There is overwhelming evidence that both elevated low-density lipoprotein (LDL) cholesterol and reduced high-density lipoprotein (HDL) cholesterol are independently associated with a substantially increased risk of developing premature atherosclerotic cardiovascular disease. Furthermore, the risk associated with low HDL cholesterol persists even when the level of LDL cholesterol has been reduced to levels below 70 mg/dL (1.8 mmol/L) by treatment with statins. This has led to a major research effort to discover therapies with the capacity to raise HDL cholesterol as effectively as statins lower LDL cholesterol. One logical approach is to find ways to shift the partitioning of cholesterol between LDLs and HDL towards the HDL fraction. Given that human plasma contains the cholesteryl ester transfer protein (CETP) that promotes the transfer of cholesterol from HDLs to LDLs, inhibition of this protein has the potential to shift the balance of plasma cholesterol in favour of the protective HDL fraction.
The possibility that CETP may be pro-atherogenic by transferring cholesterol from the anti-atherogenic HDL fraction to pro-atherogenic particles in the very low-density lipoprotein (VLDL) and LDL fractions was first raised more than 15 years ago. This provided the rationale for a major research effort to test the possibility that inhibition of CETP may be anti-atherogenic. This book documents the physiological functions of CETP, its possible contribution to the development of atherosclerosis and the evidence that its inhibition may translate into a protection against atherosclerosis.
1: Introduction 2: Plasma cholesterol transport 3: High-density lipoproteins 4: Triglyceride-rich lipoproteins 5: Low-density lipoproteins 6: Reverse cholesterol transport 7: Potential mechanisms by which CETP inhibition may be anti-atherogenic 8: The effects of CETP activity on atherosclerosis in animals 9: Effects of CETP in humans 10: Inhibition of CETP in humans: effects on plasma lipoproteins 11: Effects of CETP inhibition on cardiovascular disease in humans 12: Does CETP inhibition have a therapeutic future after torcetrapib?