What is Mazdutide?
Mazdutide (also known as IBI362 or LY3305677) is an innovative therapeutic peptide designed to address metabolic disorders through a dual-agonist mechanism. Mazdutide is currently under investigation for its potential in managing obesity, type 2 diabetes, and related cardiometabolic conditions, showing promising results in clinical trials.
Mechanism of Action
Mazdutide is a dual agonist of glucagon-like peptide-1 (GLP-1) and glucagon receptors (GCGR), functioning as an analog of oxyntomodulin (OXM). By activating GLP-1 receptors, mazdutide enhances insulin secretion in a glucose-dependent manner, reduces appetite, and delays gastric emptying, contributing to improved glycemic control and weight loss. Simultaneously, glucagon receptor activation increases energy expenditure and promotes lipid mobilization, further aiding weight reduction and improving liver fat metabolism. This dual mechanism targets key pathophysiological aspects of obesity and type 2 diabetes, offering a synergistic approach to metabolic health.
Clinical Applications
Mazdutide is primarily being investigated for chronic weight management and type 2 diabetes. Clinical trials have also explored its potential in treating metabolic dysfunction-associated fatty liver disease (MAFLD) and related conditions such as heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF) combined with obesity. Its applications may extend to other metabolic and inflammatory diseases, such as hyperuricemia, due to its ability to reduce serum uric acid levels. The drug is administered once weekly via subcutaneous injection, with ongoing research into an oral formulation to enhance patient convenience.
Benefits and Potential Impact
Mazdutide has demonstrated robust efficacy in clinical trials, achieving significant weight loss (up to 14% body weight reduction after 48 weeks at 6 mg doses) and improved glycemic control compared to placebo and other agents like dulaglutide. It also reduces liver fat content, with a mean relative reduction of 80.2% in participants with elevated baseline levels, suggesting potential benefits for MAFLD and metabolic dysfunction-associated steatohepatitis (MASH). The drug’s favorable safety profile, with primarily mild to moderate gastrointestinal side effects, enhances its appeal. If approved, mazdutide could offer a convenient, effective treatment option, potentially improving outcomes for millions with obesity and type 2 diabetes, and reducing associated comorbidities like cardiovascular disease and sleep apnea.
Recent Trials
GLORY-1 Phase 3 Trial (NCT05607680): Conducted in Chinese adults with overweight or obesity, this trial showed mazdutide (4 mg and 6 mg) achieved a mean weight reduction of up to 14% (-26.9 lb) after 48 weeks, with significant reductions in liver fat content (up to 80.2% in participants with baseline LFC ≥10%). It also improved cardiometabolic markers like blood pressure, lipids, and insulin resistance.
DREAMS-2 Phase 3 Trial (NCT05606913): Involving 731 patients with type 2 diabetes, mazdutide (4 mg and 6 mg weekly) outperformed dulaglutide (1.5 mg daily) in reducing HbA1c, body weight, blood pressure, lipids, serum uric acid, and liver enzymes, demonstrating superior efficacy in glycemic control and weight management.
Phase 2 Trial (NCT04904913): This trial in 248 Chinese adults with overweight or obesity reported mean weight loss of 6.7% to 11.3% across 3 mg, 4.5 mg, and 6 mg doses over 24 weeks, with improvements in multiple cardiometabolic risk factors and a tolerable safety profile.
Phase 1b Trial (NCT04440345): Involving 24 participants, mazdutide doses up to 9 mg and 10 mg resulted in mean weight loss of 9.8% and 6.2% more than placebo after 12 and 16 weeks, respectively, with significant reductions in waist circumference and BMI.
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