter that differentiates mazdutide from other dual agonists, each of which has a different balance of GLP-1 versus glucagon activity.

The Clinical Trial Program

Phase 1b: Dose Ranging (2022)

Ji et al. (2022) published the first human safety and efficacy data from a Phase 1b multiple-ascending-dose trial testing mazdutide at 9 mg and 10 mg in Chinese adults with overweight or obesity. The trial established that mazdutide was generally well-tolerated, with gastrointestinal adverse events (nausea, vomiting, decreased appetite) being the most common side effects, consistent with the GLP-1 agonist class.^[2] This trial identified the dose range for subsequent Phase 2 and Phase 3 studies.

Phase 2: Obesity (2023)

The Phase 2 randomized controlled trial in Chinese adults with overweight or obesity was published in Nature Communications. At 48 weeks, the 6-mg dose produced a mean body weight reduction of 14.0%, with 49.5% of participants achieving at least 15% weight loss. The 4-mg dose produced 11.0% weight loss. Both active doses separated from placebo (0.5% weight reduction) with high statistical confidence.^[1]

Beyond weight, the Phase 2 study reported improvements across multiple metabolic parameters: waist circumference, fasting glucose, HbA1c, triglycerides, and blood pressure. The pattern of metabolic improvement was dose-dependent, with the 6-mg group showing the largest improvements across all endpoints.

The liver fat reduction data from this trial generated particular interest because existing GLP-1 agonists produce modest liver fat reduction (typically 20-40%), while mazdutide's 73.3% reduction represents a potential step-change in efficacy for fatty liver disease. Liver fat was measured by MRI-proton density fat fraction (MRI-PDFF), the gold-standard non-invasive method. The magnitude of reduction was consistent across subgroups defined by baseline BMI, age, and sex, suggesting a robust pharmacological effect rather than an artifact of patient selection.

The safety profile in Phase 2 was consistent with the GLP-1 agonist class. Gastrointestinal adverse events, primarily nausea and decreased appetite, were the most common side effects. These were transient in most participants, peaking during dose escalation and diminishing at stable doses. No cases of pancreatitis, thyroid cancer, or severe hypoglycemia were reported, though the trial was not powered to detect rare adverse events.

Phase 3: Type 2 Diabetes (DREAMS-1 and DREAMS-2, 2024)

Zhang et al. (2024) published Phase 3 results from the DREAMS program testing mazdutide in Chinese adults with type 2 diabetes. Mazdutide produced dose-dependent reductions in HbA1c and body weight over 32 weeks. The DREAMS-1 and DREAMS-2 results were published back-to-back in Nature as Accelerated Article Previews, an unusual editorial decision that reflects the significance the journal assigned to this data.^[3]

The diabetes data demonstrated that mazdutide's GLP-1/glucagon dual mechanism produced glycemic control comparable to or better than established GLP-1 agonists, while simultaneously delivering weight loss that exceeded what single-agonist drugs achieve in T2D populations. For patients with type 2 diabetes, this dual benefit is clinically meaningful because over 80% of T2D patients are overweight or obese, and excess weight directly drives insulin resistance. Drugs that address both glycemia and weight attack the disease from two angles, potentially reducing the need for additional medications. The NMPA approval for glycemic control in September 2025 was based primarily on the DREAMS program data.

Phase 3: Obesity (NEJM, 2025)

The landmark obesity trial was published in the New England Journal of Medicine. Ji et al. (2025) reported results from a Phase 3 study of once-weekly mazdutide in Chinese adults with obesity or overweight. At 48 weeks, the 6-mg dose produced 14.0% body weight reduction versus 0.5% for placebo, and 82.0% of participants in the 6-mg group achieved at least 5% weight loss.^[4] This NEJM publication positioned mazdutide alongside semaglutide and tirzepatide as a credible clinical-stage obesity treatment with rigorous trial data.

DREAMS-3: Head-to-Head vs Semaglutide (2025)

The DREAMS-3 trial directly compared mazdutide to semaglutide 1 mg in patients with type 2 diabetes and obesity. At 32 weeks, mazdutide produced 10.3% body weight reduction versus 6.0% for semaglutide, and mean HbA1c reduction of 2.03% versus 1.84% for semaglutide.^[5] A higher proportion of mazdutide-treated patients achieved the composite endpoint of HbA1c below 7% with at least 10% body weight loss.

This head-to-head superiority over semaglutide is commercially and clinically relevant. Semaglutide (Wegovy/Ozempic) is the current market leader in GLP-1 weight loss drugs, and demonstrating superiority over this benchmark positions mazdutide for competitive market entry. The comparison was against semaglutide 1 mg (the diabetes dose), not semaglutide 2.4 mg (the obesity dose) or the newer 7.2 mg formulation, which limits direct cross-trial comparisons with Western weight management trials.

