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

## TL;DR

A study compares new obesity and diabetes drugs called glucagon receptor agonists, finding retatrutide and survodutide most effective for weight loss and blood sugar control.

## Contribution

This is the first network meta-analysis comparing multiple glucagon receptor agonists for their efficacy and safety in treating obesity and type 2 diabetes.

## Key findings

- Retatrutide showed the greatest weight reduction compared to placebo in individuals with obesity or type 2 diabetes.
- Mazdutide had the best safety profile among the studied glucagon receptor agonists.
- Future head-to-head trials are needed to confirm the relative effectiveness of these drugs.

## Abstract

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.

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.

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.

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.

This network meta‐analysis compares emerging glucagon receptor agonists for obesity and type 2 diabetes. Retatrutide and survodutide demonstrated the most favourable efficacy profiles for weight reduction with acceptable safety, supporting their potential as promising therapeutic options and highlighting the need for future head‐to‐head clinical trials.