Body Protection Compound-157 (BPC-157) is an unapproved synthetic peptide marketed directly to consumers despite limited human evidence on benefits and risks. We characterized the use of BPC-157 and patient-reported outcomes from 2020 through 2026 using Large Language Model (LLM) curation of de-identified clinical notes from a U.S. federated network with physician validation of each LLM-curation exercise. Of 1,536 patients with a note mentioning BPC-157, 1,039 (67.6%) had documented use, and quarterly newly confirmed users increased 33-fold between 2020 and 2026. Among 972 BPC-157 users with recorded race, 95.9% were White, compared with 78% of the background care population, representing a 1.23-fold enrichment (chi-square test across racial categories, P < 0.001). Among patients with newly documented BPC-157 use, the male proportion increased from 57% in 2020 to 70% in 2026 (Cochran–Armitage trend test across years, P < 0.001), while mean age decreased from 55 years in 2020 to 49 years in 2026. Among 205 patients with a documented consumer source (19.7% of confirmed users), BPC-157 was most commonly obtained from compounding pharmacies (36%) or gray-market peptide vendors (35%). Other therapeutic agents were co-used with BPC-157 by 525 of 1,039 users (50.5%), most commonly testosterone (17.0%), NSAIDs (14.7%), TB-500 (12.9%), and corticosteroids (11.7%), while physical therapy (15.3%), surgery (12.6%), exercise counseling (8.3%), and diet counseling (6.3%) were the documented non-drug co-interventions. Physician-adjudicated extraction accuracy was 96.0% for BPC-157 co-therapies and 74.4% for non-drug interventions, which were treated as exploratory. Reasons for use were documented for 644 patients and included pain (33% of all 1,039 users), gastrointestinal conditions including reflux, inflammatory bowel disease or gastritis (14%), prior injury (11%), and post-surgical healing (10%), physician adjudicated LLM accuracy of 83.9%. Among 80 users with ascertainable start timing, BPC-157 use preceded first clinician documentation by a mean of 60 days. Reported use averaged 2.2 months among 130 patients (12.5%) with an explicitly documented BPC-157 use duration, with 96.7% extraction accuracy. The specialties most often first documenting use were family medicine, internal medicine, gastroenterology, and orthopaedic surgery. Symptomatic improvement of pain, wound or tissue healing and functional return was documented in 79% of 354 BPC-157 users with a directional response, and symptomatic worsening in 5% of the users (LLM-extraction accuracy 78.4%). Response direction was unavailable for 685 of 1,039 users (65.9%). These reports cannot establish efficacy or distinguish BPC-157 effects from peptide stacking, other co-treatments, non-drug interventions, placebo effects or selection, reporting and confirmation biases. LLM-curated adverse events during BPC-157 use were infrequently noted and likely subject to under-reporting, with documented evidence of neuropsychiatric (1.4%), injection-site hypersensitivity (1.4%), and gastrointestinal (1.3%) events, with physician-adjudicated accuracy of 93.9% for drug-attributed adverse-events. With BPC-157 use rising rapidly despite minimal prospective studies and limited evidence-backed consumer awareness of its risk–benefit profile, this study highlights the need for facilitating structured EHR capture of broader gray-market peptide use and a continuous assessment of guidelines to better support healthcare practitioners.

