What is CETP?
Cholesteryl ester transfer protein (CETP) is a glycoprotein that is secreted mainly by the liver. CETP circulates in the plasma bound to lipoproteins, mainly high-density lipoproteins (HDL).
What does CETP do?
CETP promotes the re-distribution of cholesteryl esters (CE, the main form of cholesterol in the plasma), triglycerides (TG) and phospholipids between plasma lipoproteins. The net effect of CETP is to promote transfer of CE between HDL and TG-rich lipoproteins (also referred to as very-low density lipoproteins, VLDL).
What role does CETP play in lipid transport?
CETP is a key player in the transport of cholesterol. Lipids are transported in the plasma via two different pathways.
Exogenous pathway
This pathway is involved in the transport of TG from food to body tissues as a source of energy or for storage in adipose tissue. In addition, cholesterol in the food is also taken up by intestinal cells, converted to CE and then incorporated into chylomicrons.
The chylomicrons are secreted from intestinal cells and transported to the blood stream. In the plasma, TG in the chylomicrons are broken down by lipoprotein lipase releasing free fatty acids (FFA) for use in energy production or for storage in the fat cells as TG.
CETP has a role in the transfer of TG in the chylomicrons to HDL in exchange for CE. This leads to the formation of chylomicron remnants, which are normally rapidly cleared from the plasma.
Endogenous pathway
This pathway is involved in the transfer of hepatic fat to other tissues as a source of energy or for storage in adipose tissue.
TG and CE are incorporated into VLDL in the liver and then secreted into the blood. The action of both lipoprotein lipase, which hydrolyses TG in these VLDL, and CETP, which transfers additional CE from HDL to VLDL, leads to the formation of LDL. Binding of LDL to cells that are depleted of cholesterol delivers LDL where it is needed for biological processes such as membrane synthesis.
Further reading
Barter P, Rye K-A. CETP inhibition – where now? A handbook for clinicians. Sherborne Gibbs Ltd, 2007.
How does CETP influence HDL?
Role of CETP in reverse cholesterol transport
CETP is involved in transporting CE in HDL from extra-hepatic tissues to the liver, either for elimination from the body in the bile or for re-incorporation into VLDL. This process is known as reverse cholesterol transport. The steps involved include:
- A: Transfer of unesterified cholesterol in cell membranes to acceptors in the extracellular space, where it is incorporated into HDL. There are at least 4 distinct pathways involving the ATP-binding cell membrane transporters ABCA1 or ABCG1, the HDL receptor SR-B1 (scavenger receptor B-1) or passive diffusion (see Figure).
Pathway 1:
Unesterified cholesterol is delivered directly to the liver by a process involving hepatic SR-B1. In humans, this pathway accounts for most of the cholesterol transported from the plasma to the liver.
Pathway 2:
Unesterified cholesterol is converted to CE in HDL by the enzyme LCAT (lecithin:cholesterol acyltransferase). These CE are then delivered directly to the liver via SR-B1.
Pathways 3 and 4:
CETP is involved in the transfer of CE from HDL to the VLDL/LDL fraction. CE in the VLDL/LDL fraction is then taken up by the liver after binding of LDL to LDL receptors in the liver. In humans, a proportion of CE in HDL is transferred by this pathway.
Role of CETP in HDL remodelling
CETP is also important in the remodelling of HDL particles, transferring CE from HDL to TG-rich lipoprotein in exchange for TG that is transferred to HDL. This leads to the formation of HDL particles that are depleted of CE and enriched in TG. These particles are the preferred substrate for hepatic lipase, which hydrolyses the TG in these HDL, leading to the formation of small, dense HDL particles (see Figure).
However, the implications of the remodelling of HDL by CETP are currently not understood.
CETP also has a role in the remodelling of LDL and TG-rich lipoproteins. In the case of LDL, the combined activity of hepatic lipase and CETP leads to remodelling of the LDL particles, in a similar way to that for HDL (see above). This results in the formation of small, dense LDL particles. In the case of TG-rich lipoproteins, the action of CETP increases the CE content of these particles, making them more atherogenic.
Further reading
Barter P, Rye K-A. CETP inhibition – where now? A handbook for clinicians. Sherborne Gibbs Ltd, 2007.
What are the implications of CETP inhibition?
Inhibition of CETP has the potential to slow or prevent the development of atherosclerosis, by increasing the plasma concentration of HDL and reducing the cholesterol content of the pro-atherogenic VLDL/LDL fraction.
Increasing plasma levels of HDL may be protective by enhancing the efflux of cholesterol from the artery wall to HDL in the extracellular space via reverse cholesterol transport (see above). In addition, increasing the level of HDL may increase the capacity of additional potentially anti-atherogenic properties of HDL (see Table).
