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Cholesteryl ester transfer protein (CETP) plays an important role in lipid metabolism and has presented an attractive target for drug development, primarily resting on the hope that CETP inhibition would reduce cardiovascular events through its ability to increase levels of high-density lipoprotein cholesterol (HDL-C). However, clinical development of CETP inhibitors has proven disappointing, with a spectrum of results spanning from evidence of harm, to futility, to only modest benefit in large-scale cardiovascular outcomes trials. A number of additional insights from genomic studies have suggested potential benefits from these agents in specific clinical settings. We review the current state of CETP inhibitors as an approach to targeting cardiovascular risk.

Supplemental Digital Content is available in the text., Background: Exploratory analyses of previous randomized trials generated a hypothesis that the clinical response to cholesteryl ester transfer protein (CETP) inhibitor therapy differs by ADCY9 genotype, prompting the ongoing dal-GenE trial in individuals with a particular genetic profile. The randomized placebo-controlled REVEAL trial (Randomized Evaluation of the Effects of Anacetrapib through Lipid-Modification) demonstrated the clinical efficacy of the CETP inhibitor anacetrapib among patients with preexisting atherosclerotic vascular disease. In the present study, we examined the impact of ADCY9 genotype on response to anacetrapib in the REVEAL trial. Methods: Individuals with stable atherosclerotic vascular disease who were treated with intensive atorvastatin therapy received either anacetrapib 100 mg daily or matching placebo. Cox proportional hazards models, adjusted for the first 5 principal components of ancestry, were used to estimate the effects of allocation to anacetrapib on major vascular events (a composite of coronary death, myocardial infarction, coronary revascularization, or presumed ischemic stroke) and the interaction with ADCY9 rs1967309 genotype. Results: Among 19 210 genotyped individuals of European ancestry, 2504 (13.0%) had a first major vascular event during 4 years median follow-up: 1216 (12.6%) among anacetrapib-allocated participants and 1288 (13.4%) among placebo-allocated participants. Proportional reductions in the risk of major vascular events with anacetrapib did not differ significantly by ADCY9 genotype: hazard ratio (HR) = 0.92 (95% CI, 0.81–1.05) for GG; HR = 0.94 (95% CI, 0.84–1.06) for AG; and HR = 0.93 (95% CI, 0.76–1.13) for AA genotype carriers, respectively; genotypic P for interaction = 0.96. Furthermore, there were no associations between ADCY9 genotype and the proportional reductions in the separate components of major vascular events or meaningful differences in lipid response to anacetrapib. Conclusions: The REVEAL trial is the single largest study to date evaluating the ADCY9 pharmacogenetic interaction. It provides no support for the hypothesis that ADCY9 genotype is materially relevant to the clinical effects of the CETP inhibitor anacetrapib. The ongoing dal-GenE study will provide direct evidence as to whether there is any specific pharmacogenetic interaction with dalcetrapib. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01252953. URL: http://www.isrctn.com. Unique identifier: ISRCTN48678192. URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2010-023467-18.

Background According to epidemiological studies, there is no clear relationship between the plasma cholesteryl ester transfer protein (CETP) concentration and the development of atherosclerosis in human populations. Although some studies suggest that increased CETP activity relates to undesirable profiles of plasma lipoproteins, promoting an anti-atherogenic plasma lipoprotein profile by drugs that inhibit CETP has not succeeded in preventing atherosclerosis in humans. Materials and Methods This review describes 28 investigations in human populations dealing with plasma CETP, 11 in mice that express human CETP and seven in animals (six in rabbits and one in mice) in which plasma CETP activity was inhibited by drugs. Results Present review shows that models in mice expressing human CETP are not illuminating because they report increase as well reduction of atherosclerosis. However, investigations in rabbits and mice that develop severe hypercholesterolaemia clearly indicate that impairment of the plasma CETP activity elicits protection against the development of atherosclerosis; in all of these experiments are attained substantial reductions of the atherogenic lipoproteins, namely, plasma apoB containing lipoproteins. Conclusion These models are strong indicators that the benefit in preventing atherosclerosis should be earned in cases of hyperlipidemia by CETP inhibitors.

