Efficacy and Safety of Dual GLP-1/Glucagon Receptor Agonism in Overweight and Obesity: A Class-Specific Systematic Review and Meta-Analysis.
Dual GLP-1/glucagon receptor agonists may lead to significant weight loss and metabolic improvements, but further long-term studies are necessary to confirm these effects.
Where it sits
this study against the rest of the mazdutide (ibi362) corpusSummary and findings
This study evaluated the efficacy and safety of dual GLP-1/glucagon receptor agonists, including mazdutide, in adults with overweight or obesity. The analysis included 19 randomized controlled trials. The results indicated significant reductions in body weight and improvements in metabolic parameters.
Abstract
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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).<h4>Conclusion</h4>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.
Background
This paper addresses the efficacy and safety of dual GLP-1/glucagon receptor agonists in treating obesity, a condition with rising prevalence and associated health risks. Prior studies have often grouped these agents with GIP-containing drugs or focused on a limited number of agents, resulting in incomplete characterization of their effects. This systematic review and meta-analysis aims to clarify the specific impacts of dual agonists on weight and metabolic health.
Methods
The study conducted a systematic search of multiple databases for randomized controlled trials involving mazdutide, survodutide, cotadutide, and efinopegdutide in adults with overweight or obesity. Nineteen trials were included in the analysis, which utilized random-effects meta-analysis to calculate mean differences and risk ratios, along with various statistical analyses to assess heterogeneity and bias.
Results
The primary endpoint showed a significant absolute body weight reduction of -6.65 kg (MD), with moderate certainty. Additionally, relative weight decreased by -7.15% (MD). The likelihood of achieving ≥ 5% weight loss was significantly higher (RR: 4.75), though this finding is of low certainty. Improvements were also noted in HbA1c, BMI, waist circumference, systolic blood pressure, and triglycerides. Adverse events occurred more frequently with dual agonists (RR: 1.16), while serious adverse events were not significantly different from controls (RR: 0.90, high certainty).
Interpretation
The findings indicate that dual GLP-1/glucagon receptor agonists can lead to significant weight loss and metabolic improvements, aligning with previous literature on GLP-1 receptor agonists. However, the clinical significance of the weight loss and the low certainty of some outcomes warrant caution. The presence of increased adverse events highlights the need for careful patient selection and monitoring. Limitations such as short follow-up periods and the need for longer-term studies to assess durability and cardiovascular safety are critical.
Key findings
- -6.65 kg absolute body weight reduction, MD, moderate certainty.
- -7.15% relative weight reduction, MD.
- RR of ≥ 5% weight loss was 4.75, low certainty.
- Any adverse events were more frequent with dual agonists (RR: 1.16).
- Serious adverse events did not differ from controls (RR: 0.90, high certainty).
Limitations
- Low certainty for some findings.
- Short follow-up period.
- Lacks long-term data on durability and cardiovascular safety.
- Potential confounding from combining multiple agents.
- Industry funding not reported in abstract.