Neurosensory Risk After Semaglutide or Tirzepatide Is Lower Than Matched Antidiabetic and Bariatric Surgery Cohorts and Tracks Glycemic Burden

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 (<5.7%) to 32.0% for severe hyperglycemics at HbA1c >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.