Ketoacidosis Risk in Non-diabetic Patients Using Semaglutide Versus Tirzepatide for Obesity: A Disproportionality...

Background Glucagon-like peptide-1 receptor agonists, including semaglutide and tirzepatide, are frequently prescribed for obesity management in non-diabetic patients. Euglycemic ketoacidosis has emerged as a concerning complication in this patient population, yet no study has directly compared ketoacidosis reporting signals between these two agents in non-diabetic patients using real-world pharmacovigilance data. Methods  We conducted a retrospective disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database from January 2021 through December 2025. Following deduplication, reports were filtered for semaglutide and tirzepatide as primary suspect medications. Non-diabetic patients were identified by excluding reports with diabetes-related indications. Ketoacidosis cases were identified using MedDRA preferred terms. Reporting odds ratios (RORs) and proportional reporting ratios (PRRs) with 95% confidence intervals (CIs) were calculated for each drug. Results  Following deduplication, 7,349,591 unique reports were analyzed. Among non-diabetic patients, 48,082 semaglutide and 98,295 tirzepatide reports were identified. Ketoacidosis was reported in 261 semaglutide cases and 209 tirzepatide cases. Semaglutide demonstrated a significant disproportionality signal (ROR 3.15, 95% CI 2.78-3.56; PRR 3.14, 95% CI 2.78-3.54). Tirzepatide also showed a significant but lower signal (ROR 1.22, 95% CI 1.06-1.39; PRR 1.21, 95% CI 1.06-1.39). Hospitalization was required in 74.3% and 71.3% of semaglutide and tirzepatide cases, respectively. Tirzepatide-associated reports showed a marked upward trend, increasing from 1-2 cases per quarter in 2022 to 28-34 cases per quarter by 2025. Conclusions  Both semaglutide and tirzepatide are associated with significant ketoacidosis reporting signals in non-diabetic patients, with semaglutide demonstrating a higher disproportionality signal. The high rates of hospitalization and rapidly increasing tirzepatide reports highlight an emerging safety concern requiring clinical vigilance in patients using these agents for obesity management.