Real-world comparative outcomes of GLP-1 RA and semaglutide prescription among individuals with type 2 diabetes.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly prescribed for type 2 diabetes (T2D) and weight management, yet their broad health impacts in real-world settings remain understudied. Using data from the All of Us Research Program (n=18,746), we conducted both intention-to-treat and per-protocol phenome-wide association studies comparing diagnoses following GLP-1 RA prescription, including semaglutide-specific analyses, to those following sodium-glucose cotransporter-2 inhibitor (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP4i) prescriptions in individuals with T2D. GLP-1 RAs were associated with reduced risks of genitourinary and dental conditions relative to comparators, while semaglutide was linked to lower risks of cardiac arrhythmia, hyperglycemia, and chronic kidney disease. However, GLP-1 RAs were also associated with increased risks of dysthymic disorder and vitamin D deficiency. Time-to-event analyses revealed modest delays in diagnosis for key outcomes. These findings underscore differences in downstream associations across second-line T2D therapies and highlight semaglutide's distinct profile. Results may inform clinical decision-making and motivate further research on effectiveness, safety, and personalized prescribing.