MON-617 Challenges in Hyperglycemia Management in a Patient Treated With a Phosphatidylinositol 3-Kinase Inhibitor

Abstract Disclosure: N.L. Tsao: None. L.E. Carafone: None. Introduction: Phosphatidylinositol 3-kinase (PI3K) signaling is involved in regulation of cell survival, growth, proliferation, and glucose metabolism. Aberrant activation of the PI3K pathway is found in solid and hematologic malignancies, and is associated with the development of treatment resistance to several anticancer therapies. Inhibitors of this pathway have become important agents in cancer therapeutics. Hyperglycemia is an on-target side effect of PI3K inhibitors that presents unique challenges in glycemic management for patients receiving these therapies. Clinical Case: A 72-year-old woman with a history of type 2 diabetes on empagliflozin monotherapy, hypertension, hyperlipidemia, and uterine clear cell carcinoma presented with shortness of breath, hyperglycemia, and word finding difficulty. She had been started on the PI3K inhibitor alpelisib 300 mg daily eight days prior to admission and developed worsened hyperglycemia. Prior to admission, the patient had been trialed on metformin, but this was discontinued due to diarrhea and persistent hypomagnesemia. Pioglitazone, one of the preferred options as it does not interfere with the PI3K pathway, was not recommended due to recent history of Takotsubo cardiomyopathy and reduced ejection fraction. Labs on admission demonstrated pH 7.21 (7.32-7.42), glucose 227 mg/dL (60-99), anion gap 37 (7-16), bicarbonate 8 mmol/L (20 - 28), beta hydroxybutyrate 11.45 mmol/L (0.02 - 0.27), and 4+ urine ketones. Empagliflozin was discontinued at the time of admission due to DKA. She was treated with an insulin drip, then transitioned to subcutaneous insulin with 30 units of insulin glargine and 10 units of insulin lispro with correction scale. Following discharge, alpelisib was resumed and insulin lispro was further uptitrated. During this time blood glucose ranged from 78-240 mg/dL. Following discontinuation of alpelisib secondary to a stroke, the insulin regimen was tapered to 12 units of insulin lispro and she no longer required insulin glargine. Conclusion: Hyperglycemia is an on-target side effect of PI3K inhibitors. Metformin, SGLT2 inhibitors and thiazolidinediones are preferred medications to treat PI3K-induced hyperglycemia because their mechanism of action does not affect the PI3K signaling pathway. However, this case report illustrates the challenges that ensue when a patient is unable to use preferred antihyperglycemic medications. Insulin is generally considered a last resort in PI3K-induced hyperglycemia, in part because insulin can activate PI3K signaling and therefore theoretically compromise the efficacy of the PI3K inhibitor treatment. More research to directly compare antihyperglycemic agents, as well as evaluate the potential impact of those affecting the PI3K pathway on the efficacy of PI3K inhibitor therapy, is needed to guide optimal glycemic management in patients receiving PI3K inhibitors. Presentation: Monday, July 14, 2025