Semaglutide Exposure and Risk of Oral Mucositis, Systemic Complications, and Mortality Among Patients with a History of Hematopoietic Stem-Cell Transplantation: A Propensity-Matched Real-World Cohort Study

Background: Oral mucositis is a major toxicity of hematopoietic stem-cell transplantation (HSCT). In preclinical models, glucagon-like peptide-1 (GLP-1) signaling promotes intestinal epithelial repair after chemotherapy-induced injury, but its relationship to oral mucositis after transplantation is undefined. We hypothesized that semaglutide would be associated with a lower risk of stomatitis and oral mucositis, without increased xerostomia, and with fewer systemic complications. Methods: Using the TriNetX COVID-19 Research Network (88 healthcare organizations; query executed 13 August 2026), adults aged 18–90 with stem-cell transplant status (ICD-10-CM Z94.84) were classified as semaglutide-exposed or unexposed. The index date was the first date on which all cohort-defining criteria were met; because Z94.84 is a status code, the index date does not correspond to the date of transplantation. Long-term outcomes were assessed from day 30 after the index date until the end of available records; oral mucositis was assessed as a 3-month outcome (days 1–90 after the index date) in a separate propensity-matched analysis that additionally balanced underlying hematologic diagnoses. The primary endpoint was stomatitis and related lesions (K12); oral mucositis (K12.3, a subcategory of K12) was the key secondary endpoint. Dry mouth, taste/smell disturbances, candidal stomatitis, food and fluid intake codes, systemic inflammation, influenza/pneumonia, graft-versus-host disease, and mortality were exploratory endpoints. One-to-one propensity-score matching was used to balance age, sex, race/ethnicity, type 2 diabetes, external causes of morbidity, body-mass index, and Eastern Cooperative Oncology Group (ECOG) performance status. Results: During long-term follow-up (1355 matched pairs), stomatitis occurred in 4.0% versus 10.6% (risk ratio [RR] 0.378, 95% CI 0.262–0.545; hazard ratio [HR] 0.476, 95% CI 0.323–0.700; p < 0.001). At 3 months (1152 matched pairs), oral mucositis occurred in 2.7% versus 9.6% (RR 0.280, 95% CI 0.178–0.442; risk difference −6.9 percentage points; p < 0.001; the proportional-hazards assumption was not met, so the hazard ratio is reported only as an average effect). Dry mouth and taste/smell disturbances did not differ. In exploratory analyses, exposed patients had lower observed risks of sepsis-spectrum inflammation (6.2% versus 13.1%), influenza/pneumonia (11.6% versus 23.8%), and death (6.7% versus 25.0%), although follow-up was considerably shorter in the exposed cohort. Conclusions: Among patients with a documented history of HSCT, semaglutide exposure was inversely associated with ICD-coded stomatitis and oral mucositis, without a detectable increase in coded xerostomia, and with lower observed risks of infectious outcomes and death. Because the timing of exposure relative to transplantation could not be determined and residual confounding is likely, these findings are hypothesis-generating, require prospective confirmation, and do not establish a preventive indication.