Semaglutide shows higher ketoacidosis risk signal than tirzepatide in non-diabetic obesity patients
Background
The increasing use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) like semaglutide and dual GLP-1/GIP receptor agonists such as tirzepatide for obesity management in non-diabetic individuals has raised concerns about euglycemic ketoacidosis. This serious complication, characterized by metabolic acidosis despite normal blood glucose, warrants careful monitoring. Despite growing post-marketing reports, a direct comparison of ketoacidosis reporting signals between these two widely prescribed agents in non-diabetic patients using real-world pharmacovigilance data has been lacking.
Study Design
Researchers performed a retrospective disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database, covering data from January 2021 through December 2025. After 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 to assess disproportionality.
Results
Out of 7,349,591 unique reports analyzed, 48,082 semaglutide and 98,295 tirzepatide reports were identified among non-diabetic patients. Ketoacidosis was reported in 261 semaglutide cases and 209 tirzepatide cases. Semaglutide demonstrated a significant disproportionality signal, indicating a higher likelihood of reporting ketoacidosis compared to other adverse events. Tirzepatide also showed a significant signal, but it was notably lower than semaglutide's.
Semaglutide's disproportionality signal was ROR 3.15 (95% CI 2.78-3.56) and PRR 3.14 (95% CI 2.78-3.54), while tirzepatide's signal was ROR 1.22 (95% CI 1.06-1.39) and PRR 1.21 (95% CI 1.06-1.39). Hospitalization was required in 74.3% of semaglutide cases and 71.3% of tirzepatide cases. 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.
Key Findings
- Semaglutide showed a significant ketoacidosis reporting signal (ROR 3.15) in non-diabetic patients.
- Tirzepatide also showed a significant but lower ketoacidosis signal (ROR 1.22) in non-diabetic patients.
- Ketoacidosis led to hospitalization in 74.3% of semaglutide and 71.3% of tirzepatide cases.
- Tirzepatide-associated ketoacidosis reports increased from 1-2 cases/quarter in 2022 to 28-34 cases/quarter by 2025.
Why It Matters
This study provides crucial real-world evidence highlighting the differential risk of ketoacidosis between semaglutide and tirzepatide in non-diabetic patients using these drugs for obesity. Clinicians should be highly vigilant for symptoms of ketoacidosis in all non-diabetic patients prescribed GLP-1RAs, particularly semaglutide. The high hospitalization rates underscore the severity of this adverse event. While tirzepatide showed a lower disproportionality signal, its rapidly increasing reporting trend necessitates ongoing monitoring and patient education. This data suggests that current protocols for patient selection and counseling may need refinement to mitigate this serious, albeit rare, complication, especially as these medications become more widespread.
semaglutide
tirzepatide
ketoacidosis
obesity
adverse-events
pharmacovigilance