Background: Tirzepatide is a dual incretin (GLP-1 and GIP) receptor agonist approved for Type 2 Diabetes Mellitus (T2DM) and chronic weight management with significant cardiovascular and renal benefits. Gastrointestinal discomfort is the most commonly reported adverse effect with this drug, with uncommon occurence of acute kidney injury, gall bladder disease and pancreatitis. We present 2 cases to report the occurrence of diabetic ketoacidosis (DKA) in T2DM patients and its noteworthy temporal association with Tirzepatide, the first clinical encounter of its kind. The purpose of this case report is to document a potential adverse outcome associated with this drug that mandates further research.

Case presentation: Case 1- A 35 year old,female, BMI-36.92, with T2DM since 4 years, presented with severe nausea, vomiting and abdominal pain one week following increase in the dose of Tirzepatide. The patient had a prior episode of DKA which led to hospitalization within a week of her first Tirzepatide injection 2 months back. Initial investigation upon admission was consistent with euglycemic DKA- pH-7.31, HCO3-9.9, blood glucose-178, beta-hydroxybutyrate-13.5, anion gap-31, C-peptide-3.6 and GAD antibody <5.

Case 2- A 46 year old male, BMI-31.93, with T2DM since 23 years, presented with severe nausea and vomiting that developed after he took his dose of Tirzepatide the previous day. He had been on this drug for about 6 months and reported persistent GI discomfort that he associates with this medication. Initial investigation was consistent with the diagnosis of DKA-blood glucose-507, betahydroxybutyrate -7.7, pH -7.44, HCO3-16.6, anion gap-24, C-peptide-2.8 and GAD antibody <5.

Other possible triggers for DKA including infection, trauma, alcohol use and withdrawal were ruled out in both the cases through history and labs. Both the patients were hospitalized and managed with DKA protocol in the ICU.

Discussion: The aforementioned cases illustrate a rare but notable risk of DKA with either hyperglycemia and euglycemia in patients on Tirzepatide. This has not been observed previously. One plausible explanation is that significant reduction in calorie intake due to Tirzepatide can potentially trigger starvation ketoacidosis. Another concern is the potential for Tirzepatide to unmask ketosis-prone diabetes in individuals who are not phenotypically T1DM characterized by absolute insulin deficiency. This case report emphasizes the importance of recognizing this rare complication in patients prescribed this increasingly used drug.