A CETP inhibitor is a member of a class of drugs that inhibit cholesterylester transfer protein (CETP). They are intended to reduce the risk of

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...

(a cardiovascular disease) by improving blood lipid levels. At least three medications within this class have failed to demonstrate a beneficial effect.

Types

These drugs have generally failed in clinical trials, either causing a marked increase in deaths (

torcetrapib Torcetrapib (CP-529,414, Pfizer) was a drug being developed to treat hypercholesterolemia (elevated cholesterol levels) and prevent cardiovascular disease. Its development was halted in 2006 when phase III studies showed excessive all-cause mor ...

), or having no meaningful clinical improvement despite HDL increases (

dalcetrapib Dalcetrapib (INN, codenamed JTT-705) is a CETP inhibitor which was being developed by Hoffmann–La Roche until May 2012. The drug was aimed at raising the blood levels of HDL cholesterol. Prevailing observations indicate that high HDL levels ...

evacetrapib Evacetrapib was a drug under development by Eli Lilly & Company (investigational name LY2484595) that inhibits cholesterylester transfer protein ( CETP inhibitor). CETP collects triglycerides from very low-density lipoproteins (VLDL) or low-dens ...

). Failed: *

Torcetrapib Torcetrapib (CP-529,414, Pfizer) was a drug being developed to treat hypercholesterolemia (elevated cholesterol levels) and prevent cardiovascular disease. Its development was halted in 2006 when phase III studies showed excessive all-cause mor ...

, failed in 2006 due to excess deaths in Phase III clinical trials. *

Dalcetrapib Dalcetrapib (INN, codenamed JTT-705) is a CETP inhibitor which was being developed by Hoffmann–La Roche until May 2012. The drug was aimed at raising the blood levels of HDL cholesterol. Prevailing observations indicate that high HDL levels ...

, development halted in May 2012 when Phase III trials failed to show clinically meaningful efficacy. *

Evacetrapib Evacetrapib was a drug under development by Eli Lilly & Company (investigational name LY2484595) that inhibits cholesterylester transfer protein ( CETP inhibitor). CETP collects triglycerides from very low-density lipoproteins (VLDL) or low-dens ...

, development discontinued in 2015 due to insufficient efficacy. * Obicetrapib (TA-8995, AMG-899), Phase II results reported in 2015, discontinued in 2017 Succeeded: *

Anacetrapib Anacetrapib is a CETP inhibitor which was being developed to treat elevated cholesterol levels in an effort to prevent cardiovascular disease. In 2017 its development was abandoned by Merck. Evidence In 2017 REVEAL trial anacetrapib was shown t ...

. In 2017, the REVEAL trial based on more than 30,000 participants showed a modest benefit of the addition of anacetrapib to statin therapy. Despite the successful trial,

Merck Merck refers primarily to the German Merck family and three companies founded by the family, including: * the Merck Group, a German chemical, pharmaceutical and life sciences company founded in 1668 ** Merck Serono (known as EMD Serono in the Unite ...

halted the development of the drug.

Mechanism

Drugs in this class substantially increase

HDL cholesterol High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are t ...

, lower

LDL cholesterol Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall dens ...

, and enhance

reverse cholesterol transport Reverse cholesterol transport is a multi-step process resulting in the net movement of cholesterol from peripheral tissues back to the liver first via entering the lymphatic system, then the bloodstream. Cholesterol from non-hepatic peripheral ti ...

. CETP inhibitors inhibit cholesterylester transfer protein (CETP), which normally transfers cholesterol from

to very low density or

low density lipoprotein Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...

s (VLDL or LDL). Inhibition of this process results in higher HDL levels and reduces LDL levels. CETP inhibitors do not reduce rates of mortality, heart attack, or stroke in patients already taking a statin.

Pharmacogenomics

In 2015, a pharmacogenomic sub-study of the dal-OUTCOMES clinical trial on 5,749 individuals identified a genetic variant in the ADCY9 gene which modulates response to

. In patients with the rs1967309 'AA' genotype, there was a significant reduction in the rate of cardiovascular events in the dalcetrapib arm whereas non-carriers were at increased risk. Beginning in 2015, the efficacy of dalcetrapib in the genetic sub-population was being investigated in the dal-GenE trial.

Chemical structures

File:Anacetrapib.svg,

File:Dalcetrapib.svg,

File:Evacetrapib.svg,

File:Obicetrapib.svg, Obicetrapib File:Torcetrapib.svg,

References

{{Lipid modifying agents Drugs acting on the cardiovascular system