Mazdutide First Approval: Dual GLP-1R/GcgR Agonist Opens a New Chapter in Metabolic Disease Treatment

The internationally renowned journal Drugshas published the first approval report on Mazdutide (Xin'ermei®). Originally developed by Eli Lilly and subsequently developed and commercialized in the Chinese market through a licensing collaboration with Innovent Biologics, Mazdutide received its first global approval in China in June 2025 for the long-term management of body weight in adults with obesity or overweight. In September 2025, its approval was extended to include glycemic control in type 2 diabetes (T2D). As the world's first approved dual glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GcgR) agonist, its clinical studies continue to explore indications for metabolic dysfunction-associated steatotic liver disease (MASLD) and obstructive sleep apnea, among others. This article aims to comprehensively analyze this breakthrough therapy, which offers a new approach to treating metabolic diseases, covering its development history, core characteristics, clinical data, and approval status.

1. Drug Basic Information

Mazdutide is an acylated single-chain peptide compound with multiple drug attributes: an anti-hyperglycemic agent, a gastrointestinal hormone, an anti-obesity drug, and a peptide therapeutic. It also has potential applications in liver protection, anti-gout treatment, and management of alcohol dependence. Its molecular structure mimics the function of mammalian oxyntomodulin. The molecular formula is C₂₀₇H₃₁₇N₄₅O₆₅. Exposure at clinically relevant doses is proportional to the dose.

① Mechanism of Action:

Exerts synergistic effects by potently binding to and activating the dual targets: glucagon receptor (GcgR) and glucagon-like peptide-1 receptor (GLP-1R).

GcgR Activation: Promotes hepatic gluconeogenesis and fatty acid oxidation, increasing energy expenditure.

GLP-1R Activation: Enhances glucose-dependent insulin secretion, delays gastric emptying, and suppresses appetite.

Overall Effect: Achieves core efficacy in lowering blood glucose and reducing body weight, while also improving metabolic parameters such as blood lipids and uric acid.

② Administration Route and Dosing Regimen:

Route: Subcutaneous injection (abdomen recommended), once weekly, offering high convenience.

Dosing: Recommended starting dose is 2 mg. The dose is increased to 4 mg after 4 weeks, and can be further titrated to 6 mg if necessary (adjusted based on tolerability).

③ Pharmacokinetic Profile:

Absorption & Distribution:​ Peak plasma concentration (Tₘₐₓ) is reached 7-28 hours after subcutaneous injection. Steady-state plasma concentration is achieved after 4 weeks of once-weekly administration. In adults with obesity/overweight, the mean apparent volume of distribution is 11.2 L, and the mean apparent clearance is 0.0368 L/h.

Elimination & Metabolism:​ Elimination half-life is approximately 10 days, supporting once-weekly dosing. Metabolism involves peptide chain hydrolysis and fatty acid chain oxidation. Excretion is primarily via urine and feces.

2. Approval Milestone: First in China, Globally Watched

The approval journey for Mazdutide began in January 2020 when the National Medical Products Administration (NMPA) of China accepted its clinical trial application. New Drug Applications for obesity and T2D were submitted in 2024. Final approval for the weight management indication was granted on June 27, 2025, followed by an extension for T2D treatment on September 19, 2025, making it the world's first approved dual GcgR/GLP-1R agonist.

3. Indications and Dosing Regimen

Mazdutide currently has two main approved indications: 1) Long-term weight management in adults with a BMI ≥28 kg/m² (obesity) or in adults with overweight (BMI ≥24 kg/m²) and at least one weight-related comorbidity; 2) Glycemic control in adults with type 2 diabetes.

Regarding the dosing regimen, the recommended starting dose is 2 mg once weekly, increased to 4 mg once weekly after 4 weeks. For additional weight loss, the dose can be further increased to 6 mg once weekly after maintaining the 4 mg dose for at least 4 weeks. Dose adjustments should be gradual, based on patient tolerability and treatment goals, to reduce the risk of gastrointestinal adverse reactions. For special populations, mild hepatic impairment or renal impairment of any degree has no significant impact on pharmacokinetics. However, data for patients with moderate to severe hepatic impairment or end-stage renal disease require further study.

