Cardiovascular and kidney outcomes of GLP‐1 receptor agonists in adults with obesity: A target trial emulation study

Aims Glucagon‐like peptide‐1 receptor agonists ( GLP ‐ 1RAs ) provide cardiovascular and renal benefits in type 2 diabetes, but their real‐world effects in individuals with obesity without diabetes are unclear. This study aimed to evaluate the cardiovascular and kidney outcomes of GLP ‐ 1RAs versus other anti‐obesity medications ( AOMs ) in adults with obesity. Materials and Methods This target trial emulation used TriNetX electronic health records (July 2021–May 2025) to identify adults with obesity and no diabetes history who initiated GLP ‐ 1RAs (liraglutide, semaglutide, or tirzepatide) or other AOMs . Outcomes included major adverse cardiovascular events ( MACE ), major adverse kidney events ( MAKE ), all‐cause mortality, mental health conditions, and safety outcomes. Propensity score matching (1:1) balanced baseline characteristics; Cox models estimated hazard ratios ( HRs ) with 95% confidence intervals ( CIs ). Results The study included 140 169 matched pairs of GLP ‐ 1RA and AOM initiators. Mean follow‐up was 392 days for GLP ‐ 1RA users and 564 days for AOM users. Compared to AOMs , GLP ‐ 1RA use was associated with lower risks of MACE ( HR , 0.76; 95% CI , 0.72–0.81), MAKE ( HR , 0.64; 95% CI , 0.55–0.74), and all‐cause mortality ( HR , 0.49; 95% CI , 0.42–0.57). Mental health outcomes also improved, with reduced risks of depression ( HR , 0.63), suicidal ideation/attempt ( HR , 0.42), and substance use disorder ( HR , 0.58). GLP ‐ 1RAs were not associated with increased risks of acute pancreatitis ( HR , 1.17), hypoglycemia ( HR , 1.08), or gastrointestinal symptoms ( HR , 0.99). Conclusions Among adults with obesity but without diabetes, GLP ‐ 1RA use was associated with reduced cardiovascular, kidney, mortality, and mental health risks compared to other AOMs .