Efficacy and Safety of High-Dose Retatrutide in Adults with Obesity and Type 2 Diabetes: A Systematic Review and Bayesian Meta-Analysis

Abstract

Abstract Purpose To evaluate the efficacy and safety of high-dose retatrutide in adults with overweight or obesity through a systematic review and Bayesian meta-analysis of randomized controlled trials. Methods A systematic search of PubMed, Embase, Cochrane CENTRAL, LILACS, ClinicalTrials.gov, and WHO ICTRP was conducted from inception to April 2026. Randomized controlled trials evaluating retatrutide in adults with overweight or obesity, with or without type 2 diabetes (T2DM), were included. The primary outcomes were change in body weight and glycated hemoglobin (HbA1c) in individuals with T2DM. Safety outcomes included total adverse events, serious adverse events, and treatment discontinuation due to adverse events. Bayesian random-effects meta-analyses with weakly informative priors were performed, with results expressed as mean differences or risk ratios with 95% credible intervals (CrI). Heterogeneity was assessed using the between-study standard deviation (τ) and the frequentist I² statistic. Results Five randomized clinical trials comprising 814 participants were included. Retatrutide was associated with clinically relevant reductions in body weight compared with placebo in adults with overweight or obesity. Separate analyses suggested clinically relevant weight loss and reductions in HbA1c in individuals with T2DM. The intervention increased the risk of treatment discontinuation due to adverse events, whereas serious adverse events were infrequent. Substantial between-study heterogeneity was observed for efficacy outcomes, with considerable uncertainty reflecting the limited number of trials. Conclusions Available evidence suggests that high-dose retatrutide may be associated with clinically relevant reductions in body weight and HbA1c, but the certainty of evidence is limited by sparse data, heterogeneity, and reliance on preliminary phase 3 results. Adverse events were predominantly gastrointestinal and generally mild to moderate; however, higher rates of treatment discontinuation indicate potential tolerability limitations. These findings should be interpreted with caution pending full publication of phase 3 trial results. Registration PROSPERO CRD420251275485.