Single Dose of Phosphatidylinositol 3-Kinase Inhibitor Alpelisib Induces Insulin Resistance in Healthy Adults: A Randomized Feasibility Study.

Our objective was to test a single dose of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib as a tool for acute modeling of insulin resistance in healthy volunteers. This single-center double-blind phase 1 clinical trial randomly assigned healthy adults to a single oral dose of 300 mg alpelisib (n = 5) or placebo (n = 6) at bedtime, followed by measurement of glucose, insulin, and C-peptide levels after an overnight fast and during a 3-h 75-g oral glucose tolerance test (OGTT). Fasting plasma glucose trended higher with alpelisib (mean ± SD 93 ± 11 mg/dL) versus placebo (84 ± 5 mg/dL); mean fasting serum insulin increased nearly fivefold (23 ± 12 vs. 5 ± 3 μU/mL, respectively), and HOMA of insulin resistance (IR) scores were 5.4 ± 3.1 for alpelisib and 1.1 ± 0.6 for placebo. During OGTT, incremental area under the curve (AUC) for insulin was more than fourfold greater with alpelisib (22 ± 15 mU/mL × min) than with placebo (5 ± 2 mU/mL × min); glucose AUC trended higher with alpelisib. Single-dose alpelisib was well tolerated and produced metabolic alterations consistent with acute induction of IR, validating its use for mechanistic study of insulin action in humans.