SGLT2 inhibition improves PI3Kα inhibitor-induced hyperglycemia: findings from preclinical animal models and from patients in the BYLieve and SOLAR-1 trials.

IF 3 3区医学 Q2 ONCOLOGY Breast Cancer Research and Treatment Pub Date : 2024-11-01 Epub Date: 2024-08-23 DOI:10.1007/s10549-024-07405-8

Manuel Ruiz Borrego, Yen-Shen Lu, Felipe Reyes-Cosmelli, Yeon Hee Park, Toshinari Yamashita, Joanne Chiu, Mario Airoldi, Nicholas Turner, Luis Fein, Farhat Ghaznawi, Jyotika Singh, Kristyn Pantoja, Christian Schnell, Murat Akdere, Stephen Chia

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Abstract

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).

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SGLT2 抑制可改善 PI3Kα 抑制剂诱发的高血糖：临床前动物模型以及 BYLieve 和 SOLAR-1 试验中患者的研究结果。

目的：在PIK3CA突变的HR+ /HER2-晚期乳腺癌（ABC）（SOLAR-1）患者中，阿培利西布联合氟维司群与氟维司群相比具有显著的无进展生存期获益。高血糖是PI3Kα抑制的靶向不良反应，可导致剂量调整，从而可能影响alpelisib的疗效。我们报告了临床前模型和两项临床试验（SOLAR-1 和 BYLieve）中关于使用葡萄糖钠共转运体 2 抑制剂（SGLT2i）改善 PI3Kα 抑制剂相关高血糖的数据。方法：用二甲双胍和达帕利曲嗪（SGLT2i）以及阿来替尼的疗效分析健康棕色挪威鼠（BN）、轻度糖尿病扎克糖尿病脂肪鼠（ZDF）和接受阿来替尼治疗的Rat1-myr-p110α/HBRX3077肿瘤裸鼠的血糖和胰岛素控制情况。在这两项试验中，比较了接受SGLT2i与阿来替尼治疗的患者（n = 19）与未接受SGLT2i治疗的倾向得分匹配队列（n = 74）之间的高血糖不良事件（AEs）：结果：用达帕格列净和二甲双胍治疗BN和ZDF大鼠后，阿来替尼能使血糖恢复正常并降低胰岛素水平。二甲双胍和达帕格列净与阿来替尼同时使用时，未观察到酮症或药物相互作用的迹象。在肿瘤大鼠体内与达帕利洛嗪同时使用时，阿来替尼的抗肿瘤疗效得以保持。与未使用SGLT2i的匹配患者相比，接受SGLT2i治疗的患者发生≥3级高血糖AEs和导致阿来替尼剂量调整、中断或停药的高血糖AEs的比例分别降低了4.9倍和6.4倍，发生这些AEs的风险也相对降低了（70.6%和35.7%）：这些数据表明，添加 SGLT2i 可以有效控制高血糖，从而减少 PIK3CA 突变 HR+ /HER2- ABC 患者阿来利昔剂量调整和停药的次数（SOLAR-1：NCT02437318；BYLieve：NCT03056755）。

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来源期刊

Breast Cancer Research and Treatment 医学-肿瘤学

CiteScore

6.80

自引率

2.60%

发文量

342

审稿时长

1 months

期刊介绍： Breast Cancer Research and Treatment provides the surgeon, radiotherapist, medical oncologist, endocrinologist, epidemiologist, immunologist or cell biologist investigating problems in breast cancer a single forum for communication. The journal creates a "market place" for breast cancer topics which cuts across all the usual lines of disciplines, providing a site for presenting pertinent investigations, and for discussing critical questions relevant to the entire field. It seeks to develop a new focus and new perspectives for all those concerned with breast cancer.