Zepbound (tirzepatide) is among the most effective obesity medicines for weight reduction, in both clinical trial and real-world settings. Product marketing largely centers on weight-loss magnitude, which may reinforce the expectation that larger reductions are always better. Using de-identified EHRs, we compared 1,039 Zepbound initiators (1.7%) whose first-year weight loss reached ≥30% (“excessive weight loss”) with 20,668 Zepbound initiators (34.7%) who lost 5%-15% (“moderate weight loss”). After 1:4 propensity score matching (837 versus 3,348 patients), large language model (LLM)-curation extracted 24 adverse events that physician notes explicitly attributed to weight loss. The rate of any weight loss-attributable adverse event was significantly higher with excessive weight loss, at 39.4 versus 14.4 per 100 patient-years, representing 294 (35.1%) versus 479 (14.3%) patients (rate ratio [RR]: 2.78, 95% confidence interval [CI] 2.40-3.21; P<0.001). Falls, weakness, syncope, alopecia, low blood pressure, gastro-intestinal symptoms, and muscle loss were significantly enriched in the excessive weight loss cohort after false-discovery-rate correction (all q<0.001). Hospitalization was documented in 215 patients (25.7%) with excessive weight loss versus 527 patients (15.7%) with moderate weight loss (RR: 1.63, 1.42-1.87), Intensive care admission in 44 patients (5.3%) versus 77 patients (2.3%) (RR: 2.29, 1.59-3.28) (both q<0.001), and newly recorded heart-failure diagnosis in 11 patients (1.3%) versus 16 patients (0.5%) (RR: 2.75, 1.28-5.91; q=0.028). Laboratory tests and vital measurements recorded within 30 days of the lowest achieved body weight corroborated these findings, including significant enrichments in systolic (<90 mmHg) or diastolic (<60 mmHg) hypotension (RR: 3.19, 95% CI 2.51-4.05), anemia (RR: 1.86, 1.45-2.40), hyponatremia (RR: 2.74, 1.63-4.60), hypokalemia (RR: 2.34, 1.58-3.46), hypocalcemia (RR: 3.25, 1.87-5.68), hypoalbuminemia (RR: 2.93, 1.83-4.70), and hypoproteinemia (RR: 3.89, 2.32-6.52) in excessive weight loss patients (all q<0.001). While residual confounding and documentation differences may contribute to some real-world associations, the significantly greater burden of adverse events, hospitalization rates, laboratory test anomalies, and vital-sign abnormalities among Zepbound patients with excessive weight loss warrants further investigation. These findings support moving towards individualized weight-loss goals, motivate the need for prospective studies into the risk-benefit profile of Zepbound, and call for closer scrutiny of pharmaceutical marketing to clarify that the greatest weight reduction may not translate into better health outcomes.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for type 2 diabetes and obesity, but emerging evidence from randomized trials and real-world anecdotes suggest that neurosensory adverse events merit systematic investigation. We analyzed 670,422 initiators of semaglutide or tirzepatide across a large-scale federated EHR network and ascertained 14 new-onset neurosensory phenotypes over 12 months using AI-assisted clinical-note curation harmonized with ICD-10-CM codes. Among 128,377 at-risk GLP-1RA initiators — new users with at least two prescriptions within 12 months and complete 12-month follow-up, free of any studied phenotype at baseline — 29,519 (23.0%) had at least one newly documented phenotype, most commonly hypoesthesia/numbness in 16,143 patients (12.6%) and paresthesia in 15,415 patients (12.0%). Outcome ascertainment was validated by physician-led curation, with the review of 223 AI-identified events yielding a positive predictive value of 88.8% (95% CI, 84.0–92.3). In propensity-score–matched analyses, GLP-1RA initiators were associated with a 23% lower risk than initiators of the antidiabetic medications metformin, dipeptidyl-peptidase-4 (DPP-4) inhibitors, or sodium-glucose co-transporter-2 (SGLT2) inhibitors (19.7% versus 25.6%; RR, 0.77; 95% CI, 0.75–0.79; q<0.001), with significantly lower risks of hypoesthesia, paresthesia, radiculopathy or sciatica, polyneuropathy, mononeuropathy and painful dysesthesia. GLP-1RA initiators also had a 22% lower associated risk than bariatric-surgery recipients who were additionally matched on achieved weight loss (21.1% versus 27.0%; RR, 0.78; 95% CI, 0.75–0.82; q<0.001). Within GLP-1RA initiators, neurosensory event incidence increased (P for trend<0.001) from 19.3% at a normal HbA1c baseline (12%, but showed no ordered association with achieved weight loss (P=0.867), baseline body-mass index (BMI, P=0.784) or BMI reduction (P=0.740). Maximum attained semaglutide/tirzepatide dose was also not enriched among neurosensory event developers in the matched cohort. Taken together, this observational study suggests the hallmark of neurosensory risk after GLP-1RA initiation may be glycemic burden, not the magnitude of achieved weight loss, and emphasizes that population-level neurosensory risk after GLP-1RA initiation was consistently lower than among matched antidiabetic-medication and bariatric-surgery recipients.

