MON-631 - A Dangerous Rebound: Severe Capivasertib-Induced Insulin Resistance with Subsequent Prolonged Hypoglycemia after Drug Cessation

Introduction:
Capivasertib is an oral AKT inhibitor used to treat hormone receptor-positive breast cancer. By inhibiting AKT in the PI3K/AKT signaling pathway, it interferes with insulin signaling, often resulting in hyperglycemia. While mild glucose elevation is common, severe refractory insulin resistance is rare. We describe a case of severe insulin resistance requiring massive insulin doses, at times exceeding 900 units daily, followed by abrupt and prolonged hypoglycemia upon drug cessation.

Case Presentation:
An 86-year-old woman with type 2 diabetes mellitus (T2DM) (baseline regimen: insulin aspart 8 units three times daily with meals, insulin glargine 9 units nightly, linagliptin 5 mg daily; pre-admission A1c 6.2%) and hormone receptor-positive breast cancer previously treated with capivasertib was admitted for an acute cerebrovascular accident. Admission blood glucose was 168 mg/dL. Following capivasertib reinitiation, glucose rapidly rose to 493 mg/dL. A non-DKA insulin infusion was initiated, and basal insulin glargine was increased to 25 units daily. Despite escalating insulin dosages, glucose remained in the 500 mg/dL range despite minimal oral intake. Metformin 500 mg twice daily and pioglitazone 30 mg daily were then initiated, and capivasertib was discontinued.

On hospital day three, after a cumulative insulin dose of approximately 900 units over 24 hours, euglycemia was briefly achieved. Within 24 hours of the final capivasertib dose, the patient's insulin resistance abruptly resolved, resulting in severe hypoglycemia (nadir of 39 mg/dL). All insulin and pioglitazone administrations were discontinued. Persistent hypoglycemia required escalation from continuous infusion of D5W to D10W. By day seven, glycemic stability was finally achieved, and the patient was discharged with plans to restart capivasertib at a reduced dosage.

Discussion:
AKT inhibitor-associated insulin resistance presents unique management challenges due to both severe insulin resistance and the rapid reversal of insulin resistance following drug discontinuation. The rapid onset of profound insulin resistance, requiring a nearly 100-fold increase over baseline basal insulin requirements, emphasizes the drug’s potent inhibition of insulin signaling and glucose transport. These findings highlight the need for proactive insulin de-escalation, and cautious use of long-acting insulin sensitizers prior to drug discontinuation may help mitigate the risk of severe hypoglycemia resulting from abrupt restoration of insulin sensitivity.

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