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Review
. 2025 Jan;25(1):1-11.
doi: 10.1016/j.clbc.2024.09.017. Epub 2024 Sep 28.

Effective Strategies for the Prevention and Mitigation of Phosphatidylinositol-3-Kinase Inhibitor-Associated Hyperglycemia: Optimizing Patient Care

Heather N Moore  1 , Marcus D Goncalves  2 , Abigail M Johnston  3 , Erica L Mayer  4 , Hope S Rugo  5 , William J Gradishar  6 , Dylan M Zylla  7 , Richard M Bergenstal  8
Affiliations
Free article
Review

Effective Strategies for the Prevention and Mitigation of Phosphatidylinositol-3-Kinase Inhibitor-Associated Hyperglycemia: Optimizing Patient Care

Heather N Moore et al. Clin Breast Cancer. 2025 Jan.
Free article

Abstract

Hyperglycemia is a common adverse event (AE) associated with phosphatidylinositol-3-kinase inhibitors (PI3Kis) and considered an on-target effect. Presence of hyperglycemia is associated with poor outcomes in patients with cancer, and there is need for further refinement of hyperglycemia prevention and mitigation strategies in patients receiving PI3Kis. In this review, the authors highlight effective strategies for preventing PI3Ki-induced hyperglycemia before and during treatment as well as hyperglycemia management. Prior to initiating treatment with PI3Ki, identify baseline risk factors of patients at increased risk for developing hyperglycemia, which include older age, obesity, and glycosylated hemoglobin (HbA1c) 5.7%-6.4% (prediabetes or Type 2 diabetes). To prevent new-onset hyperglycemia, optimize blood glucose, and recommend a low-carbohydrate (60-130 g/day) diet along with regular exercise to all patients prior to initiating the PI3Ki. Prophylactic metformin may be considered in all patients starting a PI3Ki with HbA1c ≤6.4%. Although existing recommendations support monitoring fasting blood glucose (FBG) once weekly (twice-weekly for intermediate-risk, daily for high-risk patients) and HbA1c every 3 months upon initiation of PI3Ki, more frequent FBG monitoring may be considered for prompt detection of hyperglycemia. Experts also recommend considering postprandial glucose monitoring because it is an early indicator of glucose intolerance. If hyperglycemia develops, metformin (first-line) and/or sodium glucose co-transporter 2 inhibitors or thiazolidinediones (second-/third-line) are the preferred agents; consider early referral to an endocrinologist. In conclusion, hyperglycemia is a common but manageable AE associated with PI3Kis. Multidisciplinary approach to the prevention, monitoring, and management of hyperglycemia optimizes patient care and allows patients to maintain therapy on PI3Ki.

Keywords: Alpelisib; Breast cancer; PI3K inhibition; PIK3CA; Prophylaxis.

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Conflict of interest statement

Disclosure H. N. Moore: Consulting or advisory roles with Novartis, Eli Lilly, Daiichi Sankyo, AstraZeneca, Pfizer, RACE Oncology, and Seattle Genetics; M. D. Goncalves: Consulting or advisory roles with Scorpion Therapeutics; stock or other ownership interests in Faeth Therapeutics; honoraria from Novartis, Pfizer, Scorpion Therapeutics, and BridgeBio; patents, royalties, and other intellectual property with Weill Cornell Medicine; A. M. Johnston: declarations of interest: none; E. L. Mayer: Consulting or advisory roles with AstraZeneca, Lilly, Novartis; H. S. Rugo: Institutional research funding from AstraZeneca, Daiichi Sankyo, Inc., F. Hoffmann-La Roche AG/Genentech, Inc., Gilead Sciences, Inc., Eli Lilly, Merck & Co., Inc., Novartis, Pfizer, Stemline Therapeutics, OBI Pharma, and Ambryx; Consultancy or advisory roles with Chugai, Puma, Sanofi, Mylan/Viatris, and NAPO; W. J. Gradishar: Consulting or advisory roles with AstraZeneca, Eli Lilly, Seattle Genetics, Gilead Sciences, Inc., and Daiichi Sankyo; D. M. Zylla: declarations of interest: none; R. M. Bergenstal: Research support and funding, consultant, or advisory board member for Abbott Diabetes Care and DexCom. Dr. Bergenstal's employer, nonprofit HealthPartners Institute, contracts for his services and he receives no personal income from these activities.

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