Mazdutide

Background

Mazdutide (development codes IBI362 and LY3305677) is a synthetic, long‑acting peptide that functions as a dual agonist at the glucagon‑like peptide‑1 receptor (GLP‑1R) and the glucagon receptor (GCGR).[11][12] It belongs to the class of multi‑incretin peptide therapeutics being developed for obesity, type 2 diabetes mellitus (T2DM), and related metabolic disorders.[10][11][12] Mazdutide originated from early oxyntomodulin‑analog design work at Eli Lilly and was further developed and clinically advanced by Innovent Biologics, with most clinical data to date generated in Chinese populations.[2][11][12][13]

Chemically, mazdutide is a modified GLP‑1/glucagon analog engineered for once‑weekly subcutaneous administration through sequence substitutions and fatty‑acid conjugation that prolong plasma half‑life via albumin binding.[1][11] As of 2025, it is among the most clinically advanced GLP‑1/GCGR dual agonists and has completed phase 2 trials for obesity and T2DM, and at least one pivotal phase 3 obesity program (GLORY‑1) in China.[1][12][13]

Mechanism of action

Mazdutide is a dual agonist with high affinity for GLP‑1R and GCGR, designed to combine incretin‑like glucose lowering with glucagon‑driven energy expenditure.[1][10][11]

At the GLP‑1 receptor, mazdutide:

• Enhances glucose‑dependent insulin secretion from pancreatic β‑cells.
• Suppresses glucagon secretion from α‑cells in hyperglycemic states.
• Slows gastric emptying and promotes satiety via central and vagal pathways.[10][11][13]

At the glucagon receptor, mazdutide:

• Increases hepatic glucose production but, in the context of enhanced insulin action and caloric deficit, may not cause net hyperglycemia.[10][11][13]
• Stimulates lipolysis and fat oxidation, increasing energy expenditure and contributing to weight loss.[1][10][11]

Preclinical work in high‑fat diet mice and db/db mice shows that mazdutide reduces body weight, improves glycemic control, and exerts beneficial effects on hepatic steatosis, liver iron content, and cognitive function beyond those seen with GLP‑1R mono‑agonists.[5][6] In a 9.4‑T MRI study in high‑fat‑diet mice, mazdutide reduced liver fat fraction and iron content more than semaglutide, supporting GCGR‑mediated modulation of hepatic lipid and iron metabolism.[6]

Multi‑omics analyses in db/db mice indicate that mazdutide modulates pathways related to synaptic function, neuroinflammation, and mitochondrial metabolism, consistent with observed improvements in cognitive performance compared with dulaglutide.[5] Additionally, animal and human data suggest that mazdutide may lower serum uric acid, possibly by promoting renal urate excretion.[4][3]

Evidence summary

Obesity – adult phase 1b

A randomized, double‑blind, placebo‑controlled phase 1b trial evaluated once‑weekly mazdutide in Chinese adults with overweight or obesity (BMI ≥24 or ≥28 kg/m²).[11] Participants (n=108; 2:1 active:placebo within cohorts) received 12 weeks of dose‑escalated mazdutide up to 9 mg or 16 weeks up to 10 mg, versus placebo.[11]

• At week 12 in the 9‑mg cohort, mean placebo‑adjusted weight loss reached approximately 9–10% from baseline; at week 16 in the 10‑mg cohort, mean placebo‑adjusted weight loss was approximately 11–12%.[11]
• Reductions in waist circumference, blood pressure, and serum lipids were observed, with improvements in markers of insulin resistance and hepatic steatosis.[11]
• Adverse events were primarily mild to moderate gastrointestinal (GI) symptoms (nausea, vomiting, diarrhea) and transient decreases in heart rate and blood pressure; no new major safety signals were detected over 12–16 weeks.[11]

Obesity – adult phase 2

A multicenter, double‑blind, placebo‑controlled phase 2 trial (24 weeks) examined mazdutide in Chinese adults with overweight or obesity.[12] In this trial (n≈320; multiple dose arms up to 6 mg weekly), mazdutide produced clinically meaningful weight loss:

• At week 24, mean weight loss with higher doses approached or exceeded 15% from baseline in some cohorts, with significant placebo‑adjusted reductions.[12]
• Improvements were also observed in waist circumference, blood pressure, fasting glucose, lipid parameters, and liver enzymes.[12]
• GI adverse events were dose‑related but mostly mild to moderate and transient.[12]

