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Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene

Reecha Sofat1, Aroon D Hingorani, Liam Smeeth

  • 1Centre for Clinical Pharmacology, Department of Medicine, University College London, London, United Kingdom.

Circulation
|December 23, 2009
PubMed

Insights

Cholesteryl ester transfer protein (CETP) inhibitors affect HDL cholesterol, but torcetrapib caused high blood pressure. Genetic analysis revealed torcetrapib

Area of Science:

  • Pharmacogenomics
  • Cardiovascular Medicine
  • Lipid Metabolism

Background:

  • Cholesteryl ester transfer protein (CETP) inhibitors increase HDL cholesterol.
  • Torcetrapib, a CETP inhibitor, unexpectedly raised blood pressure and cardiovascular events.
  • The cause of torcetrapib's hypertensive effect (CETP inhibition vs. off-target action) was debated.

Purpose of the Study:

  • To determine if CETP gene single-nucleotide polymorphisms (SNPs) could differentiate mechanism-based from off-target effects of CETP inhibitors.
  • To validate CETP as a therapeutic target by analyzing genetic versus drug effects.

Main Methods:

  • Compared effects of CETP SNPs and torcetrapib on lipids, blood pressure, and electrolytes.
  • Utilized data from genetic studies (67,687 individuals) and randomized trials (17,911 participants).
  • Analyzed lipid fractions, blood pressure, and electrolyte changes in relation to CETP activity.

Main Results:

  • Both CETP SNPs and torcetrapib reduced CETP activity and consistently affected 8 lipid traits, including HDL cholesterol.
  • Torcetrapib (60 mg) significantly elevated systolic (4.47 mm Hg) and diastolic (2.08 mm Hg) blood pressure.
  • CETP SNPs had a null effect on blood pressure (systolic: 0.16 mm Hg, diastolic: -0.04 mm Hg), differing significantly from torcetrapib's impact.

Conclusions:

  • The discordance in blood pressure effects between CETP SNPs and torcetrapib suggests torcetrapib's hypertension is not due to CETP inhibition.
  • Torcetrapib's hypertensive action is unlikely to be shared by other CETP inhibitors.
  • Genetic studies offer a valuable tool for drug development, providing randomized evidence for drug-target validation in humans.
Abstract

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