Inhibition of cholesteryl ester transfer protein (CETP) has emerged as a potential way to decrease cardiovascular risk by raising high density lipoprotein (HDL) cholesterol and lowering low density lipoprotein (LDL) cholesterol concentrations. However, high profile withdrawals of several CETP inhibitors have cast doubt over this hypothesis. Despite this concern, anacetrapib appears to be safe, well-tolerated and delivers a substantial increases in HDL cholesterol and reductions in LDL cholesterol as monotherapy and when combined with a statin.We discuss the role of CETP and HDL cholesterol as therapeutic targets, describe the pharmacokinetics and pharmacodynamics of anacetrapib, as well as report on the recent clinical trials.The focus of CETP inhibition has shifted from HDL cholesterol-raising to LDL cholesterol-lowering. Although anacetrapib appears to be safe and is effective in altering lipid-related biochemical parameters of interest, its effect on cardiovascular outcomes remains unknown. Extrapolation of LDL cholesterol lowering to improved cardiovascular outcomes is not possible, because LDL and HDL functionality in the setting of anacetrapib treatment is unclear. The results of the phase III REVEAL randomised controlled trial will be critical for anacetrapib to establish a place in clinical care.

Purpose This article reviews therapies that affect HDLs. Findings Lipid-modifying agents in current use (including statins, fibrates, and niacin) increase the concentration of HDL cholesterol to some extent. However, these agents have additional effects (beyond raising HDL) with the potential to reduce atherosclerotic cardiovascular disease (ASCVD) risk, making it difficult to determine (one way or the other) whether an increase in HDL concentration affects risk. New investigational approaches targeting HDLs include infusions of reconstituted HDLs, reinfusion of selectively delipidated plasma in which the concentration of pre-β HDLs (the preferred acceptor of cell cholesterol) has been increased, and inhibitors of cholesteryl ester transfer protein (CETP). Positive results of the effects of reconstituted HDL infusions on coronary atheroma burden encourage further investigation of these agents. One small study on the effects of reinfusing selectively delipidated plasma has also provided results supporting additional development of this approach. CETP inhibitors are the most effective HDL-raising agents developed yet, with the ability to more than double the concentration of HDL cholesterol. They also reduce LDL cholesterol by up to 50%. Clinical outcome trials with the first 2 of these agents (torcetrapib and dalcetrapib) failed and, in the case of torcetrapib, treatment increased ASCVD events and increased both cardiovascular and noncardiovascular death. However, the subsequent discovery that torcetrapib had serious adverse effects unrelated to CETP inhibition meant that trials with this agent were unable to test the hypothesis that inhibiting CETP (or raising the level of HDL cholesterol) would translate into a reduction in ASCVD risk. The trial with dalcetrapib, a relatively weak inhibitor of CETP, was conducted in people soon after an acute coronary event when HDL functionality is impaired. The CETP inhibitor hypothesis will remain untested until completion of ongoing trials with CETP inhibitors that are more potent than dalcetrapib and that do not have the adverse effects of torcetrapib. Implications Positive trials with reconstituted HDL infusions and reinfusions of selectively delipidated plasma will establish HDLs as important therapeutic targets. However, although a positive result in the trials with CETP inhibitors will establish CETP inhibition as a valid strategy to reduce ASCVD risk, it will not be possible to determine with certainty whether the reduction in risk is the consequence of effects on the HDL fraction or whether it is the result of CETP inhibitor−mediated reductions in LDL cholesterol.

PURPOSE OF REVIEW This article summarizes the latest studies relevant to cholesteryl ester transfer protein (CETP) inhibition and cardiovascular risk and proposes a series of patient populations that might eventually derive benefits from CETP inhibition. RECENT FINDINGS Results of recently published genetic epidemiology studies have helped shape our understanding of the association between lipoprotein-lipid levels and cardiovascular disease risk. These studies have confirmed the proatherogenic role of apolipoprotein B-containing lipoproteins and triglycerides and renewed our interest for lipoprotein(a) as a significant and causal predictor of cardiovascular risk. The association between HDL cholesterol levels and cardiovascular risk, albeit strong and consistent, is unlikely to be of causative nature, at least according to genetic epidemiology. However, a handful of intriguing studies have highlighted a predictive role for HDL cholesterol efflux capacities in predicting cardiovascular risk independently of HDL cholesterol levels. Potent CETP inhibitors, currently under investigation, significantly decrease apolipoprotein B-containing lipoproteins and lipoprotein(a) and increase both HDL cholesterol levels and HDL cholesterol efflux capacities. SUMMARY Two phase 3 cardiovascular outcomes trials testing the hypothesis that CETP inhibition will reduce cardiovascular outcomes in high-risk patients are well underway. The future of CETP inhibition will depend on the outcomes of these trials.

