Evacetrapib was a

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

under development by

Eli Lilly and Company Eli Lilly and Company, Trade name, doing business as Lilly, is an American multinational Medication, pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 count ...

(investigational name LY2484595) that inhibits

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 ...

(

CETP inhibitor 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 (a cardiovascular disease) by improving blood lipid levels. At least three medications ...

). CETP collects

triglyceride A triglyceride (from '' tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other vertebrates ...

s from

very low-density lipoprotein Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins (chylomicrons, VLDL, intermediate-density lipoprotein, LDL, low-density ...

s (VLDL) 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 (LDL) and exchanges them for

cholesteryl ester 300px, Cholesteryl oleate, a member of the cholesteryl ester family Cholesteryl esters are a type of dietary lipid and are ester derivatives of cholesterol. The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl g ...

s from

high-density lipoprotein 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 ...

s (HDL), and vice versa, but primarily increasing high-density lipoprotein and lowering low-density lipoprotein. It is thought that modifying lipoprotein levels modifies the risk of

cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...

. The first CETP inhibitor,

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 morta ...

, was unsuccessful because it increased levels of the hormone

aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays ...

and increased

blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

, which led to excess cardiac events when it was studied. Evacetrapib does not have the same effect. When studied in a small

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

in people with elevated LDL and low HDL, significant improvements were noted in their lipid profile. Evacetrapib evaluation for treatment of high-risk vascular disease was discontinued due to lack of efficacy, as had already happened in the past with two other CETP inhibitors (

and dalcetrapib) due to increased deaths and little identifiable cardiovascular benefit (despite substantial increases in HDL). Some hypothesize that CETP inhibitors may still be useful in the treatment of dyslipidemia, though significant caution is warranted.

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 ...

is the fourth CETP inhibitor being tried for cardiovascular benefit

Trials

ACCELERATE

In a 2014 study in 165 Japanese patients evacetrapib decreased CETP activity alone or in combination with

atorvastatin Atorvastatin, sold under the brand name Lipitor among others, is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a ...

. Phase III trial was terminated due to futility. ACCELERATE studied evacetrapib in participants with high-risk vascular disease (previous myocardial infarction, stroke or peripheral vascular disease, or several cardiovascular risk factors). An interim analysis performed in October 7 led the Data Monitoring Committee to support a recommendation to stop the study as the totality of evidence suggested that evacetrapib was unlikely to be superior to placebo. ACCENTUATE is studying patients with hyperlipidemia or diabetes. On April 3, 2016 at the

American College of Cardiology The American College of Cardiology (ACC), based in Washington, D.C., is a nonprofit medical association established in 1949. It bestows credentials upon cardiovascular specialists who meet its qualifications. Education is a core component of the ...

cardiologists first saw the data for Eli Lilly's ACCELERATE trial of evacetrapib involving 12,000 patients. They were "stunned" by the result which showed there was no benefit from taking evacetrapib—434 participants who took evacetrapib died from "cardiovascular disease, such as a heart attack or a stroke" and 444 participants who took a placebo died. The ACCELERATE trial led by Stephen J. Nicholls who observed,

References

{{Lipid modifying agents CETP inhibitors Tetrazoles Trifluoromethyl compounds Carboxylic acids Abandoned drugs