Exposure-adjusted safety and efficacy of GLP-I and GLP-1/GIP receptor agonists compared with non-GLP-I for weight management and type 2 diabetes: Based on FDA medical and statistical reports of 34 280 safety and 36 312 efficacy subjects.

AIMS: This work aimed to contextualize glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists safety and efficacy regarding weight management (WM); we analysed Food and Drug Administration (FDA) Medical Reviews to analyse 14 medications using patient-exposure year normalization and compared GLP-1 RAs with older WM medications. METHODS: We searched the FDA database for medical reports on non-GLP medications for WM and both WM and type 2 diabetes (T2D)-related GLP-1 RA and GLP/GIP dual receptor agonist medications up to September 2025. From these reports, we collected data on trial participants' patient exposure years, body weight, morbidity and mortality. RESULTS: Weight loss was greatest with GLP-1/GIP dual agonists. The rate ratios (RRs) for mortality and morbidity were as follows: non-GLP agents (RR: 0.8 and 1.1), WM GLP-1 RAs (RR: 0.7 and 1.4), T2D GLP-1 RAs (RR: 0.7 and 0.9) and GLP-1/GIP RAs (RR: 0.1 and 1.1). PEY-adjusted RRs confirmed lower mortality risk across most GLP-1 trials and variable patterns in serious adverse events; 71% of pivotal trials have been indexed in PubMed. Postmarketing reports of neoplasms were 0.9% for non-GLP agents, 5.4% for WM GLP-1 RAs, 4.1% for T2D GLP-1 RAs and 0.7% for GLP-1/GIP RAs. CONCLUSIONS: Using FDA regulatory data, we compared GLP-1 RAs, GLP-1/GIP dual agonists and non-GLP-1 weight loss agents, finding the greatest weight reductions with tirzepatide and liraglutide. While efficacy outcomes were favourable, safety signals were limited by small sample sizes. Expanded real-world evidence is needed to better characterize long-term safety.