Mazdutide
Also known as: IBI362, LY3305677
Mazdutide is a dual GLP-1 and glucagon receptor agonist based on an oxyntomodulin analog, developed by Innovent Biologics in partnership with Eli Lilly, and the first drug of its class to receive regulatory acceptance for obesity in China.
Key Findings at a Glance
- •The GLORY-1 Phase 3 trial demonstrated 14.0 percent mean weight loss with mazdutide 6 mg at 48 weeks, with 49.5 percent of participants achieving at least 15 percent weight loss versus 2.0 percent with placebo.
- •Mazdutide is the first dual GLP-1 and glucagon receptor agonist to complete a positive Phase 3 clinical trial for obesity and have its New Drug Application accepted by a regulatory authority.
- •Phase 1b data showed rapid weight loss of 11.7 percent in just 12 weeks with the 9 mg dose, suggesting dose-dependent efficacy that may increase at higher doses being evaluated in GLORY-2.
- •Exploratory analyses showed significant reductions in liver fat content and transaminases, suggesting potential utility for metabolic dysfunction-associated steatotic liver disease beyond weight management.
Mazdutide Overview & Molecular Profile
Mazdutide (IBI362/LY3305677) is a novel once-weekly subcutaneous dual agonist of the glucagon-like peptide-1 (GLP-1) and glucagon receptors, developed as an engineered analog of the endogenous hormone oxyntomodulin. Originally licensed from Eli Lilly, mazdutide has been primarily developed by Innovent Biologics for the Chinese and broader Asian markets. The compound leverages the complementary metabolic effects of GLP-1 receptor activation (appetite suppression, insulin secretion) and glucagon receptor activation (increased energy expenditure, hepatic fat reduction) to achieve substantial weight loss and metabolic improvement. The Phase 3 GLORY-1 trial demonstrated up to 14.0% weight loss at 48 weeks in Chinese adults with obesity, and China's National Medical Products Administration (NMPA) accepted the first New Drug Application for mazdutide in chronic weight management in February 2024. The GLORY-2 trial evaluating a higher 9 mg dose and the DREAM program for type 2 diabetes are currently underway.
Mechanism of Action: Receptor Agonism & Metabolic Pathways
Mazdutide functions as a balanced dual agonist of GLP-1 and glucagon receptors, designed to mimic and enhance the physiological effects of the endogenous intestinal hormone oxyntomodulin. GLP-1 receptor activation in pancreatic beta cells promotes glucose-dependent insulin secretion and suppresses glucagon release, while central GLP-1 receptor activation in hypothalamic appetite centers reduces food intake and promotes satiety. Simultaneously, glucagon receptor activation in hepatocytes stimulates glycogenolysis, gluconeogenesis, lipid oxidation, and thermogenesis, increasing total energy expenditure and directly reducing hepatic steatosis. The balanced ratio of GLP-1 to glucagon receptor activity ensures that the hyperglycemic potential of glucagon signaling is offset by the insulinotropic and appetite-suppressive effects of GLP-1 signaling, resulting in net improvements in both glycemic parameters and body weight. Additional metabolic effects include increased amino acid catabolism, enhanced ketogenesis, and stimulation of fibroblast growth factor 21 secretion.
Research-Observed Effects
Weight Loss
The Phase 3 GLORY-1 trial in 610 Chinese adults with overweight or obesity demonstrated dose-dependent weight loss with mazdutide at 48 weeks. The 6 mg dose produced mean weight loss of 14.0% compared to a 0.3% weight gain with placebo, while the 4 mg dose achieved 11.0% loss. At the primary 32-week endpoint, 82.0% of participants on 6 mg achieved at least 5% weight loss compared to 10.5% with placebo. By 48 weeks, 49.5% of participants on 6 mg achieved at least 15% weight loss versus only 2.0% with placebo. These results were competitive with or exceeded weight loss reported with semaglutide 2.4 mg and tirzepatide 10 mg in Chinese populations from the STEP-7 and SURMOUNT-CN trials respectively.
Hepatic Fat Reduction
Exploratory analyses from clinical trials have demonstrated significant reductions in hepatic fat content with mazdutide treatment. The glucagon receptor agonism component directly promotes hepatic lipid oxidation and reduces de novo lipogenesis, providing fat reduction that extends beyond what would be expected from weight loss alone. Reductions in liver transaminases (ALT and AST) have been consistently observed across trials, suggesting improvements in liver inflammation and hepatocellular injury. These hepatic effects are particularly relevant given the high prevalence of metabolic dysfunction-associated fatty liver disease in the Asian populations studied and position mazdutide as a potential therapeutic for MASH in addition to obesity.
Cardiometabolic Improvement
Clinical trials have documented comprehensive improvements in cardiometabolic risk factors with mazdutide. Significant reductions in waist circumference, systolic and diastolic blood pressure, total cholesterol, LDL cholesterol, triglycerides, and uric acid have been reported across Phase 2 and Phase 3 studies. A systematic meta-analysis of seven randomized controlled trials encompassing 680 participants confirmed mean reductions in systolic blood pressure of 7.57 mmHg and diastolic pressure of 2.98 mmHg. These broad cardiometabolic improvements suggest mazdutide may provide cardiovascular risk reduction beyond weight loss, though dedicated cardiovascular outcomes trials have not yet been conducted.
