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Purpose of Review <p>Cholesteryl ester transfer protein (CETP) inhibitors are a promising class of drugs aimed at managing dyslipidemia by modulating lipoprotein levels, particularly low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), to mitigate cardiovascular (CV) risk. The main aim of this narrative review is to discuss the future of CETP inhibition.</p> Recent Findings <p>Previous CETP inhibitors (namely, torcetrapib, dalcetrapib, anacetrapib and evacetrapib) failed to be commercialized due to toxic adverse events and negative CV effects (torcetrapib), neutral impact on CV outcomes (dalcetrapib and evacetrapib) and lack of effectiveness together with concerns on long half-life and accumulation in the fat (anacetrapib). Obicetrapib, a novel, oral, once-daily CETP inhibitor, has demonstrated significant efficacy in reducing LDL-C, non-HDL-C, apolipoprotein B (apoB) and lipoprotein (a) [Lp(a)] levels, while increasing HDL-C and apoA-1 levels. Clinical studies have shown its effectiveness both as monotherapy and in combination with statins ± ezetimibe, indicating enhanced lipid-altering efficacy and safety. Advances in computational modeling, such as QSAR models and molecular docking, have furthered the development of CETP inhibitors by predicting and enhancing their efficacy and selectivity. MK-8262 has shown some promise as a novel CETP inhibitor, but additional studies are indicated.</p> Summary <p> This narrative review highlights the potential of obicetrapib in achieving lipid goals and better CV outcomes in various patient populations. The future of CETP inhibitors hinges on addressing past limitations, focusing on improving selectivity, exploring combination therapies, and employing personalized medicine approaches to maximize benefits while minimizing adverse effects. Furthermore, long-term safety studies, demonstrating cost-effectiveness, are crucial for regulatory approval and market acceptance. Such clinical trials are on-going with obicetrapib and their results, when available, will further elucidate its clinical implications/indications.</p> Graphical Abstract <p></p>

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Cholesteryl Ester Transfer Protein Inhibitors: State of the Science

  • 期刊论文

  • 发表日期：

    2026年1月6日

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  • Mojgan Nejabat,
  • Niki Katsiki,
  • Debabrata Mukherjee,
  • Farzin Hadizadeh,
  • Amirhossein Sahebkar

摘要

Purpose of Review

Cholesteryl ester transfer protein (CETP) inhibitors are a promising class of drugs aimed at managing dyslipidemia by modulating lipoprotein levels, particularly low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), to mitigate cardiovascular (CV) risk. The main aim of this narrative review is to discuss the future of CETP inhibition.

Recent Findings

Previous CETP inhibitors (namely, torcetrapib, dalcetrapib, anacetrapib and evacetrapib) failed to be commercialized due to toxic adverse events and negative CV effects (torcetrapib), neutral impact on CV outcomes (dalcetrapib and evacetrapib) and lack of effectiveness together with concerns on long half-life and accumulation in the fat (anacetrapib). Obicetrapib, a novel, oral, once-daily CETP inhibitor, has demonstrated significant efficacy in reducing LDL-C, non-HDL-C, apolipoprotein B (apoB) and lipoprotein (a) [Lp(a)] levels, while increasing HDL-C and apoA-1 levels. Clinical studies have shown its effectiveness both as monotherapy and in combination with statins ± ezetimibe, indicating enhanced lipid-altering efficacy and safety. Advances in computational modeling, such as QSAR models and molecular docking, have furthered the development of CETP inhibitors by predicting and enhancing their efficacy and selectivity. MK-8262 has shown some promise as a novel CETP inhibitor, but additional studies are indicated.

Summary

This narrative review highlights the potential of obicetrapib in achieving lipid goals and better CV outcomes in various patient populations. The future of CETP inhibitors hinges on addressing past limitations, focusing on improving selectivity, exploring combination therapies, and employing personalized medicine approaches to maximize benefits while minimizing adverse effects. Furthermore, long-term safety studies, demonstrating cost-effectiveness, are crucial for regulatory approval and market acceptance. Such clinical trials are on-going with obicetrapib and their results, when available, will further elucidate its clinical implications/indications.

Graphical Abstract