Real-world benefit from incretin-based therapies depends on actual treatment initiation and sustained exposure, yet structured prescription records may capture prescribing intent rather than confirmed use. Using a large federated, de-identified US EHR platform spanning over 29 million patients, we analyzed patterns of glucagon-like peptide-1 receptor agonists (GLP-1RA) initiation, persistence, and compounding from clinical notes using an evidence-linked large language model (LLM) pipeline evaluated against an independent physician-adjudicated extracted-event reference standard, achieving 98.4% accuracy for structural chunk triage and 88.2% accuracy for medication-status adjudication. Among 553 073 adults with at least one semaglutide (n = 376 697) or tirzepatide (n = 176 376) prescription and baseline weight availability, documented initiation within ±3 months of the first structured prescription was identified in 141 189 semaglutide patients and 62 040 tirzepatide patients. Among these patients with documented initiation, frictionless starts accounted for 70.1% of semaglutide and 77.9% of tirzepatide starts, initiation after documented friction accounted for 17.2% and 15.9%, and early interruption after initiation within 3 months accounted for 12.7% and 6.2%, respectively. We analyzed treatment persistence over an 18-month period in a subset of 69 976 patients with "frictionless initiation." Clinical note-based and structured prescription-derived persistence yielded materially different trajectories within each drug (log-rank P < .001). A note-derived ascertainment approach showed that 42.3% and 43.1% of semaglutide and tirzepatide patients, respectively, continued therapy, while structured prescription-based ascertainment yielded higher persistence estimates of 55.4% for semaglutide and 58.3% for tirzepatide. Among the patients with a documented 3-18-month barrier or discontinuation event, insurance, cost barriers, perioperative holds and gastrointestinal adverse events were the top documented reasons. Compounded exposure was detected in 1696 frictionless initiators, with the first compounding signal occurring on or before the first structured prescription in 50.8% of semaglutide and 57.9% of tirzepatide patients. These findings show that AI curation of clinical notes can distinguish prescription intent from verified exposure. With the potential time-to-market confounding, semaglutide shows higher initiation and lower non-initiation than tirzepatide, with comparable note-confirmed persistence at 18 months. More broadly, these findings support integrative exposure ascertainment to strengthen real-world GLP-1 evidence generation, payer decision-making, safety surveillance, and strategies to improve sustained access and treatment continuity.
