Efficacy and Safety of Mazdutide in Adults with Obesity or Overweight, With or Without Diabetes: A Bayesian Network Meta-Analysis
This Bayesian network meta-analysis systematically evaluated the dose-dependent efficacy and safety of mazdutide — a dual GLP-1 receptor and glucagon receptor agonist — in adults with obesity or overweight, with or without type 2 diabetes. Researchers searched five major databases through January 2026 and included nine randomized controlled trials comprising 2,292 participants. The study found that, compared with placebo, multiple mazdutide doses were associated with statistically significant improvements across a broad range of cardiometabolic outcomes, including body weight, waist circumference, BMI, HbA1c, fasting plasma glucose, blood pressure, LDL cholesterol, and liver enzymes (ALT). Subgroup analyses suggested that weight loss effects were more pronounced in non-diabetic individuals, while glycemic benefits were greater in those with type 2 diabetes. Gastrointestinal adverse events were notably more frequent with mazdutide relative to placebo, though serious adverse events were not significantly elevated. Key limitations include the relatively small number of included trials (n=9) and total participants, the indirect comparisons inherent to network meta-analysis methodology, potential heterogeneity across trial populations, and the preprint status of this work, meaning it has not yet undergone formal peer review.
Why this grade: While the analysis pools data from multiple RCTs in humans, the evidence is downgraded to moderate due to the small number of included trials (9 RCTs, ~2,292 participants), reliance on indirect Bayesian network comparisons, and unconfirmed preprint status pending peer review.
Abstract Background : 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. Methods : 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. Results : 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. Conclusions : 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.
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