Comparative Efficacy and Safety of Glucagon Receptor Agonists on Metabolic Outcomes: A Network Meta-Analysis of Randomised Controlled Trials

Department

Internal Medicine

Document Type

Article

Publication Title

Endocrinology, Diabetes & Metabolism

Abstract

Introduction: Glucagon receptor agonists (GRAs) are an emerging class of therapies for obesity and type 2 diabetes, demonstrating encouraging metabolic and weight-reducing effects. Several investigational GRA-based agents, including retatrutide, cotadutide, mazdutide, and survodutide, have reported promising results across early and mid-phase clinical trials. This comprehensive meta-analysis evaluates the efficacy and safety of these agents in individuals with type 2 diabetes, overweight, or obesity.

Methods: PubMed, Cochrane, Embase, and Scopus databases were systematically searched. Fourteen randomised controlled trials meeting the inclusion criteria were analysed using frequentist network meta-analysis. Random-effects models were applied to assess mean differences (MD) in weight change, both absolute and percent changes, HbA1c, adverse events, and discontinuation due to adverse events. Heterogeneity was quantified using the I2 statistic.

Results: Retatrutide demonstrated the greatest weight reduction versus placebo (MD -13.44 kg; 95% CI [-18.38, -8.51]), followed by survodutide (MD -10.74 kg; 95% CI [-15.68, -5.80]) and mazdutide (MD -6.47 kg; 95% CI [-10.71, -2.24]). Cotadutide showed the smallest and nonsignificant effect (MD -3.41 kg; 95% CI [-11.63, 4.81]). Regarding HbA1c reduction, retatrutide showed the largest effect, followed by survodutide, mazdutide, and cotadutide; however, only the effect of retatrutide reached statistical significance. In terms of safety, mazdutide demonstrated the most favourable tolerability profile, whereas retatrutide and cotadutide were associated with comparatively lower tolerability.

Conclusions: Retatrutide and survodutide exhibit the most favourable efficacy profiles for obesity and T2DM, with acceptable safety. These findings support their potential clinical use and highlight the need for future head-to-head trials.

First Page

e70187

DOI

10.1002/edm2.70187

Volume

9

Issue

2

Publication Date

3-1-2026

Medical Subject Headings

Humans; Diabetes Mellitus, Type 2; Randomized Controlled Trials as Topic; Receptors, Glucagon; Obesity; Network Meta-Analysis as Topic; Hypoglycemic Agents; Treatment Outcome; Weight Loss; Overweight

PubMed ID

41787737

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