SAT-570 - Diabetic Ketoacidosis in the Setting of Alpelisib Therapy: Mechanisms and Management of PI3K Inhibitor-Associated Hyperglycemia

Background
Alpelisib, a selective phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitor approved for phosphatidylinositol 3-kinase catalytic subunit alpha–mutated breast cancer, frequently causes hyperglycemia through disruption of insulin signaling. Diabetic ketoacidosis (DKA) represents a life-threatening and underrecognized complication of therapy.

Case Presentation
A 55-year-old woman with type 2 diabetes mellitus on insulin, metastatic breast cancer treated with alpelisib, hypertension, and hypothyroidism presented with lethargy, abdominal pain, anorexia, nausea, vomiting, and progressive shortness of breath. Symptoms evolved over several days despite outpatient insulin adjustments. She had recently been treated for right sialadenitis with amoxicillin-clavulanate and was on day 4 of a 5-day methylprednisolone dose pack. Notably, her alpelisib dose had been increased from 150 mg to 300 mg daily shortly before presentation. At baseline, she was also receiving metformin 1,000 mg daily.

Laboratory evaluation revealed a hemoglobin A1c of 11.2%, serum glucose of 336 mg/dL, an anion gap of 28.7, venous blood gas pH of 7.27, bicarbonate level of 15 mmol/L, potassium level of 4.6 mmol/L, and large serum and urine ketones, consistent with DKA.
The patient was admitted to the intensive care unit and treated with intravenous fluids, insulin infusion, and electrolyte replacement with frequent metabolic monitoring, and alpelisib was held. Her anion gap closed and she was transitioned to subcutaneous insulin with clinical improvement. The patient was discharged home with Endocrinology and Oncology follow-up and counseled on the risks and benefits of continued alpelisib therapy.

Conclusion
The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in insulin signaling through activation of protein kinase B (AKT), facilitating glucose uptake and glycogen synthesis in insulin-sensitive tissues. Alpelisib-mediated inhibition of PI3Kα impairs this pathway, leading to marked insulin resistance, increased hepatic gluconeogenesis, and enhanced lipolysis, thereby increasing the risk of severe hyperglycemia and ketosis. Additional stressors, including glucocorticoid exposure, infection, or dose escalation, may further amplify this risk. This case emphasizes the importance of understanding the mechanism of alpelisib-associated hyperglycemia and highlights the need for proactive glucose monitoring, anticipatory insulin adjustment, and multidisciplinary management to prevent serious metabolic complications.

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