To analyze the clinical features and risk factors of tirzepatide-associated ketoacidosis using real-world data, thereby providing evidence for safer clinical use.

A systematic literature search was conducted in both Chinese and English databases from inception until August 31, 2025, to identify case reports on tirzepatide-induced ketoacidosis. Data were also extracted from the FDA Adverse Event Reporting System (FAERS) spanning January 2004 to June 2025. Disproportionality analysis using the reporting odds ratio (ROR) was employed for signal detection, and descriptive statistics was applied to summarize the demographic, clinical, treatment, and outcome variables.

Fourteen published case reports and 229 cases from the FAERS were included. A higher proportion of cases occurred in females (78.57% in case reports; 51.96% in FAERS). Ketoacidosis often developed early during treatment (median time: 5 weeks), with common clinical features including nausea, vomiting, abdominal pain, dehydration, and metabolic acidosis. Significant signals were detected linking tirzepatide to various forms of ketoacidosis, particularly starvation ketoacidosis (ROR=107.36, 95%CI: 71.75~160.63) and euglycemic diabetic ketoacidosis (ROR=3.52, 95%CI: 2.51~4.93). Concomitant use of sodium-glucose co-transporter 2 inhibitors (SGLT-2i) was most frequently reported (52 cases). Most patients recovered after drug discontinuation and supportive care, although four fatal cases were documented in FAERS.

Tirzepatide is associated with a significant risk of ketoacidosis, particularly in female patients, non-diabetic state, and those using SGLT-2i concurrently. Enhanced vigilance, patient education, and early intervention are recommended to mitigate the risk of serious metabolic adverse events.