Glycemic Control
In Phase 2 trials in patients with type 2 diabetes, mazdutide demonstrated HbA1c reductions ranging from 1.46 to 2.23 percentage points compared to 0.87 with placebo, with efficacy comparable to dulaglutide 1.5 mg. The dual mechanism provides glucose lowering through both GLP-1-mediated insulin secretion and glucagon-mediated improvements in hepatic insulin sensitivity resulting from reduced hepatic fat content. Weight loss itself also contributes to improved insulin sensitivity and glycemic control. The DREAM program of Phase 3 trials is evaluating mazdutide specifically for type 2 diabetes management across multiple dosing regimens.
Energy Expenditure Enhancement
Like other dual GLP-1/glucagon receptor agonists, mazdutide increases total energy expenditure through glucagon receptor-mediated pathways including hepatic thermogenesis, brown adipose tissue activation, and enhanced substrate oxidation. Preclinical studies demonstrated that the glucagon receptor component contributes to body weight reduction through increased metabolic rate rather than appetite suppression alone. This mechanism provides a distinct advantage over pure GLP-1 receptor agonists, which primarily reduce energy intake without substantially affecting expenditure. The energy expenditure increase may help explain the magnitude of weight loss and the observed preferential reduction in visceral and hepatic fat with dual agonist treatment.
Research Dosing Information
In the GLORY-1 Phase 3 trial, mazdutide was administered as a once-weekly subcutaneous injection with dose escalation from 1.5 mg, titrating up to target doses of 4 mg or 6 mg over several weeks. A higher 9 mg dose is being evaluated in the GLORY-2 trial with a longer titration period.
Note: Dosing information is provided for research reference only and is based on published studies using research subjects. This is not a recommendation for any use.
Research Studies & References
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
Ji L, Jiang H, An P, et al. (2022). eClinicalMedicine
This Phase 1b, randomized, placebo-controlled trial evaluated higher doses of mazdutide (9 mg and 10 mg) in 24 Chinese adults with overweight or obesity. Participants were assigned to the 9 mg cohort (12-week treatment with escalation from 3 to 6 to 9 mg) or the 10 mg cohort (16-week treatment with escalation from 2.5 to 5 to 7.5 to 10 mg) in a 2:1 randomization with placebo. The 9 mg dose produced mean weight loss of 11.7% at 12 weeks compared to 1.8% with placebo, while the 10 mg dose achieved 9.5% at 16 weeks versus 3.3% with placebo, both reaching statistical significance. No serious adverse events were reported, and the most common side effects were gastrointestinal symptoms including nausea, vomiting, and decreased appetite, all mild to moderate in severity. These results demonstrated the feasibility of higher dosing and supported dose selection for subsequent Phase 2 and Phase 3 trials. The rapid weight loss kinetics observed even at 12 weeks suggested robust metabolic effects of dual receptor agonism at higher doses.
A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity
Ji L, Gao L, Jiang H, et al. (2023). Nature Communications
This Phase 2 randomized, double-blind, placebo-controlled trial evaluated mazdutide at doses of 3 mg, 4.5 mg, and 6 mg weekly in 248 Chinese adults with overweight or obesity over 24 weeks. All mazdutide doses produced statistically significant and dose-dependent weight loss compared to placebo. At week 24, mean body weight reductions were 6.7% with 3 mg, 10.4% with 4.5 mg, and 11.3% with 6 mg compared to 1.0% with placebo, all highly significant. Improvements in waist circumference, blood pressure, lipid profiles, liver enzymes, and metabolic biomarkers were observed across dose groups. Gastrointestinal adverse events were the most common treatment-emergent events, occurring in a dose-dependent manner but remaining predominantly mild to moderate. The discontinuation rate due to adverse events was low across all groups. These results established dose-response efficacy for mazdutide in an Asian population and supported the selection of 4 mg and 6 mg doses for Phase 3 evaluation in the GLORY program.
Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight
Ji L, Jiang H, Cheng Z, et al. (2025). New England Journal of Medicine
The GLORY-1 Phase 3 trial was a pivotal randomized, double-blind, placebo-controlled study evaluating mazdutide at 4 mg and 6 mg weekly in 610 Chinese adults with overweight (BMI 24 or greater with comorbidity) or obesity (BMI 28 or greater). The primary co-endpoints were percentage change in body weight and proportion achieving at least 5% weight loss at 32 weeks. At week 32, the 6 mg dose produced 12.55% weight loss versus 0.45% weight gain with placebo, with 82.0% achieving at least 5% loss compared to 10.5% with placebo. By 48 weeks, weight loss reached 14.0% with the 6 mg dose, with 49.5% achieving at least 15% loss versus 2.0% with placebo. Comprehensive cardiometabolic improvements were observed including reductions in waist circumference, blood pressure, lipids, uric acid, liver fat content, and hepatic transaminases. The safety profile was favorable with predominantly mild to moderate gastrointestinal adverse events and low discontinuation rates of 0.5-1.5%. This trial established mazdutide as the first dual GLP-1/glucagon receptor agonist to complete a positive Phase 3 obesity trial worldwide.
Frequently Asked Questions
Semaglutide (GLP-1)
C187H291N45O59
Semaglutide is a long-acting GLP-1 (glucagon-like peptide-1) receptor agonist that mimics the incretin hormone GLP-1, regulating blood glucose levels, appetite, and body weight through multiple metabolic pathways.
Retatrutide (Triple Agonist)
C221H342N46O68
Retatrutide is a first-in-class triple hormone receptor agonist targeting GLP-1, GIP, and glucagon receptors simultaneously, producing the most profound metabolic effects seen in obesity research to date.
Survodutide
C192H289N47O61
Survodutide is a dual glucagon and GLP-1 receptor agonist developed by Boehringer Ingelheim and Zealand Pharma, investigated for obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis (MASH).