Incretin-Based Dual and Triple Agonists in Overweight or Obese Individuals: A Systematic Review and Meta-Analysis.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of randomized controlled trials
PubMed 41711462 · doi:10.1097/CRD.0000000000001209
What was done
A systematic review and random-effects meta-analysis was performed using searches of PubMed, the Cochrane Library, and Google Scholar up to June 2025. The authors included randomized controlled trials evaluating dual or triple incretin agonists (tirzepatide, retatrutide, or mazdutide) versus placebo in overweight or obese adults. Clinical outcomes were pooled as mean differences (MDs) or risk ratios (RRs) across 10 randomized controlled trials comprising 3,236 participants.
What was found
Compared with placebo, incretin polyagonists significantly reduced body weight (MD -11.47; 95% CI: -14.00 to -8.95), waist circumference (MD -9.40; 95% CI: -11.91 to -6.89), glycated hemoglobin (MD -0.96; 95% CI: -1.16 to -0.75), and fasting plasma glucose (MD -26.89 mg/dL; 95% CI: -33.48 to -20.30). Incretin polyagonists were associated with an increased risk of any adverse event (RR 1.13; 95% CI: 1.08 to 1.19), adverse events leading to withdrawal (RR 1.96; 95% CI: 1.17 to 3.30), and hypoglycemic episodes (RR 3.08; 95% CI: 1.61 to 5.89). No significant difference was observed for serious adverse events (RR 0.87; 95% CI: 0.65 to 1.14).
Why it matters
This study provides pooled evidence that multi-receptor incretin agonists produce substantial weight loss and glycemic improvements in obesity, while quantifying the elevated risk of gastrointestinal adverse effects and study withdrawals.
Limits
The abstract pools three distinct pharmacologic agents together rather than detailing agent-specific or dose-specific outcomes. Measurement units for body weight and waist circumference were not stated in the abstract, and trial durations or long-term post-treatment outcomes were not described.
Cited by
- contradicts Retatrutide has fewer gastrointestinal side effects compared to earlier GLP-1 agonists.