Abstract P137: SGLT2 inhibition improves BYL719-induced hyperglycemia and hyperinsulinemia in rat pre-clinical models

Abstract

Background In phase III SOLAR-1 trial (NCT02437318), the PI3K alpha selective inhibitor alpelisib (ALP) + fulvestrant significantly improved progression-free survival vs. fulvestrant alone in patients with HR+/HER2- advanced breast cancer with PIK3CA mutations. Hyperglycemia is an on-target adverse effect of ALP that led to 6% of patient discontinuation in the ALP arm. Recently, Sodium-glucose co-transporter 2 (SGLT2) inhibition was reported to reduce PI3K inhibition-induced glucose and insulin increase. For 6 SOLAR-1 patients, the addition of an SGLT2 inhibitor to metformin (MET) and ALP stabilized blood glucose levels, allowing them to continue ALP treatment. Methods Brown Norway (BN) rat and Rat1-myr-p110α tumor bearing nude rat in vivo models were used to further investigate the degree of glucose and insulin control achievable upon treatment with ALP and a SGLT2 inhibitor dapagliflozin (DAPA) +/- MET and effects on ALP tolerability and efficacy. Results In both rat models tested, the addition of DAPA to ALP nearly suppressed ALP-induced hyperglycemia, was associated with insulin level reduction and insulin sensitivity improvement and no signs for ketoacidosis upon single agent (S.A) nor combination were observed under fed conditions. ALP S.A efficacy in the Rat1-myr-p110α tumor bearing nude rats was maintained when used in combination with DAPA and there was no influence of DAPA on ALP-induced body weight loss (BWL). In BN rats, when combining MET with ALP, a delay in blood glucose reduction was observed vs. DAPA + ALP combination. The triple combination of MET + DAPA + ALP improved further blood glucose levels reduction with the same kinetic as DAPA + ALP. MET + DAPA + ALP triple combination was more effective in reducing plasma insulin levels when compared to MET + ALP or DAPA + ALP double combinations. All combinations tested with MET slightly increased BYL719-induced BWL in BN rats. Conclusions SGLT2 inhibitors such as DAPA significantly reduced hyperglycemia and improved hyperinsulinemia induced by ALP in rat models without further BWL induced by ALP. These results warrant further clinical investigation of adding SGLT2 inhibitors +/- metformin to treat ALP-induced hyperglycemia. Citation Format: Christian R. Schnell, Daniel Wyss, Walter Tinetto, Thomas Ferrat, Jiaping Gao, Panza Darrell, Josh Gold, Valerie Beaulieu, John Diener, Christine Fritsch. SGLT2 inhibition improves BYL719-induced hyperglycemia and hyperinsulinemia in rat pre-clinical models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P137.

Sodium-Glucose Cotransporter-2 Inhibitors for Hyperglycemia in Phosphoinositide 3-kinase Pathway Inhibition

“…The glucose-lowering effectiveness for SGLT2 inhibition in this study is consistent with previous animal data, clinical case reports, and exploratory observational analyses [9,12,14,15]. This study's strengths relative to previous work are that it is hypothesis testing rather than exploratory, controlled for important confounders (particularly steroid use), and includes sensitivity analysis using an MSM.…”

“…Of alternative antidiabetic drug classes, sodium-glucose cotransporter-2 (SGLT2) inhibitors have received special attention. In animal models with cancer exposed to PI3K inhibitors, SGLT2 inhibitors reduced glucose and insulin levels more than metformin and intriguingly were also associated with reduced cancer progression [11][12][13]. In humans, several clinical case reports describe impressive glycemic responses to SGLT2 inhibitors in patients on alpelisib [3,14,15].…”

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

“…For example, SGLT2 inhibitors are a newer class of diabetic medications that inhibit renal glucose reabsorption. In preclinical studies, SGLT2 inhibitors successfully suppress PI3K inhibitor‐induced hyperglycemia 10,26 . Clinically, several case reports have highlighted success in managing alpelisib‐associated hyperglycemia with SGLT2 inhibitors; use of these agents is associated with greater reductions in serum glucose levels compared with metformin 27–29 .…”

“…inhibitors successfully suppress PI3K inhibitor-induced hyperglycemia. 10,26 Clinically, several case reports have highlighted success in managing alpelisib-associated hyperglycemia with SGLT2 inhibitors; use of these agents is associated with greater reductions in serum glucose levels compared with metformin. [27][28][29] Dietary strategies may also be successful adjuncts to reducing hyperglycemia and may even contribute antitumor effects.…”