Comparative efficacy and safety of glucagon-like peptide 1 based drugs for weight loss in adults with overweight or obesity without diabetes: network meta-analysis of randomised controlled trials.

OBJECTIVE: To compare the efficacy and safety of glucagon-like peptide 1 (GLP-1) based drug treatments for weight loss in adults with overweight or obesity without diabetes.

DESIGN: Network meta-analysis of randomised controlled trials.

DATA SOURCES: Embase, PubMed (Medline), and Web of Science, 1 January 2000 to 6 March 2026.

ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials that enrolled adults with overweight or obesity, comparing GLP-1 receptor agonists or related co-agonists with placebo or active comparators, with a minimum intervention duration of 12 weeks. Excluded were trials that enrolled participants with diabetes, or where diabetes status could not be clearly determined.

RESULTS: 58 trials of 24 214 participants were analysed. Compared with placebo, weight loss was greatest with retatrutide (-22.10%, 95% confidence interval -25.60% to -18.60%), followed by tirzepatide (-19.28%, -20.39% to -18.16%), and CagriSema (a combination of cagrilintide and semaglutide, -17.32%, -19.32% to -15.32%). Conventional GLP-1 receptor agonists showed more modest effects. Similar patterns were seen for waist circumference and lipid outcomes. Treatment rankings suggested a probabilistic hierarchy favouring next generation incretin based treatments, although confidence intervals overlapped for several comparisons. Low certainty evidence suggested higher rates for discontinuing treatment with danuglipron and retatrutide, whereas mazdutide showed better tolerability.

CONCLUSIONS: In adults with overweight or obesity without diabetes, next generation incretin based treatments achieved greater weight loss than conventional GLP-1 receptor agonists. Differences in tolerability, limited head-to-head evidence, and residual uncertainty, however, should be considered when interpreting comparative treatment effects.

STUDY REGISTRATION: PROSPERO CRD420261279841.