Hyperglycemia secondary to phosphatidylinositol-3 kinase (PI3K) inhibition
Summary: Phosphatidylinositol-3 kinase (PI3K) is a crucial intracellular pathway that regulates cell growth, metabolism, and survival, and it has been implicated in the development of many human cancers. Targeting this pathway has been approved for the treatment of breast cancer and lymphoma (e.g., alpelisib, idelalisib), with several clinical trials underway for other types of cancer. However, since PI3K plays a key role in insulin action, the use of PI3K inhibitors has been linked to hyperglycemia. We report the case of a 53-year-old woman with metastatic breast cancer who developed acute grade 3 hyperglycemia after treatment with the novel PI3K inhibitor, inavolisib. In this report, we review treatment options for managing PI3K inhibitor-associated hyperglycemia. Strategies that minimize hyperinsulinemia may be preferable, as animal models have shown that hyperinsulinemia can partially reactivate the PI3K pathway and potentially counteract the anti-cancer effects of PI3K inhibitors.
Learning Points: Phosphatidylinositol-3 kinase (PI3K) regulates key physiological functions, including cell growth, metabolism, survival, and angiogenesis. Hyperactivation of the PI3K pathway is common in many human cancers, making PI3K inhibition a potential treatment for select cancers. The action of insulin, such as glucose uptake in muscle and the inhibition of glycogenolysis and gluconeogenesis, is mediated by the PI3K pathway. Therefore, PI3K inhibition can lead to hyperinsulinemic hyperglycemia. Patients treated with PI3K inhibitors should undergo pre-treatment screening for hyperglycemia, receive lifestyle advice, and use a glucometer to monitor fasting blood glucose (BGL) and 2-hour post-dinner BGL levels twice weekly for at least the first 30 days of treatment. Since insulin or insulin secretagogues (e.g., sulfonylureas) may interfere with the anti-tumor effects of PI3K inhibitors, alternative approaches, such as a low carbohydrate diet, metformin, SGLT2 inhibitors, or dose reduction of the PI3K inhibitor,GDC-0077 are preferred for managing PI3K inhibitor-associated hyperglycemia.