Type 2 diabetes is a causal risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). While treatment with a statin reduces the risk of having an ASCVD event in all people, including those with type-2 diabetes, statin treatment also increases the likelihood of new onset diabetes when given to those with risk factors for developing diabetes. Treatment with the cholesteryl ester transfer protein (CETP) inhibitor, anacetrapib, reduces the risk of having a coronary event over and above that achieved with a statin. However, unlike statins, anacetrapib decreases the risk of developing diabetes. If the reduced risk of new-onset diabetes is confirmed in another CETP inhibitor outcome trial, there will be a case for considering the use of the combination of a statin plus a CETP inhibitor in high ASCVD-risk people who are also at increased risk of developing diabetes.

Inhibitors of cholesteryl ester transfer protein (CETP) were developed due to their ability to raise HDL-C levels. Preclinical studies demonstrated favorable effects on atherosclerotic plaque with CETP inhibitory approaches in animal models. While these agents raise HDL-C and lower LDL-C, most have not proven to reduce cardiovascular event rates in large outcome trials. The state of opinion after all of these clinical trials is reviewed.

Current cholesteryl ester transfer protein (CETP) inhibitors are designed based on the unglycosylated crystal structure, and most of them have failed to cure cardiovascular disease (CVD). It is particularly important for us to investigate the glycosylation structure of CETP (CETP-G) and effect of glycans on the structure and function of CETP. Here, we used a total of 3.0-μs molecular dynamics (MD) trajectories of nascent structure of CETP (CETP-N) and CETP-G to study their structural differentiations, to shed new light on the CETP-mediated lipid exchange. In accordance with our simulations and previous mutation studies, relative to CETP-N, CETP-G adopts a more stretched shape with higher hydrophobic and hydrophilic solvent-accessible surface area (SASA) of N-terminal oscillating with larger amplitude, in which Glycan88 provides partial assistance for CEs through the N-terminal. Glycan341 reduces the flexibility of neck flap, with the interference of CEs through the neck region. Besides, Glycan240 reduces the flexibility of Helix-X to interfere the CEs transfer. Glycan396 decreases the flexibility and increases the hydrophobic SASA of C-terminal. Overall, these glycans affect the dynamics and structure of CETP through forming H-bonds with surrounding residues, and the sampled conformations of glycan is also affected by its surrounding residues. Thus, glycans are an integral part of CETP, further studies on the CETP inhibition and treatment of CVD should fully consider the effect of glycans.

One new cleistanthane-type diterpene named engleromycenolic acid A (1), one new rosane-type diterpene named engleromycenolic acid B (2) and one new natural rosane-type diterpene, engleromycenol (3), along with three known rosane-type diterpenes, rosololactone (4), rosenonolactone (5) and 7-deoxyrosenonolactone (6) were isolated from cultures of the fungus Engleromyces goetzii, where it naturally grows on Alpine bamboo culms. The new compounds were elucidated based on their spectroscopic data. In addition, compounds 1–6 were evaluated for their cholesterol ester transfer protein (CETP) inhibition activity. This paper reports the isolation, structural elucidation, and CETP inhibition activity of these compounds. Graphical Abstract Electronic supplementary material The online version of this article (doi:10.1007/s13659-015-0055-5) contains supplementary material, which is available to authorized users.

BACKGROUND: Although reductions in cardiovascular risk can be achieved by lowering low-density lipoprotein cholesterol, treated patients remain at substantial risk. Epidemiological studies have established that higher levels of high-density lipoprotein cholesterol (HDL-C) are strongly associated with reduced cardiovascular risk, and therefore raising levels of HDL-C may be beneficial. The activity of cholesteryl ester transfer protein (CETP) appears to be inversely correlated with HDL-C levels and thus CETP is an attractive target for intervention to raise levels of HDL-C and potentially reduce residual cardiovascular risk. OBJECTIVES: This paper reviews the evidence for an atheroprotective role of higher levels of HDL-C, the function of CETP in cholesterol metabolism, and the concept of CETP inhibition as a potential new strategy for decreasing cardiovascular risk. An analysis of clinical studies of CETP inhibition was also performed. METHODS: MEDLINE (1966 to June 2006), EMBASE (1974 to June 2006), and cardiology conference proceedings were searched for clinical trials of CETP inhibition. RESULTS: Thirteen reports involving vaccine-based and pharmacological inhibition of CETP were found. Modest and inconsistent elevation of HDL-C was observed with vaccine-based therapy, whereas HDL-C elevation with pharmacological inhibitors was greater and more consistent. CONCLUSIONS: Elevation of HDL-C via CETP inhibition appears to be a potentially promising approach to reduce cardiovascular disease. Preliminary studies suggest benefits of CETP inhibition on serum lipid levels, and ongoing studies should establish the effects on atherosclerosis and cardiovascular events.

