Cholesteryl ester transfer protein (CETP) inhibition and high-density lipoprotein particle composition: consequences for atherogenesis and neurodegeneration
Abstract
Cholesteryl ester transfer protein (CETP), required for transferring triglyceride from very-low-density lipoprotein in exchange for cholesteryl ester from high-density lipoprotein (HDL), is also involved in lipophilic antioxidant exchange. We aimed to determine the effects of the next generation potent CETP inhibitor, obicetrapib, on concentrations and plasma distributions of lipophilic antioxidants, apolipoproteins (apo), and sphingosine-1-phosphate (S1P) in an 8-week, Phase 2 trial of placebo and 2.5, 5, and 10 mg/d obicetrapib in Japanese participants (n = 12 per group). Obicetrapib robustly increased all antioxidant levels in the HDL fraction and decreased plasma levels of oxidized low-density lipoprotein. In specific analyses of the low-dose group, obicetrapib also raised HDL2 cholesterol, apoA1, S1P, apoM, and apoE. Increased levels of monomeric-apoA1 were found in the HDL2 and HDL3 fractions and these correlated with apoM and S1P. Furthermore, we analyzed the relationship between plasma and cerebrospinal fluid (CSF) lipophilic antioxidants in a proof-of-concept study of obicetrapib 10 mg/d in early Alzheimer’s disease patients (n = 13) and demonstrated that HDL2 and CSF carotenoid and tocopherol levels were increased by obicetrapib. These results offer a first insight into the mechanism of action for obicetrapib in terms of HDL metabolism and function, with implications for both atherogenesis and neurodegeneration.
Related
- Reinforcement learning–coupled neural ode modelling reveals ferroptotic resolution failure as a shared dynamical axis linking periodontitis and coronary atherogenesis
- Comparative biomarker efficacy of cholesteryl ester transfer protein inhibitors: a network meta-analysis
- Coronary microvascular disease as potential mechanism of coronary epicardial atherogenesis: an overview of current evidence
- A novel mouse model of cholesteryl ester storage disorder with Lipa exon 8 splicing junction mutation
- Phospholipids that Plug the Pores of Cholesteryl Ester Transfer Protein Control Its Triglyceride Transfer
BibTeX
@article{niesor2026cholesteryl,
title = {{Cholesteryl ester transfer protein (CETP) inhibition and high-density lipoprotein particle composition: consequences for atherogenesis and neurodegeneration}},
author = {Eric J. Niesor and Marc Ditmarsch and Serge Rezzi and Andrew Hodgson and Pablo Haenggi and Mary R. Dicklin and Andrew Hsieh and Mathijs A. C. de Kleer and Philip Scheltens and Everard Vijverberg and Michael Szarek and Michael H. Davidson and John J. P. Kastelein},
journal = {Scientific Reports},
year = {2026},
month = oct,
doi = {10.1038/s41598-026-73480-0},
url = {https://www.nature.com/articles/s41598-026-73480-0},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cholesteryl ester transfer protein (CETP) inhibition and high-density lipoprotein particle composition: consequences for atherogenesis and neurodegeneration
AU - Eric J. Niesor
AU - Marc Ditmarsch
AU - Serge Rezzi
AU - Andrew Hodgson
AU - Pablo Haenggi
AU - Mary R. Dicklin
AU - Andrew Hsieh
AU - Mathijs A. C. de Kleer
AU - Philip Scheltens
AU - Everard Vijverberg
AU - Michael Szarek
AU - Michael H. Davidson
AU - John J. P. Kastelein
PY - 2026
DA - 2026/10/16
JO - Scientific Reports
DO - 10.1038/s41598-026-73480-0
UR - https://www.nature.com/articles/s41598-026-73480-0
AB - Cholesteryl ester transfer protein (CETP), required for transferring triglyceride from very-low-density lipoprotein in exchange for cholesteryl ester from high-density lipoprotein (HDL), is also involved in lipophilic antioxidant exchange. We aimed to determine the effects of the next generation potent CETP inhibitor, obicetrapib, on concentrations and plasma distributions of lipophilic antioxidants, apolipoproteins (apo), and sphingosine-1-phosphate (S1P) in an 8-week, Phase 2 trial of placebo and 2.5, 5, and 10 mg/d obicetrapib in Japanese participants (n = 12 per group). Obicetrapib robustly increased all antioxidant levels in the HDL fraction and decreased plasma levels of oxidized low-density lipoprotein. In specific analyses of the low-dose group, obicetrapib also raised HDL2 cholesterol, apoA1, S1P, apoM, and apoE. Increased levels of monomeric-apoA1 were found in the HDL2 and HDL3 fractions and these correlated with apoM and S1P. Furthermore, we analyzed the relationship between plasma and cerebrospinal fluid (CSF) lipophilic antioxidants in a proof-of-concept study of obicetrapib 10 mg/d in early Alzheimer’s disease patients (n = 13) and demonstrated that HDL2 and CSF carotenoid and tocopherol levels were increased by obicetrapib. These results offer a first insight into the mechanism of action for obicetrapib in terms of HDL metabolism and function, with implications for both atherogenesis and neurodegeneration.
SN - 2045-2322
ER -