Is Anacetrapib Better Than Its CETP Inhibitor Counterparts?

Abstract

Cholesterol metabolism and transport has been a major focus in cardiovascular disease risk modification over the past several decades. Hydroxymethylglutaryl-CoA reductase inhibitors (statins) have been the most commonly used agents, with the greatest benefit in reducing both the primary and secondary risks of cardiovascular disease. However, heart disease remains the leading cause of death in both men and women in the United States. Further investigation and intervention are required to further reduce the risk for cardiovascular disease and cardiovascular-related deaths. This review will focus on high-density lipoprotein metabolism and transport, looking particularly at cholesteryl ester transfer protein (CETP) inhibitors. While studies of the other CETP inhibitors in its class have not shown a significant improvement in the prevention of primary or secondary cardiovascular risk, anacetrapib, the fourth and latest of the CETP inhibitors to be investigated, may be more promising.

Apolipoprotein B and Cardiovascular Disease: Biomarker and Potential Therapeutic Target

“…Three CETP inhibitors, torcetrapib, dalcetrapib and evacetrpib, when tested in humans, which either increased cardiovascular risk or were neutral, while a fourth, anacetrapib, showed modest cardiovascular benefit [ 205 , 206 , 207 , 208 ]. Of these drugs, only anacetrapib, in the phase 3 randomized, placebo-controlled REVEAL trial (Randomized Evaluation of the Effects of Anacetrapib through Lipid-Modification), showed a 9% relative risk reduction in major coronary events in persons with pre-existing ASCVD after a median of 4 years of treatment [ 209 , 210 ]. This effect of anacetrapib has been attributed to decreased LDL-C accompanied by a reduction in apoB-containing lipoprotein particles but may also be explained by a decrease in small VLDL particles [ 211 ].…”

High Density Lipoprotein and Its Precursor Protein Apolipoprotein A1 as Potential Therapeutics to Prevent Anthracycline Associated Cardiotoxicity

“…This focus on raising HDL cholesterol levels has led to the development of CETP inhibitors which block the CETP mediated transfer of cholesterol from HDL to triglyceride rich lipoproteins such as VLDL. These drugs increase HDL cholesterol levels by more than 25% (up to 60%), but largely have not reduced cardiovascular events (107,109,(112)(113)(114)(115)(116)(117)(118). More recent attempts at increasing HDL particle number and/or function have focused on infusion of reconstituted HDL, administration of ApoA1 mimetics, or upregulation of ApoA1 production by liver (119)(120)(121)(122)(123)(124).…”

A Population Pharmacokinetic and Pharmacodynamic Model of CKD-519

“…It has been reported that CETP plays a key role in atherosclerosis through its impact on lipid metabolism [1]. Thus, there have been many efforts to modify the composition of the plasma lipoprotein favorably through inhibition of CETP activity [3].…”