Mazdutide significantly reduces weight in adults with overweight or obesity

1. In this randomized controlled trial, weekly administration of Mazdutide resulted in significant weight reduction in adults classified as overweight or obese.

2. The most common side effect was gastrointestinal upset; however, discontinuation rates among those receiving Mazdutide were comparable to placebo.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Obesity (BMI >28) and overweight (BMI 24 to <28) are well-known risk factors for multiple comorbidities. Although glucagon receptor antagonists lower blood glucose, they can cause dyslipidemia, weight gain, and hepatic steatosis. This has led to growing interest in dual GLP-1/glucagon receptor agonists, which may better support weight loss and hepatic lipolysis. Mazdutide, a once-weekly dual GLP-1/glucagon agonist, showed promising weight reduction in phase two trials involving individuals with type 2 diabetes. This phase three trial evaluated the long-term efficacy and safety of Mazdutide in Chinese adults with overweight or obesity and at least one comorbidity. Participants were randomized to receive a placebo, 4 mg of Mazdutide, or 6 mg of Mazdutide. At 32 weeks, both Mazdutide groups showed significantly greater weight loss than placebo. Although the 6 mg group had a slightly larger reduction than the 4 mg group, the difference was not statistically significant. A greater proportion of participants in both treatment arms achieved ≥5% weight loss. By week 48, both doses of Mazdutide remained superior to placebo in body weight reduction, waist circumference, and the proportion achieving ≥5%, ≥10%, and ≥15% weight loss. It also significantly improved cardiometabolic markers, including systolic blood pressure, triglycerides, LDL cholesterol, serum uric acid, and ALT. Gastrointestinal side effects were the most frequent adverse events. However, discontinuation rates were lowest in the 6 mg group. Although limited by a homogeneous study population and short off-treatment follow-up, the findings support Mazdutide’s safety and efficacy for weight management.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: This randomized controlled trial evaluated the efficacy of Mazdutide, a once-weekly dual GLP-1/glucagon receptor agonist, for sustained weight reduction. Chinese adults aged 18–75 with overweight (BMI 24 to <28) or obesity (BMI >28) and at least one comorbidity (e.g., prediabetes, hypertension, dyslipidemia, fatty liver disease, joint pain, dyspnea, or sleep apnea) were eligible. Key exclusion criteria included weight fluctuations >5% in the prior 12 weeks, a positive pregnancy test, or breastfeeding. A total of 610 participants were randomized to receive placebo (n = 205), 4 mg Mazdutide (n = 203), or 6 mg Mazdutide (n = 202). At 32 weeks, the primary outcomes were percent weight reduction from baseline and the proportion achieving ≥5% weight loss. Both Mazdutide doses showed significantly greater weight loss from baseline than placebo: 12.55% (95% CI, 13.64 to 11.45) for 6 mg and 10.09% (95% CI, 11.15 to 9.04) for 4 mg (p < 0.001 for both). Only 10.5% of the placebo group achieved ≥5% weight loss, compared to 82.0% (95% CI, 76.7–87.4) in the 6 mg group and 73.9% (95% CI, 67.8–79.9) in the 4 mg group (p < 0.001). At 48 weeks, the 6 mg group remained superior to placebo across secondary outcomes, including percent weight change (-14.01% vs. 0.30%), waist circumference reduction (-10.72 cm vs. -1.41 cm), and the proportion achieving ≥5% (81.6% vs. 10.8%), ≥10% (66.7% vs. 2.6%), and ≥15% (49.5% vs. 2.0%) weight loss. The 4 mg dose also demonstrated significant improvements in these secondary outcomes compared to placebo. Additionally, Mazdutide significantly reduced systolic blood pressure, triglycerides, total cholesterol, LDL, serum uric acid, and ALT (all p < 0.001). Adverse events were common but comparable across groups (96.1% for 4 mg, 97.0% for 6 mg, and 89.3% for placebo), with nausea being most frequent (32.5% for 4 mg and 50.5% for 6 mg). In summary, this study supports the efficacy and tolerability of both 4 mg and 6 mg Mazdutide for weight management in adults with overweight or obesity.

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