Background: Tirzepatide, a GIP/GLP-1 receptor co-agonist, is increasingly used for weight management in individuals without diabetes, with weight loss of up to 22.5% in clinical trials(1). While gastrointestinal side effects are well recognised, euglycaemic ketoacidosis is an exceedingly rare but potentially life-threatening complication that has recently been described with tirzepatide use.
Case Presentation: A 27-year-old woman without diabetes presented with 48 hours of intractable nausea and vomiting. She had self-initiated non-prescribed tirzepatide three weeks earlier (2.5 mg weekly, self-escalated to 5 mg), reducing intake to ~20% of usual portions and losing 5 kg (1.6 kg/week). On examination she was clinically dehydrated, tachycardic and hypotensive with a BMI of 21.2 kg/m². Capillary glucose was normal (5.2 mmol/L) with elevated ketones (5.2 mmol/L). Investigations confirmed a high anion gap metabolic acidosis (pH 7.20, bicarbonate 7 mmol/L, anion gap 29 mmol/L, lactate 1.7 mmol/L) with normoglycaemia, consistent with euglycaemic ketoacidosis. She responded to fluid resuscitation with dextrose-containing fluids and antiemetics, without requiring insulin or intensive care, and was discharged after 14 hours with resolution of acidosis and ketosis, and re-establishment of oral intake.
Discussion: Ten cases of tirzepatide-associated euglycaemic ketoacidosis in individuals without diabetes have been reported(2-11). Nine of these cases were female, and all experienced marked appetite suppression and reduced caloric intake preceding presentation. Proposed mechanisms include severe caloric restriction combined with relative insulin deficiency and altered glucagon signalling, promoting unopposed lipolysis and ketogenesis despite normal glucose levels(6). Unsupervised use and rapid dose escalation may increase risk.
Conclusion: Euglycaemic ketoacidosis is a rare but serious complication of tirzepatide, even in individuals without diabetes. Clinicians should maintain a high index of suspicion, and presentations with persistent gastrointestinal symptoms, rapid weight loss, or markedly reduced nutritional intake should prompt assessment of ketones and acid-base status. This case highlights the importance of medically supervised prescribing, appropriate dose escalation and monitoring, and clear patient education.