The GLORY‑1 phase 3 program in China (summarized in a narrative review) reportedly confirmed substantial weight loss and a safety profile broadly similar to GLP‑1R agonists, but detailed phase 3 primary data were not fully published by early 2025.[1]

Type 2 diabetes – adult phase 2

A randomized, double‑blind, placebo‑controlled phase 2 trial in Chinese adults with T2DM inadequately controlled on diet/exercise or stable metformin evaluated mazdutide once weekly for 24 weeks (doses up to 4.5–6 mg, depending on regimen).[13]

• Sample size was 251 participants randomized to several mazdutide dose‑escalation regimens or placebo.[13]
• At week 24, mazdutide reduced HbA1c by up to ~1.9 percentage points versus baseline, with placebo‑adjusted reductions around 1.0–1.5 percentage points, depending on dose.[13]
• Mean body‑weight reductions up to ~10% were observed, along with improvements in fasting plasma glucose, HOMA‑IR, and cardiovascular risk markers.[13]
• Safety findings mirrored those in obesity trials, with GI events being most frequent and mostly mild/moderate; low rates of hypoglycemia were reported, mainly when background therapies were present.[13]

Meta‑analysis and broader synthesis

A systematic review and meta‑analysis of randomized controlled trials (RCTs) of mazdutide (including obesity and T2DM populations; 5 RCTs, n≈900) reported that mazdutide was associated with significant weight loss, HbA1c reduction in diabetes, and improvements in multiple cardiometabolic markers compared with placebo.[14][15]

• Pooled mean percentage weight loss was markedly greater with mazdutide than placebo; weight reduction was more pronounced in non‑diabetic participants and with 24‑week versus shorter treatment durations.[14][15]
• Mazdutide increased the risk of mild or moderate GI adverse events relative to placebo but did not significantly increase serious adverse events.[14][15]

Special populations and preclinical data

• A case report described a 15‑year‑old male with obesity, T2DM, and hyperuricemia treated with escalating mazdutide doses (2→4→6 mg weekly) for 36 weeks, alongside metformin and insulin.[3] The patient experienced 18.9% BMI reduction, 21.9% HbA1c reduction, 37% uric acid reduction, resolution of hepatic steatosis, and no reported adverse events or hypoglycemia.[3] This constitutes single‑patient evidence and cannot establish safety or efficacy in adolescents.
• In hyperuricemic rats, mazdutide reduced serum uric acid to a degree comparable to allopurinol, with no similar effect seen with semaglutide, suggesting a potential uricosuric mechanism.[4]
• In db/db mice, mazdutide improved cognitive function and reduced neurodegenerative pathology compared with dulaglutide, with multi‑omics data implicating changes in synaptic, inflammatory, and metabolic pathways.[5]
• In a high‑fat diet mouse model, mazdutide reduced hepatic fat and iron content more than semaglutide, assessed by multiparametric MRI and histology.[6]

Clinical and research uses

Investigational therapeutic indications

Based on completed and ongoing clinical trials and patent landscape analyses, mazdutide is under investigation for:[1][2][11][12][13][3]

• Chronic weight management in adults with overweight or obesity, with or without comorbidities.
• Type 2 diabetes mellitus as monotherapy or add‑on to metformin.
• Obesity with metabolic comorbidities, including hyperuricemia and non‑alcoholic fatty liver disease/non‑alcoholic steatohepatitis (now MASLD/MASH), primarily in exploratory or early‑phase settings.[1][3][6]
• Adolescent obesity and T2DM (only isolated case‑level data as of 2025).[3]

No large cardiovascular outcomes trial (CVOT) dedicated to mazdutide had been reported by early 2025, although class‑level data for GLP‑1–based agents suggest potential cardiometabolic benefits.[10][14]

Mazdutide remains an investigational agent globally, with use confined to clinical trials and, in some contexts, named‑patient or research settings in China. Routine clinical use outside trials, particularly in adolescents or in indications such as hyperuricemia, is not supported by controlled evidence and would be considered experimental.[1][3][4]

Dosing context

All dosing information here reflects clinical trial regimens only and does not constitute prescribing guidance.

