Mazdutide: The Weekly Oxyntomodulin, and What Its Numbers Rest On

The gut already secretes a peptide that hits the glucagon receptor and the GLP-1 receptor at once. It is called oxyntomodulin, it is weak at both, and it lasts minutes.

Mazdutide is that hormone rebuilt as a weekly injection. China approved it in June 2025 for weight management and in September 2025 for glycaemic control, making it the first glucagon and GLP-1 dual agonist approved anywhere [17].

The published weight numbers for Mazdutide are large. A phase 3 trial at 9 mg reported 16.65% body weight reduction over 60 weeks (PMID 42251595) [2]. A phase 1 trial at 16 mg reported 21% over 20 weeks in 24 people [7].

Two things about that evidence deserve attention before the numbers get quoted. Almost all of it comes from one country and one young, moderately obese population. And the human case for the glucagon half, the part that distinguishes this molecule from semaglutide, is thinner than the design story implies.

Chemical identity

Mazdutide is a 33-residue peptide built on a glucagon backbone. It carries a fatty diacid that binds albumin and stretches the half-life to weekly dosing.

Reading the structure

Three modifications separate this peptide from the hormone it copies, and none of them are original to it.

Position 2 carries aminoisobutyric acid rather than serine. That substitution blocks dipeptidyl peptidase-4, the enzyme that clips native glucagon-family peptides within minutes. Semaglutide uses the same trick at its own position 8.

The lysine near the middle of the chain carries a C20 fatty diacid, attached through a glutamate spacer and two short glycol units. Albumin binds that chain, and the complex clears slowly enough for weekly injection. Tirzepatide uses a C20 diacid and semaglutide a C18, and all three share the spacer chemistry.

So the pharmacokinetic half of Mazdutide is standard incretin engineering. The receptor pharmacology is where it differs.

The oxyntomodulin template

Proglucagon is one gene that yields several peptides. Glucagon, GLP-1 and oxyntomodulin all come out of it, which is why one sequence can activate two receptors without anything being bolted on.

Oxyntomodulin activates both receptors weakly, and the body releases it after meals [11][13]. Building a potent, long-acting version of an existing physiological signal is the argument for the whole class, and for Mazdutide in particular.

Mazdutide takes the glucagon end of that family as its starting sequence. Survodutide does the same from a different backbone, and the two are the leading members of the class.

The glucagon arm and what it is meant to add

Adding glucagon activity to a glucose-lowering drug sounds backwards. The rationale is specific, and worth separating from the evidence for it.

What glucagon does besides raising glucose

Glucagon stimulates lipolysis and mitochondrial fat oxidation in the liver. It regulates amino acid metabolism through a liver to alpha-cell axis. It reduces caloric intake, and it raises energy expenditure in animal models [13].

The mirror-image evidence is stronger than most summaries admit. Glucagon receptor antagonists, developed as diabetes drugs, increased body weight, hepatic fat and serum lipids in people with type 2 diabetes [13]. Blocking the receptor makes metabolic health worse. That is an argument for agonism which does not depend on any animal result.

GLP-1 agonism then covers the glycaemic cost. Insulin secretion and slowed gastric emptying offset the hyperglycaemic push, so the combined molecule lowers glucose in practice.

What happened when both hormones went into people

One study infused the pieces separately and together, and its result is rarely quoted alongside the design story.

Bagger and colleagues gave 15 healthy men five liquid meal tests under saline, GLP-1, glucagon, oxyntomodulin, or GLP-1 plus glucagon (PMID 26445112) [11]. Every peptide arm cut food intake by a similar amount. The combination added nothing over either hormone alone. Resting oxygen uptake did not change significantly under any infusion, including oxyntomodulin.

That is one acute study in lean young men, and chronic weekly dosing is a different experiment. It still means the additive-mechanism claim behind Mazdutide rests on animal energetics rather than on human measurement.

The same laboratory tradition shows the method can detect additivity when it exists. Co-infusing peptide YY with oxyntomodulin cut energy intake 42.7% against saline, more than either hormone produced alone [12].

Dose finding, from 3 mg to 16 mg

The dose ladder is unusually well documented, and it explains where the headline figures come from.

The phase 1b studies

The first multiple-ascending-dose study of Mazdutide ran 12 participants per cohort for 12 weeks. Weight fell 4.81%, 6.40% and 6.05% at 3.0, 4.5 and 6.0 mg, against a 0.60% gain on placebo (PMID 34430840) [3]. Three participants on drug had mild asymptomatic cardiac findings on electrocardiogram. That is worth carrying forward, given glucagon’s chronotropic effects [20].