CETP inhibition has been used as a strategy to raise HDL cholesterol, but trials with two CETP inhibitors torcetrapib and dalcetrapib failed to prevent cardiovascular events for high-risk individuals. Of note, approximately 2/3 of patients in these clinical trials were obese. Obesity and fatty liver are known to significantly impact aspects of liver cholesterol metabolism and HDL biology. We propose that high-fat diet feeding (HFD) might adversely impact the effects of CETP inhibition on HDL composition and function. Mice naturally lack CETP expression, so we used CETP transgenic mice to evaluate the effects of administering the CETP inhibitor torcetrapib on HDL composition in chow- and HFD-fed CETP-transgenic mice. Because of the very short half-life of torcetrapib we used acute intravenous infusion of torcetrapib. In both diet groups torcetrapib infusion suppressed plasma CETP activity and raised HDL cholesterol content. In chow-fed CETP mice we found that torcetrapib resulted in changes in HDL composition that would be predicted to be favorable, including increases in apoA1, apoM and apoE protein levels for 2.5-fold ( P P P

By virtue of their effects on low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and cellular cholesterol efflux, there is considerable interest in the potential use of pharmacological inhibitors of cholesteryl ester transfer protein (CETP) as a novel approach for cardiovascular disease prevention. This is supported by observations from genetic and animal studies suggesting that less CETP activity has favorable cardiovascular effects. Despite the adverse effects of the first CETP inhibitor to move forward in clinical development, torcetrapib, there remains considerable interest in developing alternative CETP inhibitors without the off-target effects of torcetrapib. The clinical development programs leading to a number of promising CETP inhibitors will be reviewed.

Using the collective body of known (CETP) inhibitors as inspiration for design, a structurally novel series of tetrahydroquinoxaline CETP inhibitors were discovered. An exemplar from this series, compound 5, displayed potent in vitro CETP inhibition and was efficacious in a transgenic cynomologus-CETP mouse HDL PD (pharmacodynamic) assay. However, an undesirable metabolic profile and chemical instability hampered further development of the series. A three-dimensional structure of tetrahydroquinoxaline inhibitor 6 was proposed from (1)H NMR structural studies, and this model was then used in silico for the design of a new class of compounds based upon an indoline scaffold. This work resulted in the discovery of compound 7, which displayed potent in vitro CETP inhibition, a favorable PK-PD profile relative to tetrahydroquinoxaline 5, and dose-dependent efficacy in the transgenic cynomologus-CETP mouse HDL PD assay.

Among the noteworthy recent stories in the management and prevention of atherosclerotic cardiovascular disease (CVD) is the saga of the development of pharmacological inhibitors of cholesteryl ester transfer protein (CETP). Inhibiting CETP significantly raises plasma concentrations of high-density lipoprotein cholesterol, which has long been considered a marker of reduced CVD risk. However, the first CETP inhibitor, torcetrapib, showed a surprising increase in CVD events, despite a dramatic increase in high-density lipoprotein cholesterol levels. This paradox was explained by putative off-target effects not related to CETP inhibition that were specific to torcetrapib. Subsequently, three newer CETP inhibitors, namely dalcetrapib, anacetrapib, and evacetrapib, were at various phases of clinical development in 2012. Each of these had encouraging biochemical efficacy and safety profiles. Dalcetrapib even had human arterial imaging results that tended to look favorable. However, the dalcetrapib development program was recently terminated, presumably because interim analysis of a large CVD outcome trial indicated no benefit. These events raise important questions regarding the validity of the mechanism of CETP inhibition and the broader issue of whether pharmacological raising of high-density lipoprotein cholesterol itself is a useful strategy for CVD risk reduction.

Human cholesteryl ester transfer protein (CETP) mediates the net transfer of cholesteryl ester mass from atheroprotective high-density lipoproteins to atherogenic low-density lipoproteins by an unknown mechanism. Delineating this mechanism would be an important step toward the rational design of new CETP inhibitors for treating cardiovascular diseases. Using EM, single-particle image processing and molecular dynamics simulation, we discovered that CETP bridges a ternary complex with its N-terminal β-barrel domain penetrating into high-density lipoproteins and its C-terminal domain interacting with low-density lipoprotein or very-low-density lipoprotein. In our mechanistic model, the CETP lipoprotein-interacting regions, which are highly mobile, form pores that connect to a hydrophobic central cavity, thereby forming a tunnel for transfer of neutral lipids from donor to acceptor lipoproteins. These new insights into CETP transfer provide a molecular basis for analyzing mechanisms for CETP inhibition.