Several contextual factors qualify the DREAMS-3 results. The trial enrolled Chinese adults, who typically have lower baseline BMI and different body fat distribution patterns compared to Western populations. Mean baseline BMI in Chinese obesity trials is often 28-32, compared to 35-40 in US and European trials. Absolute weight loss in kilograms tends to be lower in lower-BMI populations, even when percentage weight loss is comparable. The glycemic benefit in DREAMS-3 also reflects the characteristics of Chinese T2D, which is more strongly associated with beta-cell dysfunction than insulin resistance compared to T2D in Western populations.

The semaglutide 1 mg comparator deserves particular scrutiny. In the STEP trials, semaglutide 2.4 mg produced approximately 15-17% weight loss in Western populations with obesity. In a 2025 NEJM trial, the even higher 7.2 mg dose of semaglutide achieved approximately 20% weight loss.^[12] Until mazdutide is tested against these higher doses in comparable populations, its relative efficacy advantage remains an open question.

Mazdutide vs Other Dual Agonists

Mazdutide is not the only dual receptor agonist in development. It operates in a competitive landscape alongside several other molecules targeting similar pharmacological space.

Survodutide (Boehringer Ingelheim/Zealand Pharma) is another GLP-1/glucagon dual agonist in Phase 3 trials. The SYNCHRONIZE trial program is testing survodutide for obesity and MASH, with baseline characteristics published in 2026.^[6] Survodutide and mazdutide share the same dual receptor mechanism but differ in molecular structure, dosing regimen, and the populations studied.

Tirzepatide (Eli Lilly's Mounjaro/Zepbound) is a GLP-1/GIP dual agonist rather than GLP-1/glucagon. Tirzepatide's mechanism differs from mazdutide's: GIP receptor activation enhances insulin secretion and may promote fat redistribution, while glucagon activation increases energy expenditure through hepatic fat oxidation. A 2026 systematic review comparing tirzepatide and semaglutide confirmed tirzepatide's superiority for weight loss, setting the benchmark that dual agonists may outperform GLP-1 monotherapy.^[7]

The three dual agonists (mazdutide, survodutide, tirzepatide) represent a natural experiment in pharmacology: each combines GLP-1 with a different second receptor, and comparing their clinical profiles will reveal which second-receptor mechanism produces the most favorable risk-benefit profile. If glucagon-based dual agonists (mazdutide, survodutide) consistently outperform GIP-based ones (tirzepatide) on liver fat reduction, or if GIP-based agonists show better preservation of lean mass, these differences would guide rational drug selection for different patient phenotypes.

Cotadutide (AstraZeneca) is another GLP-1/glucagon dual agonist that reached Phase 2 trials for MASH and diabetes but was deprioritized. The cotadutide experience illustrates the challenges of the dual agonist approach: balancing the glucose-raising effect of glucagon against the glucose-lowering effect of GLP-1 proved difficult at the doses needed for liver fat reduction. Mazdutide appears to have solved this balancing problem, at least in the Chinese populations studied, but whether this balance holds across different doses, durations, and populations remains to be confirmed.

Retatrutide (Eli Lilly) goes one step further by combining GLP-1, GIP, and glucagon receptor agonism in a single molecule (triple agonism). In Phase 2, retatrutide achieved up to 24% weight loss at 48 weeks, the highest reported for any anti-obesity medication. The triple agonist approach represents the logical extension of the dual agonist concept and creates additional competitive pressure on mazdutide.

A 2026 review of dual glucagon and GLP-1 agonists as treatments for type 2 diabetes placed mazdutide within the broader class of molecules exploiting this pharmacological approach.^[8] The review noted that the GLP-1/glucagon combination addresses three pillars of metabolic disease simultaneously: glucose control (GLP-1), weight loss (both), and liver fat reduction (glucagon).

For a detailed analysis of how mazdutide's data compares to these Western-developed molecules, see How Mazdutide Compares to Western-Developed Metabolic Peptides.

The Liver Fat Question

Mazdutide's liver fat reduction data may represent its most differentiated clinical attribute. NAFLD affects an estimated 1.7 billion people globally, and its progressive form MASH is the fastest-growing indication for liver transplantation. No drug has been approved specifically for NAFLD/MASH treatment (resmetirom was approved for MASH with liver fibrosis in 2024, but covers only a subset of patients).

The 73.3% liver fat reduction observed in the Phase 2 trial exceeds the reductions reported for semaglutide (approximately 30-40% in the STEP trials) and is comparable to survodutide's Phase 2 liver fat data. This superior liver fat reduction is pharmacologically plausible: glucagon receptor activation directly stimulates hepatic beta-oxidation, burning stored liver fat as fuel. GLP-1 agonists reduce liver fat primarily through weight loss and improved insulin sensitivity, which are indirect mechanisms.