A second phase 1b study pushed higher. The 9 mg cohort lost 11.7% over 12 weeks; the 10 mg cohort lost 9.5% over 16 weeks [4]. Different escalation schedules and eight participants per arm make that pair uninterpretable as a dose comparison. The authors treated it as tolerability work rather than efficacy.

Where the largest number comes from

The biggest weight figure in this literature belongs to the smallest trial.

A high-dose phase 1 study escalated 24 adults to 16 mg of Mazdutide over 20 weeks, with eight on placebo. Weight fell 20.0% in one cohort and 21.0% in the other, against 0.1% on placebo. Two thirds or more of participants lost at least 15% [7], and no serious adverse events occurred.

Twenty-four people over 20 weeks is a safety and tolerability result. Anyone citing 21% should say which trial produced it, because the phase 3 programme never tested that dose.

Phase 2 and phase 3 in obesity

The registration programme settled on 4, 6 and 9 mg, and the results scale with dose and duration.

GLORY-1

The first phase 3 obesity trial randomised 610 adults to 4 mg or 6 mg of Mazdutide, or placebo, for 48 weeks (PMID 40421736) [1]. At the primary 32-week timepoint, weight fell 10.09% and 12.55% against a 0.45% gain. Some 73.9% and 82.0% of participants lost at least 5%.

By 48 weeks the curves had not flattened. Weight change reached 11.00% and 14.01%, and 35.7% and 49.5% of participants had lost at least 15%. All prespecified cardiometabolic measures improved. Discontinuation for adverse events ran at 1.5%, 0.5% and 1.0%.

GLORY-2 at 9 mg

The 9 mg trial enrolled 461 adults with a body mass index of at least 30 across 27 hospitals, and ran 60 weeks [2]. Weight fell 16.65% on Mazdutide against 1.50% on placebo. A total of 84.3% reached at least 5% reduction, against 33.1%.

Baseline matters for reading that figure. Mean age was 33.9 years, mean weight 94.0 kg, mean body mass index 34.3, and 64% of participants were female.

Mazdutide in type 2 diabetes

The diabetes programme is separate, larger in trial count, and gives the drug a second approved indication.

Against placebo

A phase 3 monotherapy trial randomised 320 adults with a mean HbA1c of 8.24% to Mazdutide at 4 mg or 6 mg, or placebo, for 24 weeks [9]. HbA1c fell 1.57% and 2.15% against 0.14%. Weight fell 5.61% and 7.81% against 1.26%.

An earlier phase 2 trial had found HbA1c reductions of 1.41% to 1.67% across 3, 4.5 and 6 mg, with weight change up to 7.1% [8].

Against dulaglutide

The comparator trial randomised 731 adults on background oral agents to 4 mg or 6 mg of Mazdutide, or 1.5 mg dulaglutide, for 28 weeks [10].

Both doses beat dulaglutide on HbA1c, by 0.24% and 0.30%. The weight separation was wider, at 3.78% and 5.76%. Gastrointestinal adverse events were more common on the dual agonist.

Note the comparator. Dulaglutide at 1.5 mg is a mid-generation GLP-1 agonist at a submaximal dose, not semaglutide and not tirzepatide. No head-to-head against either has been published.

Symptoms and dropout tell different stories

The tolerability numbers in GLORY-2 look alarming until they are set beside the discontinuation rate.

Vomiting affected 53.1% of participants on drug against 1.3% on placebo. Nausea affected 46.9% against 3.2%, and diarrhoea 39.4% against 6.5% [2]. Most events were mild or moderate.

Adverse events leading to discontinuation reached 2.9% on drug and 0% on placebo [2]. Half the trial vomited and 97% stayed.

A network meta-analysis of 262 obesity drug trials found discontinuation risk highest with orforglipron, naltrexone-bupropion, liraglutide, phentermine-topiramate, cagrilintide-semaglutide and oral semaglutide [18]. Symptom prevalence and tolerability are not the same measurement, and the two orderings differ.

Where the glucagon receptor may do something GLP-1 cannot

If the second receptor earns its place, the evidence should appear in organs where glucagon acts and GLP-1 does not. Three lines are worth separating by species.

Liver fat, against semaglutide in mice

A 9.4-tesla MRI study fed 42 male mice a high-fat diet for 13 weeks, then treated them with Mazdutide, semaglutide or vehicle for four weeks [14].

