Analysis of 15 randomized controlled trials encompassing 14,059 adults without diabetes reveals a clear hierarchy among FDA-approved weight-loss medications. Tirzepatide at maximum tolerated doses achieved the greatest weight reduction, followed by tirzepatide 15mg, tirzepatide 10mg, semaglutide 2.4mg, tirzepatide 5mg, and liraglutide 3mg. Notably, tirzepatide and semaglutide carried higher adverse event risks compared to placebo, while liraglutide did not.
This head-to-head comparison fills a critical evidence gap for clinicians and patients navigating the expanding obesity pharmacotherapy landscape. The dose-dependent efficacy pattern for tirzepatide, which targets both GLP-1 and GIP receptors, reinforces the dual-agonist mechanism's superiority over single-target approaches. However, the analysis reveals an important trade-off: greater weight loss comes with increased side effects. The lack of long-term data on weight maintenance, metabolic benefits, and real-world discontinuation rates remains a significant limitation. While confirmatory rather than paradigm-shifting, this network meta-analysis provides the most comprehensive ranking of these medications to date, informing evidence-based treatment selection in an era where obesity medications are becoming increasingly mainstream.