Comparative Efficacy and Safety of Glucagon Receptor Agonists on Metabolic Outcomes: A Network Meta-Analysis of Randomised Controlled Trials.
This network meta-analysis systematically evaluated the comparative efficacy and safety of four investigational glucagon receptor agonist (GRA)-based agents — retatrutide, cotadutide, mazdutide, and survodutide — in adults with type 2 diabetes, overweight, or obesity. Researchers searched PubMed, Cochrane, Embase, and Scopus, ultimately including 14 randomised controlled trials analyzed using frequentist network meta-analysis with random-effects models. Key outcomes included absolute and percent body weight change, HbA1c reduction, adverse events, and treatment discontinuation due to adverse events. The study found that retatrutide produced the greatest absolute weight reduction versus placebo (MD −13.44 kg), followed by survodutide (MD −10.74 kg) and mazdutide (MD −6.47 kg); cotadutide's effect did not reach statistical significance. Retatrutide also showed the largest HbA1c reduction, though only its effect was statistically significant among the agents. Regarding tolerability, mazdutide demonstrated the most favorable safety profile, while retatrutide and cotadutide were associated with comparatively lower tolerability. The authors acknowledge limitations inherent to network meta-analysis, including reliance on early- and mid-phase trial data and the absence of direct head-to-head comparisons between agents.
Why this grade: While the analysis synthesizes data from 14 RCTs in humans, the included trials are predominantly early- to mid-phase, limiting the generalizability and robustness of conclusions compared to a synthesis of large Phase III head-to-head trials.
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 I 2 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.
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