Proton density fat fraction fell further on the dual agonist at four weeks, with a median change of 5.59% against 3.30%. At one week the two drugs did not separate. Hepatic iron, read as R2*, showed no difference at either timepoint.

Fat fraction correlated with hepatic triglyceride and with histological steatosis scores. A four-week mouse result does not transfer to human liver disease, and clinical work in fatty liver is still ongoing [17].

The kidney tubule

Genetic work published in 2026 gives the receptor a kidney-intrinsic role. Tubule-specific deletion of the glucagon receptor worsened diabetic kidney disease in mice, with phospholipid accumulation in enlarged lysosomes [15].

The mechanism runs through V-ATPase assembly. Loss of the receptor disrupted its association with the ATP6V1A subunit and impaired lysosomal acidification, and re-expressing the receptor reversed the injury [15]. Tubular receptor expression was also reduced in human kidney samples from patients with the disease.

Cognition in one diabetic mouse model

Male db/db mice treated with Mazdutide outperformed dulaglutide-treated animals on behavioural testing. Multi-omics analysis pointed at neuroprotection, energy metabolism and synaptic plasticity pathways [16].

The authors state plainly that their findings apply to male mice only. Read it as a hypothesis about the second receptor, not as evidence about people.

What the trials do not establish

Four gaps sit between the published record and the claims that circulate around it.

Population

Every phase 2 and phase 3 efficacy trial ran in China [1][2][5][6][8][9][10]. The 16 mg phase 1 study is the exception, and it enrolled 32 people [7].

GLORY-1 participants averaged 87.2 kg and a body mass index of 31.1 [1]. GLORY-2 averaged 94.0 kg and 34.3, at a mean age of 33.9 [2]. Western obesity trials typically enrol heavier and older cohorts, so percentage weight change across programmes is not a like-for-like comparison.

Certainty and outcomes

The 2026 network meta-analysis placed Mazdutide among emerging agents that may produce reductions of 13.1% to 14.6%, graded very low to low certainty (PMID 42419792) [18]. Tirzepatide and cagrilintide-semaglutide carried moderate to high certainty at around 14.9% and 14.8%.

Subcutaneous semaglutide was the only drug in that analysis associated with reduced all-cause mortality [18]. No cardiovascular outcome trial has reported for Mazdutide. A 2026 review of glucagon receptor signalling in the heart treats the cardiovascular profile of multi-agonists as unsettled [20].

Approval status and open indications

Approval came in China first, and remains limited to it.

The regulator cleared Mazdutide in June 2025 for long-term weight management, alongside diet and activity [17]. The label covers adults with a body mass index of at least 28, or at least 24 with a weight-related comorbidity. Glycaemic control in type 2 diabetes followed in September 2025.

Trials continue in metabolic dysfunction-associated fatty liver disease, obstructive sleep apnoea and alcohol use disorder [17]. A meta-analysis of five randomised trials in non-diabetic adults found weight reduction of 12.42%, waist circumference down 7.98 cm, and systolic blood pressure down 7.68 mmHg [19].

Four questions to ask of any Mazdutide result

Most disagreement about this compound traces to comparing figures that were never comparable.

Which dose, and from which trial?

Reported weight change spans 4.81% to 21%, across doses from 3 mg to 16 mg and trials from 12 to 610 participants [3][7][1]. A number without its dose and its denominator says little.

Which population?

The efficacy record is Chinese, young and moderately obese [1][2]. Read percentages against baseline weight rather than against percentages from other programmes.

Which arm of the pharmacology is being credited?

Weight loss, appetite suppression and glycaemic control are all explicable through GLP-1 alone. The glucagon-specific case rests on liver, kidney and energy expenditure data, mostly in animals [13][14][15].

Is the comparator at full dose?

The only published head-to-head used dulaglutide 1.5 mg [10]. Against a maximal semaglutide or tirzepatide dose, nothing has been run.

Verifying research material

A lipidated 33-residue peptide of 4,476 Da has a specific set of analytical questions.

Identity

Intact mass is the primary check, at 4,476 Da average and 4,473.29 monoisotopic. That resolution separates this peptide cleanly from its relatives: survodutide runs at 4,232, semaglutide at 4,114 and glucagon itself at 3,483.

The C20 diacid and its spacer are the features to confirm. A backbone missing that chain differs by a defined mass increment and would clear in hours rather than days.

Peptide mapping confirms sequence. At 33 residues the tryptic map is short, and full coverage by tandem mass spectrometry is routine.

