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CETP inhibition in cardiovascular risk management: a critical appraisal
R P F Dullaart1, G M Dallinga-Thie, B H R Wolffenbuttel
1University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. r.p.f.dullaart@int.umcg.nl
Insights
Targeting cholesteryl ester transfer protein (CETP) may raise high-density lipoprotein (HDL) cholesterol, potentially reducing cardiovascular risk, especially in patients with high triglycerides and low HDL, such as those with type 2 diabetes.
Area of Science:
- Cardiovascular Pharmacology
- Lipid Metabolism
- Atherosclerosis Research
Background:
- High-density lipoproteins (HDL) offer cardioprotection, but statins and fibrates have limited effects on HDL cholesterol.
- Cholesteryl ester transfer protein (CETP) lowers HDL cholesterol and promotes an atherogenic profile, particularly with high triglycerides.
- CETP activity correlates with coronary artery calcification, intima media thickness, and cardiovascular risk in hypertriglyceridemia.
Purpose of the Study:
- To investigate the clinical relevance of raising HDL cholesterol pharmacologically to reduce cardiovascular risk.
- To evaluate cholesteryl ester transfer protein (CETP) as a therapeutic target for cardiovascular disease.
- To explore the potential of CETP inhibitors in managing dyslipidemia, particularly in specific patient populations.
Main Methods:
- Review of clinical evidence linking CETP activity and concentration to cardiovascular risk markers.
- Analysis of data from clinical trials on CETP inhibitors (JTT-705, torcetrapib) regarding their effects on HDL cholesterol levels.
- Consideration of potential therapeutic strategies and indications for CETP inhibitors.
Main Results:
- CETP inhibitors JTT-705 and torcetrapib significantly increase HDL cholesterol (up to 34% and 91-106%, respectively).
- CETP may have anti-atherogenic potential by facilitating HDL-derived cholesteryl ester delivery to the liver and enhancing cholesterol removal.
- High CETP levels may be associated with lower cardiovascular risk when triglycerides are low.
Conclusions:
- Pharmacological targeting of CETP to raise HDL cholesterol presents a promising strategy for cardiovascular risk reduction.
- CETP inhibitors show significant efficacy in increasing HDL cholesterol, with ongoing trials evaluating clinical outcomes.
- Low HDL cholesterol combined with high triglycerides, common in type 2 diabetes, represents a key potential indication for CETP inhibitors.
Abstract:
In view of the cardioprotective effect of high-density lipoproteins (HDL) and the limited effects of statin and fibrate therapy on HDL cholesterol, it is clinically relevant to test whether pharmacological treatment aimed at raising HDL lowers cardiovascular risk. Cholesteryl ester transfer protein (CETP) is a new therapeutic target, because the cholesteryl ester transfer process lowers HDL cholesterol and contributes to an atherogenic lipoprotein profile, particularly when plasma triglycerides are high. Clinical evidence suggests that coronary artery calcification as well as intima media thickness is positively related to plasma cholesteryl ester transfer, and that high plasma CETP concentration is associated with increased cardiovascular risk in hypertriglyceridaemia. However, CETP could also have anti-atherogenic potential, since it provides a potentially beneficial route for delivery of HDL-derived cholesteryl esters to the liver. In addition, CETP could also favourably stimulate peripheral cell cholesterol removal and enhance hepatic cholesterol uptake. Recent evidence suggests that a high CETP level may confer lower cardiovascular risk in the context of low triglycerides. At maximal doses, the CETP inhibitors JTT-705 and torcetrapib elicit a marked rise in HDL cholesterol of up to 34% and 91-106%, respectively. The effectiveness of these drugs on (intermediate) clinical outcome measures is currently being tested in large-scale phase III clinical trials, with torcetrapib being only evaluated in combination therapy with atorvastatin. When and how to use CETP inhibitors, e.g. in combination with a statin or a fibrate, is a major challenge. We propose that low HDL cholesterol in the context of high triglycerides, such as found in type 2 diabetes mellitus, could become an important indication area for this new class of drugs.
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