A big analysis of 19 trials shows that retatrutide, a triple‑hormone peptide (GLP‑1, GIP, glucagon), can cut about 11 kg of weight on average, which is a bit more than the best GLP‑1 drugs (around 9 kg). It also makes it far more likely to lose 15% or more of body weight, but it comes with a higher chance of side effects.

To compare the efficacy and safety of GLP-1 receptor agonists (GLP-1RAs), dual agonists (GLP-1RAs/GIP or GCGR), and retatrutide (GLP-1/GIP/glucagon) for weight loss in adults with overweight or obesity. We conducted a systematic review and Bayesian network meta-analysis (NMA) of 19 randomized controlled trials (RCTs) including 29,506 adults (BMI ≥ 25 kg/m²), assessing liraglutide, semaglutide, survodutide, tirzepatide, retatrutide, and placebo. Outcomes included mean weight loss, achievement of ≥ 5%, ≥ 10%, and ≥ 15% weight loss, waist circumference (WC), BMI, and adverse events (AEs) at ≥ 36 weeks. Subgroup and meta-regression analyses evaluated the impact of diabetes status, sex, age, and BMI. Retatrutide and dual agonists achieved equivalent mean weight loss (-11.0 kg), surpassing GLP-1RAs (-9.0 kg), with retatrutide excelling at achieving ≥ 15% weight loss (OR 54.6). Dual agonists and GLP-1RAs followed (OR 16.4 and 9.0, respectively). Retatrutide had the highest AE risk. Meta-regression showed type 2 diabetes mellitus (T2DM) reduced weight loss by 4.338 kg for GLP-1RAs and 5.016 kg for dual agonists, with enhanced outcomes in female-dominant or high-BMI cohorts. Retatrutide offers superior weight loss efficacy but with a higher AE risk. Dual agonists provide a favorable efficacy-safety balance. Personalized treatment selection based on patient characteristics is recommended.