Sodium-glucose cotransporter-2 (SGLT-2) inhibitors for alpelisib (ALP)-induced hyperglycemia: a report of 6 cases from SOLAR-1

Abstract

Background: In the phase III SOLAR‐1 trial (NCT02437318), ALP (PI3Kα inhibitor) + fulvestrant (FUL) significantly improved progression‐free survival vs. FUL alone in patients (pts) with HR+/HER2− advanced breast cancer with PIK3CA mutations. Hyperglycemia was identified as an on‐target adverse event of ALP. ADA guidelines recommend concomitant treatment with initial metformin as well as insulin sensitizers and DPP‐4 inhibitors. SGLT‐2 inhibitors have emerged as hypoglycemic agents, reducing glucose renal reabsorption to facilitate its excretion. Here we present a case report on the use of SGLT‐2 inhibitors for the management of ALP‐induced hyperglycemia in SOLAR‐1. Methods: Hyperglycemia was assessed at baseline and over time using fasting plasma glucose and glycated haemoglobin. Results: In SOLAR‐1, 284 pts were randomized to ALP + FUL, median duration of ALP exposure was 5.5 months, and 190 pts (67%) developed hyperglycemia as of 30 Sept 2019, with 18 pts (6%) discontinuing ALP treatment due to hyperglycemia. A total of 166 pts received concomitant hypoglycemic medications, mainly metformin (87%). In addition to metformin, 6 pts received an SGLT‐2 inhibitor, consisting of empagliflozin, ipragliflozin, and dapagliflozin. All 6 pts had ≥ 1 risk factor at baseline for developing hyperglycemia: prediabetes (n = 4; 1 with history of type 2 diabetes), diabetes (n = 2), and obesity (n = 2). The most severe hyperglycemia in these pts was grade (G) 3 (n = 5). After initiating an SGLT‐2 inhibitor, all subsequent hyperglycemia events were G 1/2, except one G 3 event with steroids as a confounding factor. Duration of ALP ranged from 9.5 to 27.7 months in pts who discontinued; 2 pts were continuing to receive ALP after 37.0 and 40.0 months, respectively. None of the 6 pts discontinued ALP due to hyperglycemia. Conclusions: In 166 pts treated for ALP‐related hyperglycemia, 87% received metformin‐based concomitant hypoglycemic medications. In 6 pts, addition of an SGLT‐2 inhibitor stabilized blood glucose level, allowing them to continue ALP treatment. These results warrant further investigation of using SGLT‐2 inhibitors for ALP‐induced hyperglycemia in a larger sample size study.