Tirzepatide strongly linked to starvation ketoacidosis in FDA adverse event reports.

The dual GIP/GLP-1 receptor agonist Tirzepatide is widely used for type 2 diabetes and obesity, demonstrating potent effects on glycemic control and weight reduction. While generally well-tolerated, post-marketing surveillance has revealed reports of ketoacidosis-spectrum events. A systematic pharmacovigilance characterization of these adverse events has been lacking, creating a critical gap in understanding the safety profile and guiding clinical management, particularly given the drug's significant appetite suppression and potential for caloric restriction.

Researchers conducted a disproportionality analysis of all tirzepatide reports extracted from the FDA Adverse Event Reporting System (FAERS) through March 2026. Disproportionality was assessed using the Proportional Reporting Ratio (PRR) and Reporting Odds Ratio (ROR) to identify signals. A signal threshold was defined as PRR ≥ 2, χ² ≥ 4, and n ≥ 3 reports. The analysis specifically focused on four MedDRA preferred terms: ketoacidosis NOS, euglycemic DKA, starvation ketoacidosis, and ketosis NOS, comparing reporting rates for tirzepatide against all other drugs in the database.

The analysis revealed statistically robust signals for several ketoacidosis-spectrum events associated with tirzepatide. Starvation ketoacidosis generated the most significant signal, indicating a strong disproportionality in reporting. Ketosis NOS and euglycemic DKA also produced moderate but statistically robust signals, meeting all predefined frequentist thresholds for significance. These findings suggest a notable association between tirzepatide use and these specific types of ketoacidosis events. The observed signals are biologically plausible, particularly for starvation ketoacidosis, given tirzepatide's known mechanism of action involving significant appetite suppression and subsequent caloric restriction. The euglycemic DKA signals are also clinically relevant, especially in contexts involving peri-operative fasting or other forms of dietary restriction, where patients might be more susceptible. The study highlights the importance of considering these risks in clinical practice.

Starvation ketoacidosis generated the strongest signal (PRR 70.2, χ² 1560.7; ROR 70.3 [95% CI 46.9-105.2]). Ketosis NOS produced a PRR of 4.27, and euglycemic DKA showed a PRR of 2.01, both meeting all frequentist thresholds.