Multisystem Outcomes of GLP-1 Receptor Agonists Versus Active Comparators in Type 2 Diabetes: A Multicenter Target Trial Emulation

Background: Multisystem effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) beyond cardiometabolic outcomes are incompletely characterized against active comparators in type 2 diabetes (T2D). We compared GLP-1RA with sulfonylureas (SUs), sodium-glucose cotransporter-2 inhibitors (SGLT2is), and dipeptidyl peptidase-4 inhibitors (DPP4is) in adults with T2D. Method: In a multicenter target trial emulation across 5 University of California academic medical centers (2012-2025) using harmonized electronic health record data, adults with T2D newly initiating GLP-1RA, SU, SGLT2i, or DPP4i were propensity score-matched 1-to-1 within site via least absolute shrinkage and selection operator (>11 000 covariates), with up to 5-year follow-up. We screened 181 prespecified incident outcomes across 15 body systems, pooling hazard ratios by random-effects meta-analysis. Robustness required leave-one-medical-center-out stability, E -value ≥1.5, and false discovery rate–adjusted P < .10. Results: Among 70 982 matched adults, 118 robust associations were identified (65 for reduced risk and 53 for increased risk). Risk reductions were most consistent for cardiovascular outcomes, including myocarditis/cardiomyopathy (summary hazard ratio, 0.38 [95% CI, 0.32-0.44] vs SGLT2i), acute myocardial infarction (0.53 [0.42-0.66]), heart failure (0.71 [0.58-0.88] vs DPP4i), and thromboembolism (0.69-0.72), and for nephritis/nephrosis (0.73 [0.67-0.79]), nutritional anemia (0.70-0.81), coagulation disorders (0.73-0.81), and tobacco-related disorders (0.60 [0.49-0.74]). Risk increases were found for musculoskeletal conditions (22 associations); osteoarthritis 1.48 (1.29-1.68), stress fractures 1.68 (1.15-2.47), diverticular disease (1.18-1.33), sleep-wake disorders (1.27-1.54), and menopausal disorders (1.32-1.52). Conclusions: Glucagon-like peptide-1 receptor agonist initiation was associated with reduced cardiovascular, renal, hematologic, and tobacco-related risk, consistent with outcome trials. Increased risks for musculoskeletal, gastrointestinal, and sleep-wake disorders warrant monitoring as the clinical use of GLP-1RAs continues to expand.