Efficacy and Safety of Dual GLP-1/Glucagon Receptor Agonism in Overweight and Obesity: A Class-Specific Systematic Review and Meta-Analysis.

BACKGROUND

Dual glucagon-like peptide-1/glucagon receptor (GLP-1/GCGR) agonists represent a novel obesity treatment class, but existing meta-analyses often conflate them with GIP-containing agents (tirzepatide, retatrutide) or restrict analysis to one or two drugs, leaving class-specific efficacy and safety incompletely characterized.

METHODS

We systematically searched PubMed, Embase, Cochrane Library, Scopus and ClinicalTrials.gov through 20 July 2026 for randomized controlled trials of mazdutide, survodutide, cotadutide, and efinopegdutide in adults with overweight/obesity (PROSPERO CRD420261456447). Random-effects meta-analysis pooled mean differences (MDs) and risk ratios (RRs) with 95% CIs; heterogeneity, subgroup, sensitivity, GRADE and publication bias analyses were performed.

RESULTS

Nineteen RCTs were included. Dual agonists significantly reduced absolute body weight (MD: -6.65 kg, moderate certainty), relative weight (MD: -7.15%), and increased likelihood of ≥ 5% weight loss (RR: 4.75, low certainty), with mazdutide and survodutide showing the largest effects. Significant improvements occurred in HbA1c, BMI, waist circumference, systolic blood pressure and triglycerides. Any adverse events were more frequent with dual agonists (RR: 1.16), while serious adverse events did not differ from controls (RR: 0.90, high certainty).

CONCLUSION

Dual GLP-1/GCGR agonists produce meaningful weight loss and metabolic improvements with acceptable short-term safety, though longer head-to-head trials are needed to confirm durability and cardiovascular safety.