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Published on: November 10, 2017
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
Summary
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.
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