MON-658 - A Case of Suspected Tirzepatide-Associated Diabetic Ketoacidosis in A Patient with Type 2 Diabetes

Background:
Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GIP/GLP-1) receptor agonist (RA) that is increasingly used for glycemic control and weight loss. In contrast to SGLT-2 inhibitors, the association between GIP/GLP-1 RA use and DKA is not well-defined. We report a case of DKA in a patient with type 2 diabetes (T2DM) temporally linked to tirzepatide dose escalation with no other precipitant identified.

Case Presentation:
A 50-year-old woman with T2DM complicated by neuropathy (A1C 9.2%), managed on basal-bolus insulin and tirzepatide, presented with a 3-day history of nausea and vomiting. One week prior, her tirzepatide dose was increased from 5 mg to 7.5 mg weekly to improve glycemic control. Heartburn and epigastric discomfort began the day of her second 7.5 mg dose. She had 3 standard meals with no alcohol use. The following day, she developed vomiting and hyperglycemia (glucose 300-500 mg/dL on CGM) for which she sought medical care. On admission, she had tachycardia (105 beats/min), tachypnea (21 breaths/min), and hypertension (205/110 mmHg); labs showed glucose 351 mg/dL, plasma ketones 6.29 mmol/L, pH 7.28, CO₂ 16 mmol/L, and anion gap of 24. This was her first incidence of DKA. Infectious, ischemic, and toxicologic workup was negative. There was no evidence of pancreatitis. She was treated with IV fluids and IV insulin per DKA protocol to resolution of ketosis. She was transitioned to basal-bolus insulin and discharged. Tirzepatide was discontinued as the suspected cause of DKA.

Discussion:
This case highlights a new and significant adverse event: DKA following tirzepatide dose escalation in an insulin-treated patient with T2DM without any other identifiable trigger. Mechanistically, GIP/GLP-1 RAs may induce ketosis via starvation with appetite suppression, reduced caloric intake, and GI side effects, leading to reduced glycogen stores and shift to lipolysis. This is also proposed with GLP-1 RAs, and a study found disproportionately more reports of DKA associated with GLP-1 RA use when controlled for SGLT2i and insulin use. This is particularly reported with rapid dose escalation and insulin reduction, though our patient was on a stable insulin regimen. While data specific to GIP/GLP-1 RA use is limited, this adds to early reports of DKA, and the risk may become more apparent as GIP/GLP-1 RA use is widely adopted. The risk of DKA has clinical implications and highlights the need for pharmacovigilance to inform safe use of novel incretin therapies.

Conclusion:
DKA is a rare but serious potential complication of tirzepatide use in T2DM, particularly during dose escalation and reduced food intake. This case underscores the need for clinician awareness and patient education for early identification and management of DKA. Further research is needed to elucidate the incidence, risk factors, and mechanism for DKA in patients on tirzepatide.

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