A CETP inhibitor is a member of a class of drugs that inhibit
cholesterylester transfer protein
Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-de ...
(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 atheroma, atheromatous plaque. At onset there are usu ...
(a
cardiovascular disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
) 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 densit ...
, 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
Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-de ...
(CETP), which normally transfers cholesterol from
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 ...
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 density ...
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
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 ...
. 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, 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 ...
File:Dalcetrapib.svg, 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 ...
File:Evacetrapib.svg, 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 ...
File:Obicetrapib.svg, Obicetrapib
File:Torcetrapib.svg, 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 ...
References
{{Lipid modifying agents
Drugs acting on the cardiovascular system