Efficacy and Safety of Mazdutide in Adults with Obesity or Overweight, With or Without Diabetes: A Bayesian Network Meta-Analysis
Mazdutide shows promise for managing obesity, with dose-dependent benefits on weight and metabolic health, but gastrointestinal side effects are common.
Where it sits
this study against the rest of the mazdutide (ibi362) corpusSummary and findings
A Bayesian network meta-analysis evaluated the efficacy and safety of Mazdutide at various doses in 2,292 adults with obesity or overweight, with or without type 2 diabetes. Mazdutide 16 mg reduced waist circumference by −14.46 cm, and 9 mg reduced body weight by −7.65 kg. Gastrointestinal adverse events were more common with Mazdutide, but serious adverse events were not significantly increased.
Abstract
<title>Abstract</title> <p> <bold>Background</bold> : Mazdutide, a dual glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonist, has emerged as a promising therapy for obesity and overweight. However, its comparative dose-dependent efficacy and safety across multiple cardiometabolic outcomes remain to be comprehensively evaluated. Therefore, a Bayesian network meta-analysis was conducted to assess the effects of different Mazdutide doses in adults with obesity or overweight, with or without type 2 diabetes. <bold>Methods</bold> : A systematic literature search was performed in PubMed, Embase, Web of Science, the Cochrane Library, and ClinicalTrials.gov from inception to January 15, 2026. Randomized controlled trials (RCTs) evaluating Mazdutide at any dose against placebo or active comparators in adults with obesity or overweight were included. Efficacy outcomes included changes in body weight, waist circumference, body mass index (BMI), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), blood pressure, lipid profiles, and alanine aminotransferase (ALT). Safety outcomes included adverse events (AE), serious adverse events (SAE), gastrointestinal disorders, decreased appetite, and hypoglycemia. <bold>Results</bold> : Nine RCTs with 2,292 participants were included. Compared with placebo, multiple Mazdutide doses significantly improved anthropometric and metabolic outcomes. Mazdutide 16 mg induced the largest reductions in waist circumference (mean difference [MD] −14.46 cm, 95% credible interval [CrI]: −20.83 to −8.14) and LDL cholesterol (−0.80 mmol/L, −1.27 to −0.33). Mazdutide 9 mg showed the greatest effect on body weight (−7.65 kg, −13.90 to −1.40) and BMI (−2.96, −5.35 to −0.59). For glycemic control, Mazdutide 4.5 mg and 6 mg reduced HbA1c by −0.85% (−1.43 to −0.31) and −0.82% (−1.29 to −0.38) in patients with type 2 diabetes. Subgroup analyses revealed that weight loss was significantly greater in non-diabetic individuals (e.g., Mazdutide 6 mg: −9.6 kg vs −4.5 kg in diabetic patients), whereas HbA1c reduction was more pronounced in those with type 2 diabetes (−1.6% vs −0.31%). Gastrointestinal adverse events were increased with Mazdutide (odds ratios 3.5 to 6.3 for effective doses), but serious adverse events were not significantly elevated. <bold>Conclusions</bold> : Mazdutide demonstrates dose-dependent, clinically meaningful improvements in weight, central adiposity, glycemic control, blood pressure, lipids, and liver enzymes in adults with obesity or overweight. Treatment effects are appropriately modified by diabetes status, with enhanced weight loss in non-diabetic individuals and greater glycemic benefits in patients with type 2 diabetes. These findings support Mazdutide as an effective therapeutic option for obesity management. </p>
Background
Mazdutide is a dual GLP-1R and GCGR agonist being investigated for its potential to address obesity and overweight, conditions with significant health burdens. Previous studies have shown its promise, but comprehensive evaluations of its dose-dependent efficacy and safety across various cardiometabolic outcomes are lacking. This study aims to fill that gap by providing a comparative analysis of different doses of Mazdutide.
Methods
The study employed a Bayesian network meta-analysis of randomized controlled trials. It included 2,292 adults with obesity or overweight, with or without type 2 diabetes, from nine RCTs. Efficacy outcomes measured included changes in body weight, waist circumference, BMI, HbA1c, fasting plasma glucose, blood pressure, lipid profiles, and ALT. Safety outcomes focused on adverse events, serious adverse events, gastrointestinal disorders, decreased appetite, and hypoglycemia.
Results
Mazdutide at various doses significantly improved anthropometric and metabolic outcomes compared to placebo. The 16 mg dose led to the largest reductions in waist circumference, while the 9 mg dose had the greatest impact on body weight and BMI. Glycemic control was notably improved with 4.5 mg and 6 mg doses in patients with type 2 diabetes. Gastrointestinal adverse events were more frequent with Mazdutide, but serious adverse events were not significantly increased.
Interpretation
The findings suggest that Mazdutide offers clinically meaningful improvements in weight and metabolic parameters, with effects varying by diabetes status. While the reductions in waist circumference and body weight are statistically significant, the clinical significance may vary based on individual patient profiles. The increased incidence of gastrointestinal adverse events is a noted limitation, although the lack of significant increase in serious adverse events is reassuring. The study's reliance on existing RCTs introduces potential variability in outcomes.
Key findings
- Mazdutide 16 mg reduced waist circumference by −14.46 cm (95% CrI: −20.83 to −8.14).
- Mazdutide 9 mg reduced body weight by −7.65 kg (95% CrI: −13.90 to −1.40).
- Mazdutide 4.5 mg reduced HbA1c by −0.85% (95% CrI: −1.43 to −0.31).
- Weight loss was greater in non-diabetic individuals (e.g., Mazdutide 6 mg: −9.6 kg vs −4.5 kg in diabetic patients).
- Odds ratios for gastrointestinal adverse events ranged from 3.5 to 6.3.
Limitations
- Preprint status, not peer-reviewed.
- Meta-analysis of existing RCTs, potential variability in study designs.
- Gastrointestinal adverse events were increased.
- Findings may not be generalizable beyond study populations.