Table. Potential anti-atherogenic properties of HDL
- Anti-oxidant properties
- Anti-inflammatory properties
- Anti-thrombotic properties
- Enhancement of endothelial function
- Enhancement of endothelial repair
What is the evidence to support this approach?
Evidence from animal studies
Animal studies suggest that CETP inhibition is associated with reduction in atherosclerosis, mainly due to the associated substantial increase in HDL cholesterol levels.
The rabbit is a species that has a high level of CETP activity and is very susceptible to atherosclerosis.
Studies using rabbit models have shown that inhibiting CETP leads to a marked reduction in atherosclerosis. In one study, administration of torcetrapib, a CETP inhibitor, to cholesterol-fed rabbits led to a substantial increase in HDL cholesterol (by at least three-fold normal levels), little change in non-HDL cholesterol (total cholesterol – HDL cholesterol), and substantial reduction (by 60%) in atheroma
Further reading
Morehouse LA, Sugarman ED, Bourassa PA et al. Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits. J Lipid Res 2007;48:1263-72.
Barter P, Rye K-A. CETP inhibition – where now? A handbook for clinicians. Sherborne Gibbs Ltd, 2007.
Evidence from human studies
There is also considerable data that genetic deficiency and genetic variants of CETP that lead to lower CETP activity, are also associated with elevated HDL cholesterol levels and, potentially, with protection against premature coronary heart disease (CHD).
The Taq1B polymorphism is probably the most studied CETP genetic variant. This is controlled by the alleles B1 and B2. Several studies have reported that individuals who were homozygous for the B1 allele (B1B1) had higher levels of CETP and lower levels of HDL cholesterol than individuals who were either heterozygous (B1B2) or homozygous for the B2 allele (B2B2). The association of the Taq1B polymorphism, HDL cholesterol and CHD risk was confirmed by a meta-analysis involving nearly 14,000 patients.
Conversely, men with the B2 allele had increased levels of HDL cholesterol, decreased CETP activity and also had a reduced risk of CHD.
Further reading
Curb JD, Abbott RD, Rodriguez Bl et al. A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly. J Lipid Res 2004;45:948-53.
Moriyama Y, Okamura T, Inazu A et al A low prevalence of coronary heart disease among subjects with increased high-density lipoprotein cholesterol levels, including those with plasma cholesteryl ester transfer protein deficiency. Prev Med 1998; 27:659-67.
Corella D, Saiz C, Guillen M et al. Association of TaqIB polymorphism in the cholesteryl ester transfer protein gene with plasma lipid levels in a healthy Spanish population. Atheroscolerosis 2000;152:367-76.
Brousseau ME, C-Connor JJ Jr, Ordovas JM et al. Cholesteryl ester transfer protein TaqI B2B2 genotype is associated with higher HDL cholesterol levels and lower risk of coronary heart disease end points in men with HDL deficiency: Veterans Affairs HDL Cholesterol Intervention Trial. Arterioscler Thromb Vasc Biol 2002;22:1148-54.
Boekholdt SM, Sacks FM, Jukema JW et al. Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-analysis of 13,677 subjects. Circulation 2005;111:278-87.
Klerkx AH, de Grooth GJ, Zwinderman AH et al Cholesteryl ester transfer protein concentration is associated with progression of atherosclerosis and response to pravastatin in men with coronary artery disease (REGRESS). Eur J Clin Invest 2004;34:21-8.
What are the therapeutic implications of CETP inhibition?
Taken together, evidence from animal and human studies supports the hypothesis that inhibition of CETP in humans has the potential to be anti-atherogenic. These data provide a strong rationale for the development of CETP inhibitors to prevent atherosclerosis in man.
What have clinical studies shown?
Effects on plasma lipoproteins
Clinical studies with developmental CETP inhibitors, most notably torcetrapib, have shown predictable effects on plasma lipoproteins (see Table).
Table. Effects of CETP inhibition with torcetrapib on HDL cholesterol
| Patient population | Dose | Changes in lipoproteins |
| Low HDL-C (<40 mg/dL) | 60 mg twice daily | |
| + atorvastatin | ↑ 61% HDL-C | |
| - atorvastatin | ↑ 46% HDL-C | |
| Below average HDL-C | 60 mg daily | ↑ 40-50% HDL-C |
| (<44 mg/dL in men and <54 mg/dL in women) | (± atorvastatin) | ↓ 15% LDL-C |
Effects on atherosclerosis and clinical outcomes
To date, the only studies that have investigated the effects of CETP inhibition on atherosclerosis and cardiovascular events have been with torcetrapib.
However, the torcetrapib development programme was terminated in December 2006. A pre-planned safety analysis of the ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact on Atherosclerotic Events) trial showed that there was an excess of deaths in patients taking torcetrapib (in addition to atorvastatin) compared with atorvastatin monotherapy. The explanation for this excess mortality is not yet known.