4. Clinical Trials and Efficacy Data

The GLORY-1 trial, a key Phase III study for the obesity indication, yielded encouraging results. This 48-week, randomized, double-blind, placebo-controlled trial enrolled 610 Chinese adults with obesity/overweight. Results showed that at 32 weeks, the 4 mg and 6 mg dose groups achieved weight reductions of 10.09% and 12.55% from baseline, respectively, significantly superior to the placebo group. Notably, this weight loss was accompanied by improvements in multiple cardiovascular metabolic markers, including reductions in blood pressure, blood lipids, and uric acid levels.

In the field of type 2 diabetes, the DREAMS series of trials further confirmed the outstanding efficacy of Mazdutide. The DREAMS-1 trial showed HbA1c reductions of 1.57% and 2.15% for the 4 mg and 6 mg groups, respectively, at 24 weeks. The DREAMS-2 trial demonstrated that Mazdutide was significantly superior to dulaglutide in both glycemic control and weight loss. These data fully demonstrate the drug's advantageous position in treating metabolic diseases.

5. Safety Profile and Risk Management

The evaluation of any innovative drug requires a comprehensive review of its safety. The overall safety profile of Mazdutide is manageable. The most common adverse reactions are gastrointestinal events, such as nausea (32.5% in the 4 mg group, 50.5% in the 6 mg group) and diarrhea (35.0%/38.6%). These reactions mostly occur during the initial treatment phase, are mostly mild to moderate in severity, and most patients gradually develop tolerance over time.

However, special attention must be paid to the risk of thyroid C-cell tumors. This risk necessitates that clinicians thoroughly inquire about patients' personal and family history of thyroid disease before prescription, and avoid use in patients with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2. Furthermore, similar to other GLP-1 receptor agonists, Mazdutide causes a mild increase in heart rate, which requires attention in clinical use.

Regarding drug interactions, when co-administered with glucose-lowering drugs like insulin or sulfonylureas, the dose of the latter should be reduced to avoid hypoglycemia risk. Additionally, as it may delay gastric emptying, affecting the absorption of oral medications, caution and monitoring are needed, especially when co-administered with drugs with a narrow therapeutic window, such as warfarin.

6. Development Progress and Future Prospects

Mazdutide is currently undergoing expanded research in several directions, including exploration of higher doses and development of new indications. Particularly noteworthy are its explorations in areas like metabolic dysfunction-associated steatohepatitis (MASH) and alcohol use disorder, showcasing its potential beyond traditional metabolic disease treatment.

Ongoing Phase III trials include GLORY-2 (evaluating the efficacy of a 9 mg dose in people with BMI ≥30 kg/m²), DREAMS-3 (comparing to semaglutide in patients with obesity and early T2D), and GLORY-3/GLORY-OSA (exploring treatment potential for MASLD and obstructive sleep apnea). Positive results from these studies would significantly expand the drug's clinical application landscape.

7. Summary and Clinical Value

The approval and launch of Mazdutide represent a significant milestone in the field of metabolic disease treatment. Its innovative dual-target design, robust clinical evidence, and manageable safety profile position it as a promising new option for treating obesity and type 2 diabetes. From a clinical value perspective, the dual-target design of Mazdutide achieves synergistic effects in weight loss and glycemic control, providing a new therapeutic choice for patients with metabolic diseases.

Regarding industry impact, the successful R&D of Mazdutide holds multiple significances: it demonstrates the continuously growing strength of China's innovative drug R&D; the collaboration model between Eli Lilly and Innovent Biologics provides a successful template for cooperation between multinational pharmaceutical companies and local enterprises; its dual-target design philosophy points to a new direction for subsequent drug development. In the future, with the accumulation of more clinical data and the expansion of indications, Mazdutide is expected to play an even more important role in the treatment of metabolic diseases.

Original Article：

Shirley M. Mazdutide: First Approval. Drugs. 2025 Dec;85(12):1621-1627. doi: 10.1007/s40265-025-02249-y. Epub 2025 Sep 30. 

https://link.springer.com/article/10.1007/s40265-025-02249-y