Disproportionality Analysis of Tirzepatide-Associated Ketoacidosis
Abstract
Background: Tirzepatide, a dual GIP/GLP-1 receptor agonist approved for type 2 diabetes and obesity, has generated post-marketing reports of ketoacidosis-spectrum events. Systematic pharmacovigilance characterization is lacking.
Methods: All tirzepatide reports were extracted from the FDA Adverse Event Reporting System (FAERS) through March 2026. Disproportionality was assessed using the Proportional Reporting Ratio (PRR; signal threshold: PRR ≥ 2, χ2 ≥ 4, n ≥ 3) and Reporting Odds Ratio (ROR) across four MedDRA preferred terms: ketoacidosis NOS, euglycemic DKA, starvation ketoacidosis, and ketosis NOS.
Results: Starvation ketoacidosis generated the strongest signal (PRR 70.2, χ2 1560.7; ROR 70.3 [95% CI 46.9-105.2]). Ketosis NOS and euglycemic DKA produced moderate but statistically robust signals meeting all frequentist thresholds (PRR 4.27 and 2.01, respectively).
Conclusions: The starvation ketoacidosis signal is biologically plausible given tirzepatide-mediated appetite suppression and caloric restriction. Euglycemic DKA signals are clinically relevant in peri-operative or dietary restriction contexts. FAERS limitations preclude causal inference. Physicians may consider counseling patients about ketoacidosis symptoms and maintain a low threshold for ketone testing in symptomatic individuals on tirzepatide.
Authors: Connor Frey
Journal: Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists