Oral GLP-1 Super-Responders are Characterized by Greater Pretreatment Weight Gain, Faster Early Dose Escalation, and Larger On-Treatment Blood Pressure Reductions

Early weight-loss responses to oral glucagon-like peptide-1 (GLP-1) receptor agonists vary substantially, yet the longitudinal clinical characteristics associated with super-response remain incompletely understood. Here using de-identified electronic health records, we studied 9,287 GLP-1 receptor agonist (GLP-1 RA) treatment-naive patients with a prescription for oral Wegovy. Of 8,381 patients with an index weight, 3,011 had a follow-up weight recorded between 30 and 180 days (early clinical observation period) and were classified by their best percent weight change as non-responders (no loss), responders (>0–5% loss), strong responders (>5–10%), or super-responders (>10%). Body weight was traced back five years, and HbA1c, blood pressure, comorbidities, dose escalation, and phenotypes extracted from clinical notes using AI-augmented curation were compared across these treatment response groups. At treatment initiation, super-responders weighed less than non-responders (94.1 versus 101.7 kg; P<0.001). Five years before treatment, super-responders weighed 7.6% less than at the index date, compared with 0.8% less among non-responders (P<0.001 across groups). Super-responders subsequently lost 7.2% by day 60 and 11.4% by day 90, returning on average to their weight from five years earlier within two months. Age, sex, type 2 diabetes, HbA1c, and blood pressure did not differ across groups at treatment initiation, and neither HbA1c nor blood pressure differed one, two, or five years earlier. Super-responders more often reached significantly higher doses early in treatment than non-responders: approximately 37% versus 24% were prescribed >1.5 mg at day 30 (P=0.001), 16% versus 9% were prescribed >4 mg at day 60 (P=0.056), and 6% versus 2% were prescribed >9 mg at day 90 (P=0.022; Fisher's exact test). Systolic blood pressure at day 90 fell by 10.2 mmHg in super-responders versus 3.3 mmHg in non-responders (P=0.006 across groups; P=0.003 for trend). Among 1,978 phenotypes AI-curated from unstructured clinical notes, before the first prescription, severe obesity was documented in 19.4% of super-responders versus 36.1% of non-responders (P<0.001; q=0.003). Super-responders had more pretreatment documentation of disordered eating (7.9% versus 3.1%) and less sleep-disordered breathing (35.2% versus 48.1%) and impaired fasting glucose (3.0% versus 7.5%) than non-responders, although differences were not significant after multiple-testing adjustment (all q≥0.26). Among GLP-1 RA-naive patients initiating oral Wegovy, greater early weight-loss response was associated with a more strongly rising weight trajectory over the preceding five years rather than with baseline glycemic or hemodynamic characteristics. In this observational study, pre-treatment weight trajectory and dosage emerged as associates of early oral semaglutide response, but the outcome-defined groups and short follow-up make these findings hypothesis-generating and warrant prospective validation.