TY - JOUR
T1 - SGLT2 inhibition improves PI3Kα inhibitor–induced hyperglycemia
T2 - findings from preclinical animal models and from patients in the BYLieve and SOLAR-1 trials
AU - Borrego, Manuel Ruiz
AU - Lu, Yen Shen
AU - Reyes-Cosmelli, Felipe
AU - Park, Yeon Hee
AU - Yamashita, Toshinari
AU - Chiu, Joanne
AU - Airoldi, Mario
AU - Turner, Nicholas
AU - Fein, Luis
AU - Ghaznawi, Farhat
AU - Singh, Jyotika
AU - Pantoja, Kristyn
AU - Schnell, Christian
AU - Akdere, Murat
AU - Chia, Stephen
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/11
Y1 - 2024/11
N2 - Purpose: Alpelisib plus fulvestrant demonstrated a significant progression-free survival benefit versus fulvestrant in patients with PIK3CA-mutated HR+ /HER2− advanced breast cancer (ABC) (SOLAR-1). Hyperglycemia, an on-target adverse effect of PI3Kα inhibition, can lead to dose modifications, potentially impacting alpelisib efficacy. We report data from preclinical models and two clinical trials (SOLAR-1 and BYLieve) on Sodium glucose cotransporter 2 inhibitor (SGLT2i) use to improve PI3Kα inhibitor–associated hyperglycemia. Methods: Healthy Brown Norway (BN), mild diabetic Zucker diabetic fatty (ZDF), and Rat1-myr-p110α/HBRX3077 tumor–bearing nude rats treated with alpelisib were analyzed for glucose and insulin control with metformin and dapagliflozin (SGLT2i) and alpelisib efficacy. Hyperglycemia adverse events (AEs) were compared between patients receiving SGLT2i with alpelisib (n = 19) and a propensity score–matched cohort not receiving SGLT2i (n = 74) in both trials. Results: Dapagliflozin and metformin in BN and ZDF rats treated with alpelisib normalized blood glucose and reduced insulin levels. No signs of ketosis or drug-drug interaction were observed when metformin and dapagliflozin was administered with alpelisib. Alpelisib antitumor efficacy was maintained when used with dapagliflozin in tumor-bearing rats. Compared with a matched set of patients without SGLT2i, patients receiving SGLT2i had 4.9 and 6.4 times lower rates of grade ≥ 3 hyperglycemia AEs and hyperglycemia AEs resulting in alpelisib dose adjustments, interruptions, or withdrawals, respectively, and a relative reduction in risk of experiencing these AEs (70.6% and 35.7%). Conclusion: These data suggest adding an SGLT2i can effectively manage hyperglycemia, resulting in fewer alpelisib dose modifications and discontinuations in patients with PIK3CA-mutated HR+ /HER2− ABC (SOLAR-1: NCT02437318; BYLieve: NCT03056755).
AB - Purpose: Alpelisib plus fulvestrant demonstrated a significant progression-free survival benefit versus fulvestrant in patients with PIK3CA-mutated HR+ /HER2− advanced breast cancer (ABC) (SOLAR-1). Hyperglycemia, an on-target adverse effect of PI3Kα inhibition, can lead to dose modifications, potentially impacting alpelisib efficacy. We report data from preclinical models and two clinical trials (SOLAR-1 and BYLieve) on Sodium glucose cotransporter 2 inhibitor (SGLT2i) use to improve PI3Kα inhibitor–associated hyperglycemia. Methods: Healthy Brown Norway (BN), mild diabetic Zucker diabetic fatty (ZDF), and Rat1-myr-p110α/HBRX3077 tumor–bearing nude rats treated with alpelisib were analyzed for glucose and insulin control with metformin and dapagliflozin (SGLT2i) and alpelisib efficacy. Hyperglycemia adverse events (AEs) were compared between patients receiving SGLT2i with alpelisib (n = 19) and a propensity score–matched cohort not receiving SGLT2i (n = 74) in both trials. Results: Dapagliflozin and metformin in BN and ZDF rats treated with alpelisib normalized blood glucose and reduced insulin levels. No signs of ketosis or drug-drug interaction were observed when metformin and dapagliflozin was administered with alpelisib. Alpelisib antitumor efficacy was maintained when used with dapagliflozin in tumor-bearing rats. Compared with a matched set of patients without SGLT2i, patients receiving SGLT2i had 4.9 and 6.4 times lower rates of grade ≥ 3 hyperglycemia AEs and hyperglycemia AEs resulting in alpelisib dose adjustments, interruptions, or withdrawals, respectively, and a relative reduction in risk of experiencing these AEs (70.6% and 35.7%). Conclusion: These data suggest adding an SGLT2i can effectively manage hyperglycemia, resulting in fewer alpelisib dose modifications and discontinuations in patients with PIK3CA-mutated HR+ /HER2− ABC (SOLAR-1: NCT02437318; BYLieve: NCT03056755).
KW - Advanced breast cancer
KW - Alpelisib
KW - HR + /HER2 −
KW - Hyperglycemia
KW - SGLT2 inhibitor
UR - https://www.scopus.com/pages/publications/85201949390
U2 - 10.1007/s10549-024-07405-8
DO - 10.1007/s10549-024-07405-8
M3 - Article
C2 - 39177931
AN - SCOPUS:85201949390
SN - 0167-6806
VL - 208
SP - 111
EP - 121
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 1
ER -
