INS and Hyperglycemia: Hyperglycemia occurs early in the course of treatment (median time of onset about 2 weeks from initiation of alpelisib therapy [17]) because inhibition of PI3K-α blocks the metabolic actions of insulin, preventing glucose uptake in skeletal muscle and adipose tissue and promoting hepatic glycogenolysis, which results in increased blood glucose levels and a compensatory release of insulin (Figure 1) [6,24,25,26,27].