In addition, 3 imaging trials (ILLUSTRATE, RADIANCE 1 and RADIANCE 2) (see Table) have investigated the effect on torcetrapib on atheroslerosis. All were double-blind, randomized multicentre studies. In ILLUSTRATE, patients had clinical evidence of CHD confirmed by cardiac catheterization, and the percent change in atheroma from baseline was assessed using intravascular ultrasound. RADIANCE 1 enrolled patients with heterozygous familial hypercholesterolaemia and RADIANCE 2 enrolled patients with mixed dyslipidaemia. Both RADIANCE 1 and 2 measured the change in carotid intima-media thickness (CIMT) over time, a surrogate measure of atherosclerosis using B-mode ultrasonography.
All 3 trials showed that the addition of torcetrapib to aorvastatin did not result in any additional benefit on atheroma progression over atorvastatin alone. In addition, in all 3 trials there was an increase in systolic blood pressure in patients on combination torcetrapib-atorvastatin treatment (see Table).
Table. Key findings of the torcetrapib imaging studies
| Trial | Main endpoint | Main findings |
| ILLUSTRATE Patients with clinical CHD Torcetrapib 60 mg + atorvastatin vs. atorvastatin 910 evalulable patients | Change in % atheroma volume on intravascular ultrasound | 61% ↑ HDL-C and 20% ↓ LDL-C with combination treatment vs. atorvastatin No significant difference between groups in the change in % atheroma volume Combination treatment led to an increase in SBP (+ 4.6 mmHg) |
| RADIANCE 1 Patients with familial hypercholesterolaemia Torcetrapib 60 mg + atorvastatin vs. atorvastatin 850 evaluable patients | Raw annualized progression in carotid intima-media thickness(CIMT)*, measured by ultrasound | 52% ↑ HDL-C with combination treatment vs. atorvastatin No significant difference between the groups in increase in maximum CIMT Combination treatment led to an increase in SBP (+2.8 mmHg) Combination treatment led to an increase in serious CV events |
| RADIANCE 2 Patients with mixed dyslipidaemia Torcetrapib 60 mg + atorvastatin vs. atorvastatin 752 eligible patients | Raw annualized progression in carotid intima-media thickness(CIMT), measured by ultrasound | 63% ↑ HDL-C and 18% ↓ LDL-C with combination treatment vs. atorvastatin No difference in the change in maximal CIMT at any time point between the groups Combination treatment led to an increase in SBP (+6.6 mmHg) Combination treatment led to an increase in serious CV events |
ILLUSTRATE: Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation
RADIANCE: Rating Atherosclerotic Disease Change by Imaging with a New CETP Inhibitor
SBP systolic blood pressure; CV cardiovascular
* The raw annualized progression in CIMT was defined as the change in maximal CIMT over a time interval, divided by time in years
In conclusion, while the imaging trials showed that torcetrapib did not promote regression of atherosclerosis, they also showed that treatment did not cause progression of disease. Therefore, these trials do not help in understanding why there was an excess of deaths in the ILLUMINATE trial.
Further reading
Nissen SE et al. Effect of torcetrapib on the progression of coronary atheroslerosis. N Engl J Med 2007;356:1304-16.
Kastelein JJP et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007;356:1620-30.
Bots ML, Visseren FL, Evans GW et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomized, double-blind trial. Lancet 2007;370:153-60.
Tall AR. CETP inhibitors to increase HDL cholesterol levels. N Engl J Med 2007;356:1364-6.
McKenney JM, Davidson MH, Shear CL, Revkin JH. Efficacy and safety of torcetrapib, a novel cholesteryl transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels on a background of atorvastatin. J Am Coll Cardiol 2006;48:1782-90.
Davidson MH, McKenney JM, Shear CL, Revkin JH. Efficacy and safety of torcetrapib, a novel cholesteryl transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels. J Am Coll Cardiol 2006;48:1774-81.
Current status of clinical development
Statins remains the main focus of lipid-modifying intervention. However, there is clear evidence that some people remain at high risk of cardiovascular events, even with high-dose statin therapy. Recent evidence (see TNT report;) shows that this risk is partly due to low HDL cholesterol.
CETPi offers the potential for reducing this risk due to persistent low HDL cholesterol. However, questions about the torcetrapib data need to be resolved to determine the future role of CETP inhibitors.
- Can off-target effects of torcetrapib explain the increase in blood pressure seen in these trials?
- If proven, are these off-target effects specific to torcetrapib or a class-effect of these type of drugs?
If the problems with torcetrapib are shown to be due to an off-target effect of this drug of known mechanism, and if other CETP inhibitors do not have such an effect, then there is a clear case for the continuing development of CETP inhibitor drugs.
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