A Single Dose of Phosphoinositide-3-kinase Inhibitor Alpelisib Induces Insulin Resistance in Healthy Adults: A Randomized Feasibility Study

Our objective is to test a single dose of the phosphoinositide-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 randomized healthy adults to take a single oral dose of alpelisib 300 mg (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-hour, 75-g oral glucose tolerance test. Fasting plasma glucose trended higher with alpelisib (mean ± S.D.: 93 ± 11 mg/dL) versus placebo (84 ± 5 mg/dL), while mean fasting serum insulin increased nearly fivefold (23 ± 12 µU/mL vs. 5 ± 3 µU/mL, respectively) and Homeostasis Model Assessment of Insulin Resistance scored 5.4 ± 3.1 for alpelisib and 1.1 ± 0.6 for placebo. During OGTT, incremental area under the curve (AUC) for insulin was over fourfold greater with alpelisib (22 ± 15 mU/mL x min) than placebo (5 ± 2 mU/mL x 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. (ClinicalTrials.gov registration: NCT05733455)