Purity and related substances

Deletion sequences are the expected impurity in solid-phase synthesis at this length. Each missing residue shifts intact mass by that residue, which is easy to miss inside a broad chromatographic peak.

Reversed-phase chromatography with mass detection finds them; ultraviolet detection alone often does not. Isomers of the acylation site are the second concern, since the diacid can in principle attach to the wrong lysine.

Peptide content differs from chromatographic purity. Lyophilised material carries counterions and water, so a vial labelled 10 mg by weight holds less peptide than that, and acetate or trifluoroacetate content belongs on the certificate.

Handling

Store the lyophilised powder cold, dry and dark, and reconstitute close to the point of use.

The albumin-binding chain makes the peptide surface-active. Dilute solutions lose material to plastic, so aliquot on reconstitution rather than sampling one vial repeatedly. Freeze-thaw cycling drives aggregation, which changes the species present without changing the label.

Kimera publishes third-party certificates of analysis for every lot in its COA database. Laboratories source mazdutide as a glucagon and GLP-1 receptor dual agonist reference. It sits alongside survodutide, the other dual agonist in this class, and CL-316243, a beta-3 adrenergic agonist used as an energy expenditure tool compound. It also pairs with AOD-9604 as a contrasting fragment approach and with 5-amino-1MQ, which inhibits nicotinamide N-methyltransferase in the same hepatic metabolic space. Related work appears in the peptides category.

Common questions about Mazdutide

What is mazdutide? A 33-residue oxyntomodulin analogue that activates the glucagon receptor and the GLP-1 receptor, given once weekly [17].

Where is it approved? China only, for weight management since June 2025 and for type 2 diabetes since September 2025 [17].

What did phase 3 show in obesity? Weight change of 11.00% at 4 mg and 14.01% at 6 mg over 48 weeks [1], and 16.65% at 9 mg over 60 weeks [2].

How does it compare with GLP-1 agonists? It beat dulaglutide 1.5 mg on HbA1c and weight [10]. Network meta-analysis places it near tirzepatide on weight, at much lower certainty [18].

What does the glucagon receptor add? Hepatic fat oxidation and energy expenditure in animal models [13][14]. Acute human co-infusion found no additive effect on food intake or resting energy expenditure [11].

How well is it tolerated? Vomiting in 53.1% and nausea in 46.9% at 9 mg, with 2.9% discontinuing for adverse events [2].

Summary of the evidence

Identity: 33 residues, C₂₀₇H₃₁₇N₄₅O₆₅, 4,476 Da, with aminoisobutyric acid at position 2 and a C20 diacid for albumin binding.

Design: an oxyntomodulin analogue on a glucagon backbone [11][13], using the same lipidation chemistry as semaglutide and tirzepatide.

Obesity: 11.00% and 14.01% at 4 and 6 mg over 48 weeks in 610 adults [1]; 16.65% at 9 mg over 60 weeks in 461 adults [2]; 20% to 21% at 16 mg over 20 weeks in 24 adults [7].

Diabetes: HbA1c down 1.57% and 2.15% against placebo [9], and superior to dulaglutide 1.5 mg on both HbA1c and weight [10].

Tolerability: gastrointestinal symptoms in roughly half of participants at 9 mg, with discontinuation at 2.9% [2].

Glucagon-specific evidence: greater hepatic fat reduction than semaglutide in mice [14], a kidney-intrinsic protective role for the receptor [15], and no additive human effect in acute co-infusion [11].

Limits: efficacy data almost entirely from Chinese trials in a young, moderately obese population [1][2], very low to low certainty in network meta-analysis [18], no cardiovascular outcome trial [20], and no comparison against a maximal-dose GLP-1 agonist [10].

Status: supplied for laboratory research use only.

