Oral Wegovy Broadens Care Continuum Across First-Time GLP-Starters, High Cardiometabolic Burden GLP-Switchers, and Medicare-Age Patients

Oral Wegovy (semaglutide weight-loss pill) initiation now spans two clinically distinct real-world entry states: “GLP-starters” without recent GLP-1 receptor agonist (GLP-1RA) prescriptions and “GLP-switchers” with a recent record for a different injectable or oral incretin therapy. Using a large federated U.S. electronic health record network, we studied the five-year history prior to Wegovy pill initiation. Of 891,711 patients with at least one GLP-1RA prescription, 11,215 initiated the Wegovy pill, of whom 6,283 (56.0%) were GLP-starters and 4,932 (44.0%) were GLP-switchers. GLP-starters and -switchers were similar in age (mean 52.4 vs 52.1 years; P=0.21) and sex (75.4% vs 74.4% female; P=0.22). In contrast, GLP-switchers had significantly greater pre-index cardiometabolic and neuropsychiatric burden than GLP-starters (all q<0.001, Benjamini-Hochberg FDR), including type 2 diabetes (Relative Risk [RR] 1.95), obstructive sleep apnea (RR 1.78), heart failure (RR 1.73), atrial fibrillation (RR 1.55), coronary artery disease (RR 1.38), depression (RR 1.32), and migraine (RR 1.25). Of 3,216 disease phenotypes screened, large language model (LLM)-curated clinical notes showed 819 phenotypes significantly higher at baseline in GLP-switchers and none in GLP-starters (all q<0.001), including morbid obesity (RR 1.61), excessive daytime sleepiness (RR 1.56), and fatty liver disease (RR 1.47), with concordantly higher Elixhauser comorbidity index ≥5 (RR 1.47). Among GLP-switchers to Wegovy pill, the most common prior agents in the year before index were injectable Wegovy (40.7%) and Zepbound (36.6%). Among 123 initiators of the recently launched orforglipron pill (Foundayo), only 39.8% had no GLP-1RA exposure in the preceding year, followed by switchers from Zepbound (tirzepatide) injections (31.7%). LLM curation of clinical notes shows the most common reasons for switching to the Wegovy pill include more affordable cost or better insurance coverage (42.7%), oral route or dosing preference (13.1%), and inadequate weight-loss efficacy with prior therapies (10.4%). Studying polypharmacy of Wegovy pill initiators shows significantly larger GLP-switchers (96.9%) than GLP-starters (88.3%) taking other oral medications concomitantly (p<0.001), with GLP-switchers more often taking metformin (RR 1.38), atorvastatin (RR 1.21), losartan (RR 1.28), and insulin glargine (RR 2.60) (all q≤0.001). Consequently, overall polypharmacy was markedly greater in GLP-switchers (mean 13.4 vs 9.7 distinct medications; ≥5 medications 81.6% vs 60.8%; ≥10 medications 48.9% vs 33.1%) (all q<0.001). Medicare-eligible initiators of Wegovy pill (age ≥65 at index, n=2,535) had a substantially greater burden of cardiovascular and renal disease, multimorbidity, and overall polypharmacy than the overall cohort, but less severe obesity (BMI ≥40 in 14.0% vs 23.3%; p<0.001). This study marks the first longitudinal analysis of the incretin care pathway leading up to Wegovy pill initiation and highlights better access and tolerability as leading drivers of patients preferring to switch to Wegovy pill.