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

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.

Incidence, risk factors, and management of alpelisib‐associated hyperglycemia in metastatic breast cancer

“…Finally, although insulin is still indicated for the management of severe hyperglycemia and/or ketoacidosis, it should be avoided when possible, as hyperinsulinemia can reactivate PI3K signaling despite use of a PI3K inhibitor 10 . Given the complexity of anti‐hyperglycemic treatment considerations in this setting, multidisciplinary support including consultation with dieticians and endocrinologists is warranted 31,32 . Additionally, prospective studies to identify effective anti‐hyperglycemic strategies during alpelisib treatment are underway, with four clinical trials actively recruiting patients (Table 3).…”

CDK4/6 inhibitors versus PI3K/AKT/mTOR inhibitors in women with hormone receptor-positive, HER2-negative metastatic breast cancer: An updated systematic review and network meta-analysis of 28 randomized controlled trials

“…Pooled analysis revealed the tendency for PAM inhibitors especially PI3K inhibitors to result in escalated blood glucose level. Hyperglycemia is one of the common on-target side effects of PI3K inhibitors due to the dysregulation of glucose metabolism that warrants prevention, monitoring, and treatment ( 70 , 71 ). Our original study mainly focused on the severe TRAEs of grade ≥3, whereas current study further supplemented the data regarding all grades and capivasertib-caused toxicity.…”

On-Target Side Effects of Targeted Therapeutics of Cancer

“…The hyperglycemia, induced by PI3K inhibitors is isoform specific, mainly experienced during a PI3Kα specific treatment (45). Hyperglycemia is a major problem with PI3K inhibitors, which stimulated development of guidelines (47).…”

“…The mTOR kinases form large protein complexes, the mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The activated complexes enhance the accumulation of triglycerides, promote adipogenesis and lipogenesis, and inhibit catabolic processes, such as lipolysis and β-oxidation (45,46,47,48).…”