SAR studies of the substitution effect on the central phenyl ring of the biphenyl scaffold were carried out using anacetrapib (9a) as the benchmark. The results revealed that the new analogs with substitutions to replace trifluoromethyl (9a) had a significant impact on CETP inhibition in vitro. In fact, analogs with some small groups were as potent or more potent than the CF(3) derivative for CETP inhibition. Five of these new analogs raised HDL-C significantly (20mg/dL). None of them however was better than anacetrapib in vivo. The synthesis and biological evaluation of these CETP inhibitors are described.

Initial randomized trials of cholesteryl ester transfer protein (CETP) inhibitors were terminated early owing to adverse effects or futility. The REVEAL trial now shows the benefit of CETP inhibition in coronary heart disease. Despite raising HDL-cholesterol levels, the cardiovascular effect of CETP inhibitors is probably due to lowering of non-HDL-cholesterol levels.

Elevated low-density lipoprotein-cholesterol (LDL-C) and reduced high-density lipoprotein-cholesterol (HDL-C) are major risk factors for the development of cardiovascular disease. One approach to raising HDL-C is to inhibit the cholesteryl ester transfer protein (CETP), a plasma protein that promotes transfer of cholesteryl esters from HDL and other lipoprotein fractions. Drugs that inhibit CETP increase HDL-C and some lower LDL-C. However, the development of torcetrapib, the first CETP inhibitor to be tested in a human clinical outcomes trial, was terminated because it caused an excess of deaths and cardiovascular events. There is evidence, however, that torcetrapib had adverse off-target effects unrelated to CETP inhibition. This has opened the way for retesting of the hypothesis that CETP inhibitors will be anti-atherogenic in studies conducted with agents such as dalcetrapib and anacetrapib that do not share the off-target effects of torcetrapib. Clinical outcome trials with dalcetrapib and anacetrapib are currently under way.

Cholesteryl ester transfer protein (CETP) inhibition is a promising experimental strategy to raise high-density lipoprotein cholesterol (HDL-C) and reduce cardiovascular risk. This review focuses on the highly selective and potent CE TP inhibitor anacetrapib and discusses the available preclinical and clinical information pertaining to it. We also describe strategies to target HDL-C, discuss the mechanism underlying CETP inhibition and its effects on lipid biology, and give an overview of other CETP inhibitors that are currently in development.

The recent failure to prevent coronary disease with torcetrapib, a major inhibitor of the cholesteryl ester transfer protein (CETP)2 system, indicated that this therapeutic approach is disputable. Evaluation of prior knowledge confirms that the rationale of CETP inhibition appears to be based on incorrect physiological assumptions and that the interpretation of the torcetrapib trials may be flawed because of overinterpretation or some ancillary findings, as well as a lack of consideration of some potentially very negative clinical observations. In the present report we consider the major genetic and clinical aspects of the CETP system, as well as the reasons why CETP inhibition has not proved to be a winning strategy. Reverse cholesterol transport, a classic function of HDL in humans and higher species, is handled by a transfer/exchange system regulated by CETP, which was first described 30 years ago. The major function of CETP (molecular weight 74 kDa) is the exchange of cholesterol esters with triglycerides present, particularly in VLDLs,leading to a triglyceride-enriched HDL. Triglyceride catabolism in the newly formed HDL then leads back to a “small, cholesterol ester poor HDL” capable of effective cholesterol removal (1). CETP mutations may cause a reduced effectiveness of the transfer/exchange process, eventually leading to large amounts of cholesterol esters in HDL (2). Clinical evaluation of individuals with inactivating mutations and extremely increased HDL cholesterol (HDL-C) concentrations has led to conflicting findings. Major support came from genetic studies of Japanese communities, in which a large number of citizens displayed dramatically increased HDL-C concentrations but an apparently reduced incidence of coronary heart disease (2). A more detailed examination, however, showed a paradoxically enhanced risk in many individuals with the more marked increases (3). In the Western world, epidemiologic data appear to indicate ineffective protection against cardiovascular disease by HDL-C increases due to CETP …