Semax and Selank are synthetic regulatory peptides that are not FDA-approved for human use but are marketed direct-to-consumer for cognition, mood and stress resilience. The extent of the documented use of these unapproved peptides in routine clinical care remains poorly characterized and, because neither is dispensed through regulated pathways, is largely absent from structured medication data of Electronic Health Records (EHRs). Using Large Language Model (LLM) curation of de-identified clinical notes from the nference federated data network with manual adjudication of the LLM-curated insights, here we characterize the clinically documented use of each peptide and the real-world medical contexts in which their use occurs. Clinical note documentation of both Semax and Selank increased starting in 2024, with an average quarter-over-quarter growth of 14% for Semax and 16% for Selank over the past year. Among 43 and 39 patients with clinical note-mentions of Semax or Selank, use was confirmed via LLM curation in 22 (51%) and 27 (69%) patients, respectively. Physician adjudication agreed with the LLM’s use classification in 164 of 165 individual note-level assessments (99.4%) across patients with a Semax or Selank mention, including patients whose use was not confirmed. In the pooled cohort of patients with confirmed Semax or Selank use (N = 49), cognitive enhancement (28.6%) and mood/anxiety/stress support (28.6%) were the most common reasons for use provided by the patients, with less common reasons including energy or performance, sleep, musculoskeletal and gastrointestinal indications. Manual adjudication showed 86.7% agreement with the LLM-curated reasons for use. Both peptides were commonly administered intranasally (37%), and there was documentation of “stacking” with other peptides in 33 patients (67%), such as CJC-1295, ipamorelin, semaglutide, and tirzepatide. In the pooled cohort, clinical notes recorded patient-reported positive or effective responses in 16 of 49 patients (33%) and product- or administration-related safety concerns or adverse-event sentiments in 13 of 49 (27%). Manual adjudication agreed with LLM-curated self-reported-effect classifications in 94.2% of 103 reviewed records. Manual review showed isolated dyspnea, palpitations, flushing, and emergency department visits during the temporal periods overlapping with patient-reported use of Semax or Selank (n<11). This study is not designed to evaluate the effectiveness or harm of Semax or Selank. Rather, it highlights the rising use of unapproved direct-to-consumer peptides without any structured coding mechanism in EHR systems, emphasizing the need for greater awareness among healthcare practitioners.

Background/Objectives: Oral semaglutide (Wegovy pill) and orforglipron (Foundayo) were recently approved for chronic weight management. Their safety and effectiveness have not been evaluated in real-world practice, particularly during the first few months when dose escalation, early treatment response, and tolerability may shape adherence.Methods: We retrospectively analyzed de-identified electronic health records through September 2026, including 16,220 oral Wegovy and 1,106 Foundayo recipients. Propensity matching on demographics, baseline characteristics including cardiometabolic burden, incretin history, the date of treatment initiation, and clinical visit frequency yielded 756 adult patients per drug. Clinical notes were curated with large language models (LLM), validated by physician adjudication.Results: In the unmatched cohorts, prior incretin exposure was recorded in 56.0% of oral Wegovy users versus 63.8% of Foundayo users (P<0.001). Prior injectable Wegovy use predominated among subsequent oral Wegovy users, whereas prior Zepbound use predominated among subsequent Foundayo users (both P<0.001). Dose escalation by day-90 lagged the recommended schedules for both agents. In matched cohorts, despite similar pre-treatment weight trajectories, mean weight change by 90 days after GLP-1 pill initiation was −3.1% with oral Wegovy (n=26) versus +0.4% with Foundayo (n=18), corresponding to a 3.55-percentage-point difference (95% CI, 