Management Strategies for Hyperglycemia Associated with the α-Selective PI3K Inhibitor Alpelisib for the Treatment of Breast Cancer

SIMPLE SUMMARY: Alpelisib is a drug used to treat breast cancer that has certain characteristics (hormone receptor-positive (HR+), human epidermal growth receptor 2-negative (HER2–), PIK3CA-mutated) and that has or has not spread to other organs. It is used after the cancer has progressed despite being treated with hormonal therapies. One of the most common side effects of alpelisib is an increase in blood glucose level (hyperglycemia). This can sometimes require reductions in the dose of alpelisib, or interruption or discontinuation of treatment. Early detection and initiation of treatment for hyperglycemia can help in controlling blood glucose levels and ensuring the best use and effects of alpelisib. Treatment can include lifestyle modifications (a reduced-carbohydrate diet) and administration of drugs used to treat diabetes. This report provides information on how to manage hyperglycemia caused by alpelisib, based on the experience of 14 cancer specialists and seven endocrinologists in managing this side effect. ABSTRACT: Alpelisib is an α-selective phosphatidylinositol 3-kinase inhibitor used for treating hormone receptor-positive (HR+), human epidermal growth receptor 2-negative (HER2–), PIK3CA-mutated locally advanced or metastatic breast cancer following disease progression on or after endocrine therapy. Hyperglycemia is an on-target effect of alpelisib affecting approximately 60% of treated patients, and sometimes necessitating dose reductions, treatment interruptions, or discontinuation of alpelisib. Early detection of hyperglycemia and timely intervention have a key role in achieving optimal glycemic control and maintaining alpelisib dose intensity to optimize the benefit of this drug. A glycemic support program implemented by an endocrinology–oncology collaborative team may be very useful in this regard. Lifestyle modifications, mainly comprising a reduced-carbohydrate diet, and a designated stepwise, personalized antihyperglycemic regimen, based on metformin, sodium–glucose co-transporter 2 inhibitors, and pioglitazone, are the main tools required to address the insulin-resistant hyperglycemia induced by alpelisib. In this report, based on the consensus of 14 oncologists and seven endocrinologists, we provide guidance for hyperglycemia management strategies before, during, and after alpelisib therapy for HR+, HER2–, PIK3CA-mutated breast cancer, with a focus on a proactive, multidisciplinary approach.