References

1. Ji L, Jiang H, Bi Y, Li H, Tian J, Liu D, et al. Once-weekly mazdutide in Chinese adults with obesity or overweight. N Engl J Med. 2025;392(22):2215-2225. PMID 40421736. DOI
2. Gao L, Jiang H, Cai H, Tian J, Zhang Y, Qiu W, et al. Treatment with 9-mg mazdutide for weight reduction in Chinese adults with obesity: the GLORY-2 randomized clinical trial. JAMA. 2026;336(5):377-388. PMID 42251595. DOI
3. Ji L, Jiang H, An P, Deng H, Liu M, Li L, et al. IBI362 (LY3305677), a weekly-dose GLP-1 and glucagon receptor dual agonist, in Chinese adults with overweight or obesity: a randomised, placebo-controlled, multiple ascending dose phase 1b study. EClinicalMedicine. 2021;39:101088. PMID 34430840. DOI
4. Ji L, Gao L, Jiang H, Yang J, Yu L, Wen J, et al. 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: a randomised, placebo-controlled, multiple-ascending-dose phase 1b trial. EClinicalMedicine. 2022;54:101691. PMID 36247927. DOI
5. Ji L, Jiang H, Cheng Z, Qiu W, Liao L, Zhang Y, et al. A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity. Nat Commun. 2023;14(1):8289. PMID 38092790. DOI
6. Ji L, Jiang H, Cheng Z, Li X, Wang Y, Gu J, et al. Mazdutide 9 mg in Chinese adults with a body mass index of 30 or above but without diabetes: a phase 2 randomized controlled trial. Med. 2026;7(5):101063. PMID 41875890. DOI
7. Bhattachar SN, Tham LS, Li Y, Chua L, Loghin C, Robins D, 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. PMID 40832785. DOI
8. Zhang B, Cheng Z, Chen J, Zhang X, Liu D, Jiang H, 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. PMID 37943529. DOI
9. Zhu D, Zhao J, Cai H, Chu X, Zhang B, Ji L, et al. Mazdutide versus placebo in Chinese adults with type 2 diabetes. Nature. 2025;652(8108):174-180. PMID 41407859. DOI
10. Guo L, Zhang B, Xue X, Zhang X, Jiang H, Ji L, et al. Mazdutide versus dulaglutide in Chinese adults with type 2 diabetes. Nature. 2025;652(8108):181-188. PMID 41407860. DOI
11. Bagger JI, Holst JJ, Hartmann B, Andersen B, Knop FK, Vilsbøll T. Effect of oxyntomodulin, glucagon, GLP-1, and combined glucagon plus GLP-1 infusion on food intake, appetite, and resting energy expenditure. J Clin Endocrinol Metab. 2015;100(12):4541-4552. PMID 26445112. DOI
12. Field BC, Wren AM, Peters V, Baynes KC, Martin NM, Patterson M, et al. PYY3-36 and oxyntomodulin can be additive in their effect on food intake in overweight and obese humans. Diabetes. 2010;59(7):1635-1639. PMID 20357366. DOI
13. Neff GW. Shared mechanistic pathways of glucagon signalling. Diabetes Obes Metab. 2025;27(12):6869-6883. PMID 41025406. DOI
14. Xia H, Min Y, Wang Y, Gao S, Wang H, Yan F, et al. Multiparametric MRI evaluation of liver fat and iron after glucagon-like peptide-1 receptor and glucagon receptor dual-agonist treatment in a high-fat diet-induced mouse model. Radiology. 2025;316(2):e243780. PMID 40828048. DOI
15. Qu H, Xu M, Du P, Zhang L, Li Y, Wang J, et al. Renoprotective effects of tubular glucagon receptor activation mediated by V-ATPase. Sci Adv. 2026;12(32):eaeg2534. PMID 42555719. DOI
16. Dong W, Bai J, Yuan Q, Zhang Y, Wang X, Li H, et al. Mazdutide, a dual agonist targeting GLP-1R and GCGR, mitigates diabetes-associated cognitive dysfunction: mechanistic insights from multi-omics analysis. EBioMedicine. 2025;117:105791. PMID 40479843. DOI
17. Shirley M. Mazdutide: first approval. Drugs. 2025;85(12):1621-1627. PMID 41028652. DOI
18. Nong K, Shi Q, Xie X, Wang Y, Zeng L, Guyatt G, et al. Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis. BMJ. 2026;394:e372161. PMID 42419792. DOI
19. Azam MH, Azam KU, Azam MA, Khan A. Efficacy and safety of mazdutide in managing overweight and obesity among non-diabetic adults: a meta-analysis of randomised controlled trials. Diabetes Obes Metab. 2026;28(6):4464-4473. PMID 41804840. DOI
20. Kushner PR, Michos ED. Cardiovascular effects of glucagon receptor signaling alone and combined with glucagon-like peptide-1 receptor signaling in multiagonists: a narrative review with a translational focus. J Am Heart Assoc. 2026;15(15):e049727. PMID 42535526. DOI

Mazdutide is sold for laboratory research use only. Not for human consumption, nor medical, veterinary, or household uses.

Literature retrieved from PubMed.