1.02-6.08; P=0.007). Post-treatment initiation, LLM-curated clinical notes with physician adjudication confirmed weight-gain in a higher percentage of Foundayo users (5.3%) than oral Wegovy users (2.4%) (RR 2.20; P=0.016). Higher documentation of abnormal lipids was also evident from the LLM-curated notes among Foundayo users (1.7%) versus oral Wegovy users (5; P=0.009). Serial diagnostic lab testing showed a decrease in triglycerides during oral Wegovy use (−31.6 mg/dL; P=0.011, n=19) and a decrease in non-HDL cholesterol during Foundayo use (−30.5 mg/dL; P=0.04, n=11). Statins use did not meaningfully change upon Foundayo initiation, whereas significant statin-record frequency decrease was observed upon oral Wegovy prescribing (4.8% to 1.8%; P=0.020). Among Foundayo users, those with post-index statin co-prescriptions had numerically higher documented prevalence of abnormal lipids as expected, but also dizziness, and elevated liver enzymes than those without post-index statin co-prescriptions. Furthermore, adverse liver events and elevated liver enzymes were also numerically more frequent among Foundayo users than matched oral Wegovy users, presenting an emerging hypothesis that warrants prospective validation considering the FDA's postmarketing requirement to evaluate Foundayo liver safety and a subsequent FDA adverse-event report of hepatic failure. Conclusions: In a small subset of patients with follow-up weight measurements approximately 90 days after treatment initiation, oral Wegovy was associated with greater weight loss than Foundayo in routine care. Larger-scale and prospective follow-up analyses are warranted to more robustly compare the safety and effectiveness of these agents.

Objectives: Exenatide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that slows gastrointestinal (GI) motility. Whether exenatide produces clinically detectable GI motility slowing in real-world practice — and how this compares to other GLP-1 RAs — has not been systematically evaluated. We addressed this question using federated, electronic health record (EHR) data. Further, we present clinical data on vurolenatide, a long-acting variant of exenatide, in patients with short bowel syndrome (SBS), a condition defined by nutritional insufficiency where reducing GI motility could be beneficial to patient outcomes. Methods: We queried de-identified EHR data on the nSights platform to identify treatment episodes for exenatide, semaglutide, and tirzepatide among patients with documented GI hypermotility. Anti-constipation medication prescriptions, body weight, and HbA1c trajectories were compared between pre- and post-treatment periods. Given exenatide’s GI potency, we enrolled 9 SBS patients in a Ph 1b/2a study looking at vurolenatide, dosed subcutaneously every 2 weeks. Safety, tolerability, total urine output, and total stool output were the primary endpoints with the latter serving as a metric for GI motility. Results: We identified patients on exenatide (n=387), semaglutide (10,315), and tirzepatide (5,095) and found the prevalence of anti-constipation prescriptions increased significantly in the exenatide cohort over 12 months (11.09% to 18.62%; p=6.75×10⁻⁴). No significant change was detected with semaglutide (17.54% to 17.70%, p=0.734), and tirzepatide was associated with a decrease in use (18.72% to 14.84%, p<0.001). Exenatide did not impact body weight (-0.5%, p=0.299), compared to semaglutide (-3.95%, p<0.001) and tirzepatide (-8.44%, p<0.001), nor impact HbA1c (-0.02 %-points, p=0.926), compared to semaglutide (-0.26 %-points, p<0.001) and tirzepatide (-0.56 %-points, p<0.001). Consistent with exenatide’s potency at slowing GI motility, biweekly dosing of vurolenatide in human SBS patients showed immediate reduction in total stool output and in the number of bowel movements patients experienced. Conclusions: Exenatide is associated with potent slowing of GI motility in retrospective analysis of EHR data as well as in prospective treatment of SBS patients. This real-world signal proxies the mechanism underlying vurolenatide in SBS and provides a first-in-kind pharmacoepidemiological basis for GLP-1 RA–mediated modulation of GI motility.