Innovent has announced plans to study mazdutide specifically in MASH, recognizing the unmet medical need and the molecule's pharmacological suitability. If mazdutide demonstrates histological improvement in MASH (the gold-standard endpoint, requiring paired liver biopsies), it would enter a market with limited competition and enormous patient need.

The liver fat story connects mazdutide to a broader metabolic narrative. Excess liver fat drives insulin resistance, which drives hyperglycemia, which drives cardiovascular risk. By reducing liver fat at the source through glucagon-mediated beta-oxidation, mazdutide may address a root cause of metabolic disease rather than just managing downstream symptoms. This mechanistic argument is what distinguishes mazdutide from drugs that reduce liver fat indirectly through weight loss: even at similar weight loss levels, mazdutide's direct hepatic effects may produce greater liver fat clearance.

Beyond Weight: Emerging Indications

Cognitive Effects

Dong et al. (2025) used multi-omics analysis to investigate mazdutide's effects on diabetes-associated cognitive dysfunction. Published in eBioMedicine (a Lancet journal), the study demonstrated that dual GLP-1R/GCGR activation mitigated cognitive impairment in diabetic models through mechanisms involving improved cerebral glucose metabolism and reduced neuroinflammation.^[9] The multi-omics approach (combining transcriptomics, metabolomics, and proteomics) identified specific pathway alterations that neither GLP-1 nor glucagon agonism alone could produce, suggesting synergistic neuroprotective effects from dual receptor engagement.

Diabetes-associated cognitive decline affects an estimated 60-70% of patients with long-standing type 2 diabetes and increases dementia risk by 50-100%. If mazdutide's cognitive protective effects translate to humans, the dual agonist could offer neuroprotection alongside metabolic control. This connects to the broader observation that GLP-1 receptor agonists show neuroprotective properties, as documented in GLP-1 receptor activation in the brain's reward center. Whether glucagon receptor activation adds to or modifies the neuroprotective effects of GLP-1 agonism is an active area of investigation.

High-Dose Exploration

Cheng et al. (2025) published a case report of dose-escalated mazdutide beyond the standard clinical doses, providing early data on the safety and efficacy of higher dosing.^[10] Case reports have clear limitations in sample size and generalizability, but they can signal opportunities for dose optimization that Phase 3 programs may not have explored. Given that semaglutide's efficacy improved with dose escalation from 1 mg to 2.4 mg to 7.2 mg, and that tirzepatide shows dose-dependent weight loss up to 15 mg, there may be room to push mazdutide's dose-response curve further if tolerability allows.

Cardiovascular Outcomes

Semaglutide has demonstrated cardiovascular risk reduction in the SELECT trial, with a 20% reduction in major adverse cardiovascular events in patients with obesity and established cardiovascular disease.^[11] Whether mazdutide will show similar or superior cardiovascular benefits is an open question. The addition of glucagon receptor activation could enhance cardiovascular protection through improved lipid profiles and liver fat reduction, or it could introduce cardiovascular risks through glucagon's effects on heart rate and blood pressure. A dedicated cardiovascular outcomes trial for mazdutide has not yet been announced. For context on the cardiovascular evidence for GLP-1 drugs more broadly, see GLP-1 Drugs and Heart Disease: What the Cardiovascular Trials Show.

Limitations and Considerations

Population specificity. All published mazdutide trials to date enrolled Chinese participants. East Asian populations have different body composition patterns, lower average BMI, and distinct metabolic risk profiles compared to Western populations. Whether mazdutide's efficacy translates at the same magnitude to other populations requires global trials that are currently in planning or early execution.

Comparator dose. The DREAMS-3 head-to-head compared mazdutide to semaglutide 1 mg, the diabetes dose. Semaglutide 2.4 mg (Wegovy, the obesity dose) and the newer 7.2 mg formulation were not used as comparators. Direct comparison with these higher semaglutide doses would provide a more complete picture of relative efficacy.

Long-term safety. Glucagon receptor activation has theoretical risks including hepatic glycogenolysis (which could cause hypoglycemia in fasting states) and potential effects on bone metabolism. The longest published mazdutide data covers 48 weeks. Multi-year safety data, which is standard for chronic metabolic drugs, is not yet available.

Weight regain. GLP-1 agonist-mediated weight loss is not durable after drug discontinuation. Studies of semaglutide have shown that approximately two-thirds of weight lost is regained within one year of stopping treatment. Whether mazdutide's dual mechanism alters this pattern is unknown.