Mazdutide is administered subcutaneously once weekly using dose‑escalation schedules to mitigate GI intolerance.[11][12][13]

Examples from trials include:

• Overweight/obesity (phase 1b, adults): 9‑mg cohort—3 mg weeks 1–4, 6 mg weeks 5–8, 9 mg weeks 9–12; 10‑mg cohort—2.5 mg weeks 1–4, 5 mg weeks 5–8, 7.5 mg weeks 9–12, 10 mg weeks 13–16.[11]
• Overweight/obesity (phase 2, adults): multiple regimens titrating up to 6 mg weekly over several weeks, followed by maintenance through week 24.[12]
• Type 2 diabetes (phase 2, adults): once‑weekly doses up to 4.5–6 mg using gradual escalation (e.g., starting at 1–2 mg and increasing every 4 weeks) across 24 weeks.[13]
• Adolescent case: 2 mg weekly for 4 weeks, 4 mg weekly for 16 weeks, then 6 mg weekly for 16 weeks (total 36 weeks).[3]

Optimal dosing, titration pace, and maintenance dose ranges have not been definitively established and may differ by indication, population, and regional development programs.[11][12][13]

Safety profile

Common adverse effects

Across adult obesity and T2DM RCTs, the most frequent adverse events are gastrointestinal, similar to those seen with GLP‑1R agonists:[11][12][13][14]

• Nausea
• Vomiting
• Diarrhea
• Decreased appetite and early satiety
• Abdominal discomfort

These events are usually mild to moderate, occur predominantly during dose escalation, and tend to diminish over time.[11][12][13][14]

Metabolic and cardiovascular effects

• Hypoglycemia: Very low incidence when mazdutide is used without insulin or insulin secretagogues; in the phase 2 T2DM trial, confirmed hypoglycemia was rare and typically associated with background glucose‑lowering therapy.[13]
• Heart rate and blood pressure: Small increases in heart rate and modest reductions in blood pressure were observed, consistent with GLP‑1R agonists and possibly augmented by weight loss.[11][12][13]

Hepatic and renal parameters

Mazdutide generally improved liver enzymes and imaging markers of steatosis in adults with obesity and T2DM, and in preclinical models.[6][11][12][13] No clear signal of drug‑induced liver injury has emerged in short‑term trials, although exposure durations remain limited.[11][12][13]

Preclinical and early clinical observations suggest reductions in serum uric acid, but mechanistic and long‑term renal safety data remain limited.[3][4]

Pancreas, gallbladder, and other class‑related risks

Given its GLP‑1 agonism, mazdutide may share potential class‑related concerns such as acute pancreatitis and gallbladder disease, although RCTs to date have reported low absolute event numbers and no definitive causal signal.[11][12][13][14] Long‑term surveillance and larger datasets are needed to clarify these risks, especially at higher doses and over multi‑year treatment.

Immunogenicity

As a modified peptide therapeutic, mazdutide can theoretically induce anti‑drug antibodies; limited early data indicate low immunogenicity rates, with no clear effect on efficacy or safety, but systematic reporting is sparse.[11]

Special populations and long‑term safety

• Adolescents: Evidence is restricted to single‑case experience; long‑term safety, effects on growth/puberty, and psychiatric or behavioral outcomes are unknown.[3]
• Older adults, advanced CKD, significant hepatic impairment: Dedicated studies are lacking; extrapolation from GLP‑1R agonists is uncertain due to added GCGR agonism.
• Long‑term (>1–2 years): No long‑duration RCTs or real‑world registries are yet available; durability of weight loss, glycemic control, and potential rare adverse events remain incompletely characterized.[14][15]

Regulatory status

As of early 2025, mazdutide is not approved by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for any indication. No FDA drug label or EMA assessment report for mazdutide/IBI362/LY3305677 was publicly available.[10]

In China, mazdutide has progressed through phase 2 trials for obesity and T2DM and is reported to have completed at least one phase 3 obesity program (GLORY‑1), positioning it as a leading candidate for national regulatory submission.[1][12][13] However, formal marketing authorization status and label details within China were not fully documented in English‑language primary regulatory sources by early 2025.

Globally, therefore, mazdutide should be regarded as an investigational GLP‑1/GCGR dual agonist, restricted to use within clinical trials or regulated early‑access programs. Any off‑label or non‑trial use would be outside current evidence‑based and regulatory frameworks.[1][10][11][12][13]