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

Abstract

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.

Figure 1

Elements of study design. A: Schematic representation of study procedures. B: Flow diagram indicating census of volunteers reaching each stage of study screening process and completion. C: Plasma alpelisib level 10 h after dosing by gas chromatography–mass spectrometry. White circles represent placebo arm, and black circles represent alpelisib arm; black square denotes alpelisib arm participant whose plasma alpelisib level was undetectable.

Figure 2

Blood tests drawn at 09:00 after overnight fast, 10 h after investigational agent ingestion at 23:00. A: Fasting plasma glucose. B: Fasting serum insulin level. C: Fasting serum C-peptide level. D: HOMA-IR score. White circles represent placebo, and black circles represent alpelisib; single black square represents data from alpelisib arm participant whose plasma alpelisib level was undetectable.

Figure 3

All participants underwent 3-h 75-g OGTT beginning at 09:00. Blood samples were taken at t = 0 (baseline) and 15, 30, 60, 90, 120, 150, and 180 min. A–F: Plasma glucose (A and B), serum insulin (C and D), and serum C-peptide (E and F) are each represented by mean ± SD at each individual time point (A, C, E) and as individual values superimposed on mean ± S.D. of incremental AUC for each metric (B, D, F). G: Matsuda index calculated based on glucose and insulin values at each time point. White circles represent placebo group, and black circles represent alpelisib group; black square (B, D, F, G) represents data from alpelisib arm participant whose plasma alpelisib level was undetectable.