Manufacturing and global access. Mazdutide is manufactured by Innovent Biologics in China. Scaling global production to meet potential demand, navigating regulatory pathways in the US, EU, and other markets, and competing with established supply chains for semaglutide and tirzepatide present practical challenges. The partnership with Eli Lilly provides global distribution infrastructure, but regulatory requirements differ between the NMPA, FDA, and EMA. The FDA may require additional trials in Western populations or at minimum a bridging study demonstrating consistent pharmacokinetics across ethnic groups.

Glucagon-specific risks. While the GLP-1 agonist safety profile is well-characterized from decades of clinical experience with drugs like exenatide, liraglutide, and semaglutide, the glucagon receptor agonist component introduces pharmacological territory with less clinical precedent. Glucagon's effects on cardiac chronotropy (heart rate increase), hepatic glucose output, and protein catabolism at therapeutic doses need long-term monitoring. The theoretical risk of glucagon-mediated muscle wasting, particularly relevant given the sarcopenia concerns already associated with GLP-1-mediated weight loss, has not been fully characterized.

Pricing and access. In China, mazdutide's pricing and insurance coverage will determine real-world adoption. In Western markets, mazdutide will compete against semaglutide and tirzepatide, both of which have established formulary positions and extensive real-world data. Price competition in the GLP-1/incretin space is intensifying, and latecomers face pressure to demonstrate clear clinical differentiation to justify formulary inclusion.

For the full weight loss data by subgroup, see Mazdutide Clinical Data: Weight Loss Results in Asian Populations.

The Bottom Line

Mazdutide is a once-weekly dual GLP-1/glucagon receptor agonist that has demonstrated weight loss and metabolic improvement exceeding semaglutide in head-to-head trials. Its most differentiated attribute is a 73.3% liver fat reduction, driven by glucagon receptor-mediated hepatic fat oxidation. Approved in China for weight management and type 2 diabetes, mazdutide is pursuing global regulatory pathways. All published trials enrolled Chinese participants, and long-term safety data beyond 48 weeks is not yet available.

Frequently Asked Questions

What is mazdutide and how does it work?

Mazdutide (IBI362) is a once-weekly injectable peptide that activates both the GLP-1 receptor and the glucagon receptor. GLP-1 activation suppresses appetite and slows gastric emptying, reducing food intake. Glucagon activation increases energy expenditure through hepatic fat oxidation. This dual mechanism attacks energy balance from both sides, producing greater weight loss than GLP-1 agonism alone. In Phase 3 trials, mazdutide achieved 14.0% body weight reduction at 48 weeks (Ji et al., NEJM, 2025).

Is mazdutide better than semaglutide for weight loss?

In the DREAMS-3 head-to-head trial, mazdutide produced 10.3% weight loss versus 6.0% for semaglutide 1 mg at 32 weeks in patients with type 2 diabetes. This was the diabetes dose of semaglutide; comparison with semaglutide 2.4 mg (the obesity dose) or 7.2 mg has not been published. All trials enrolled Chinese participants, so results may not directly apply to other populations.

Is mazdutide FDA approved?

No. Mazdutide is approved by China's NMPA for weight management (June 2025) and type 2 diabetes (September 2025) but has not received FDA approval. Global Phase 3 trials are underway. Potential FDA approval is estimated for 2027-2028, depending on trial completion and regulatory review timelines. Mazdutide was developed by Innovent Biologics in partnership with Eli Lilly.

How does mazdutide reduce liver fat?

Mazdutide reduces liver fat through glucagon receptor activation, which directly stimulates hepatic beta-oxidation, the process by which the liver breaks down stored fat for energy. In Phase 2 trials, subjects with baseline liver fat above 5% showed a 73.3% reduction after 24 weeks (Ji et al., Nature Communications, 2023). This exceeds the liver fat reduction seen with semaglutide, which works indirectly through weight loss and insulin sensitization.

What is the difference between mazdutide and tirzepatide?

Mazdutide activates GLP-1 and glucagon receptors. Tirzepatide (Mounjaro/Zepbound) activates GLP-1 and GIP receptors. Glucagon activation increases liver fat burning and energy expenditure. GIP activation enhances insulin secretion and may affect fat distribution. Both are dual agonists that outperform GLP-1 mono-agonists, but they achieve this through different second-receptor mechanisms.

What are the side effects of mazdutide?

The most common side effects are gastrointestinal: nausea, vomiting, decreased appetite, and diarrhea. These are consistent with the GLP-1 agonist drug class and are typically mild to moderate. Most GI side effects occur during dose escalation and diminish over time. Long-term safety data beyond 48 weeks is not yet available. Theoretical risks from glucagon activation, including effects on blood glucose during fasting and bone metabolism, require longer-term monitoring.