Abstract
Cholesteryl ester transfer protein (CETP) inhibitors significantly increase serum high-density lipoprotein cholesterol (HDL) cholesterol levels and decrease low-density lipoprotein cholesterol (LDL) cholesterol concentration. However, three drugs of this class failed to show a decrease of cardiovascular events in high-risk patients. A new CETP inhibitor, anacetrapib, substantially increases HDL cholesterol and apolipoprotein (Apo) AI levels with a profound increase of large HDL2 particles, but also pre-β HDL particles, decreases LDL cholesterol levels mainly due to increased catabolism of LDL particles through LDL receptors, decreases lipoprotein a (Lp(a)) levels owing to a decreased Apo (a) production and, finally, decreases modestly triglyceride (TRG) levels due to increased lipolysis and increased receptor-mediated catabolism of TRG-rich particles. Interestingly, anacetrapib may be associated with a beneficial effect on carbohydrate homeostasis. Furthermore, the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial showed that anacetrapib administration on top of statin treatment significantly reduces cardiovascular events in patients with atherosclerotic vascular disease without any significant increase of adverse events despite its long half-life. Thus, anacetrapib could be useful for the effective management of dyslipidemias in high-risk patients that do not attain their LDL cholesterol target or are statin intolerable, while its role in patients with increased Lp(a) levels remains to be established.
Highlights
Cholesteryl ester transfer protein (CETP) is a glycoprotein synthesized mainly in the liver, which plays a prominent role in the bidirectional transfer of cholesterol esters and triglycerides (TRG) between lipoproteins, that is the transfer of cholesterol esters from the cardioprotective high-density lipoprotein (HDL) particles to the potentially atherogenic non-high-density lipoprotein cholesterol (HDL) particles (very low-density lipoprotein (VLDL)
The administration of 100 mg of anacetrapib for a mean follow-up period of 4.1 years was associated with a significant reduction of the primary end point by 9%
This risk reduction was evident even though patients treated with anacetrapib exhibited slightly higher systolic blood pressure (SBP) and diastolic blood pressure (DBP) values at the final visit compared with the control group
Summary
Cholesteryl ester transfer protein (CETP) is a glycoprotein synthesized mainly in the liver, which plays a prominent role in the bidirectional transfer of cholesterol esters and triglycerides (TRG) between lipoproteins, that is the transfer of cholesterol esters from the cardioprotective high-density lipoprotein (HDL) particles to the potentially atherogenic non-HDL particles (very low-density lipoprotein (VLDL)particles, remnant lipoproteins and low-density lipoprotein (LDL) particles) [1,2]. The randomized placebo-controlled trials that evaluated the effects of three drugs of this class, that is torcetrapib, dalcetrapib and evacetrapib, failed to show a beneficial cardiovascular effect [4,5,6,7]. These trials were prematurely terminated due to either off-target toxicity (torcetrapib) or lack of efficacy (dalcetrapib, evacetrapib) [4,5,6,7,8]. It has been recently reported that in the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial, anacetrapib, a new CETP inhibitor, led to a significant decrease of cardiovascular events.
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