SAT-574 - Capivasertib-Induced Severe Diabetic Ketoacidosis in A Patient without Diabetes

A 63-year-old female presented to the emergency department with altered mentation, poor oral intake, abdominal pain, and diarrhea. Her medical history was notable for ER-positive, PR-positive, HER2-negative metastatic breast cancer, hypertension, and hypercholesterolemia. Her oncologic therapy consisted of intramuscular injections of fulvestrant along with oral capivasertib 160 mg twice daily for four days per week for the last year. Notably, she had no prior history of diabetes mellitus with a recent hemoglobin A1c of 5.8%. Laboratory work-up was notable for blood glucose 309 mg/dL (65-139 mg/dL), carbon dioxide 13 mmol/L (22-30 mmol/L), anion gap 17 (8-14), creatinine 3.18 mg/dL from a baseline of 0.75 mg/dL (0.6-1.0 mg/dL), beta hydroxybutyric acid level >4.00 mmol/L (0.02-0.27 mmol/L), and urinalysis with 1+ ketone. The patient was admitted to the medical intensive care unit for management of DKA. She required rapid escalation of hourly insulin doses due to persistent hyperglycemia, with blood glucose levels remaining elevated despite titration to the protocol’s maximum infusion rate. The patient remained on the DKA protocol for a total of thirty-eight hours, requiring the highest rate of forty-six units per hour for sixteen hours due to marked insulin resistance and persistent hyperglycemia. As blood glucose levels improved, the rate of the insulin infusion was rapidly titrated down to avoid hypoglycemia. The patient was transitioned to insulin glargine at a low dose of 5 units once DKA resolved, and she subsequently developed refractory hypoglycemia requiring repeated dextrose boluses and continuous dextrose infusion. A C-peptide level was ordered once glucotoxicity resolved and was found to be 2.1 ng/mL (0.5-3.3 ng/mL) with a concomitant glucose of 98 mg/dL (65-139 mg/dL). Glutamic Acid Decarboxylase Ab was mildly elevated at 6.0 IU/mL (0.0-5.0 IU/mL), and the remainder of diabetes-related autoantibodies were negative. Blood glucose levels normalized, and the patient was eventually discharged on no diabetes medications. Capivasertib was permanently discontinued, and the patient was switched to trastuzumab deruxtecan therapy.

Capivasertib is an oral AKT inhibitor approved for the treatment of HR-positive, HER2-negative locally advanced or metastatic breast cancer. Capivasertib-induced DKA presents with marked insulin resistance with the acute onset of severe insulin receptor dysfunction through inhibition of the PI3K/AKT/mTOR pathway. It is noteworthy that capivasertib-induced glucotoxicity is reversible, with a rapid decline in insulin requirement once the drug effects wear off. The relatively short half-life of this medication necessitates twice-daily dosing and can complicate the evaluation of hyperglycemia, and hemoglobin A1c may be an unreliable marker. This case highlights the importance of close metabolic monitoring during capivasertib therapy.

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