A Case of Diabetic Keto Acidosis From Alpelisib

Introduction: Alpelisib is a phosphatidylinositol-3-kinase (PI3K) inhibitor, approved for the treatment of hormone receptor positive, human epidermal growth factor receptor-2 negative, PIK3CA-mutated metastatic breast cancer. While hyperglycemia is a known side effect of this drug, diabetes ketoacidosis (DKA) is rare. Only one case was previously reported in the literature to our knowledge. Here, we report a patient with prediabetes who presented with DKA after initiation of Alpelisib. Case Presentation: A 48 y.o. woman with metastatic left breast cancer was started on Alpelisib 300mg/day. HbA1C prior to the initiation of Alpelisib was in the prediabetes range at 5.7% with a fasting glucose of 106 mg/dL. Three weeks later, she presented to the ER with abdominal pain, nausea and vomiting. Vitals were notable for sinus tachycardia of 130 bpm. Exam was notable for diminished lung sounds over left lower chest. Labs revealed elevated serum glucose of 302 mg/dL, anion gap metabolic acidosis (anion gap 19, bicarbonate 10) and elevated beta hydroxy butyrate of 7.58 (normal < 0.27 mmol/L) consistent with DKA. Intravenous insulin infusion per DKA protocol was initiated and Alpelisib was held. She was bridged and subsequently transitioned to insulin glargine with insulin lispro sliding scale. Her C-peptide was 1.47 ng/mL (normal 0.90 - 4.30 ng/mL) with negative anti-GAD antibody. She developed multiple episodes of symptomatic hypoglycemia despite reduced insulin doses, requiring eventual discontinuation of insulin, followed by stabilization of blood glucose levels. Subsequent hospital course was complicated by acute respiratory failure from malignant pleural effusion due to which hospice care was initiated. Discussion: Hyperglycemia, diarrhea, nausea and rash are common side effects of PI3K inhibitors. Insulin binds to insulin receptor substrate which activates PI3K, which in turn activates protein kinase B resulting in the translocation of the glucose transporter GLUT4 to the plasma membrane causing glucose uptake. Alpelisib inhibits PI3K resulting in hyperglycemia through decreased glucose uptake. Hyperglycemia was reported in 51–65% of the patients treated with Alpelisib. Patients with prediabetes are at increased risk of worsening hyperglycemia. Hyperosmolar and ketoacidotic states are rare, usually encountered in patients with pre-existing diabetes. DKA can be a presenting manifestation in patients with mildly impaired glucose tolerance as in our case, highlighting the importance of screening for diabetes prior to initiation and monitoring glycemic control during therapy. Once hyperglycemia is detected, prompt initiation of oral hypoglycemic agent metformin (first line) or insulin therapy is recommended depending on the severity of the hyperglycemia. Dose reduction or eventual discontinuation of Alpelisib therapy may be necessary based on the severity of hyperglycemia.