The role of CETP in the development of atherosclerosis is debatable, and few data exist regarding the total impact of CETP inhibition on cholesterol efflux.Acceptor capacities of whole serum and HDL subfractions separated by HPLC were compared using 2 different cell systems. Subjects with CETP deficiency (2 homozygous, 1 compound heterozygous, and 5 heterozygous) were analyzed along with 10 normolipidemic controls. The fractional efflux from cholesterol-labeled Fu5AH hepatoma cells was determined to be SR-BI mediated. The efflux difference between control and liver X receptor (LXR) agonist-induced ABCA1-upregulated J774 macrophages was considered as a measure of ABCA1-mediated efflux.For the Fu5AH cell system, the total acceptor capacities of whole serum and HPLC-separated HDL fraction 2 obtained from the homozygous subjects were 38% and 116% higher than the corresponding values for the controls, respectively (p0.05). For the J774 cell system, the total acceptor capacities of whole serum and HPLC-separated HDL fractions were similar among the CETP-deficient subjects and controls.Serum from homozygous subjects with CETP-null defects exhibited enhanced acceptor capacity via an SR-BI dependent pathway, which is regulated by the middle HPLC-separated HDL fraction. Further, the cholesterol acceptor capacity of serum obtained from patients having complete and partial CETP deficiency was preserved via an ABCA1-dependent pathway.

Inhibitors of cholesterol ester transfer protein (CETP) have the capacity to increase plasma high-density lipoprotein cholesterol to unprecedented levels. Still, hopes that CETP inhibition could reduce atherosclerosis were dented when the clinical development of one such inhibitor, torcetrapib, was halted because of an unexpected finding of increased cardiovascular and noncardiovascular mortality against a background of elevated blood pressure and plasma aldosterone levels. Recently, evidence has accumulated to show that these untoward effects may have been largely attributable to off-target toxicity of the compound, unrelated to the mechanism of CETP inhibition and not shared by other CETP inhibitors. In this review, we explore the rationale for CETP inhibition, compare the pharmacology of the small molecule CETP inhibitors that reached clinical development, and address the evidence relating to off-target adverse effects.

Background: The blood pressure increase associated with the cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib is probably attributable to an off-target effect but it is unknown whether activation of the renin-angiotensin-aldosterone system (RAAS) may be related to variation in the plasma CETP level. We questioned whether the plasma CETP level would affect RAAS responsiveness to low sodium diet and the blood pressure response to angiotensin-II infusion in healthy subjects. Methods: RAAS parameters and blood pressure were determined during liberal sodium diet (200 mmol/24 h) and low sodium diet (50 mmol/24 h) in 67 healthy men. Blood pressure response to incremental angiotensin-II infusion was assessed in 34 subjects during liberal sodium diet. Correlation analysis was performed to test whether RAAS responsiveness and blood pressure were related to plasma CETP mass, high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-I measured during liberal sodium diet. Results: CETP mass ranged from 1.29 to 2.95 mg/l. No significant differences in (changes) in mean arterial pressure, aldosterone and active plasma renin concentration in response to low sodium were observed between the lowest and highest tertiles of CETP mass, HDL-C and apolipoprotein A-I. These outcome variables were also not significantly correlated with CETP, HDL-C and apolipoprotein A-I, except for a modest relation of aldosterone measured during low sodium with apolipoprotein A-I (r = 0.28, p = 0.022). Blood pressure response to angiotensin-II was similar between CETP tertiles. Conclusions: Mineralocorticoid and blood pressure responsiveness to dietary salt intake are not significantly related to physiological interindividual differences in plasma CETP. We suggest that a lower CETP mass does not exert adverse effects on blood pressure regulation.

Raising plasma levels of high-density lipoprotein (HDL) cholesterol has been a therapeutic goal ever since the strong inverse association between HDL levels and the risk of coronary heart disease was first observed.1 Nearly two decades ago, the discovery that persons in Japan had extremely high levels of HDL cholesterol because of a genetic deficiency involving the cholesteryl ester transfer protein (CETP) led to the concept that pharmacologic inhibition of CETP could raise HDL cholesterol levels. When this theory proved to be true in humans, it led to great anticipation that CETP inhibition would permit the ultimate test of the “HDL . . .

Although results from clinical outcome studies and from studies on atherosclerosis progression have convincingly demonstrated that LDL-cholesterol lowering by statins may significantly reduce the incidence of cardiovascular events, these studies have also indicated that LDL lowering alone with standard statin doses leaves a considerable residual cardiovascular risk. Apart from LDL, HDL has been recognized as an important independent risk factor for coronary heart disease and HDL raising has been associated with coronary heart disease reduction, probably by its anti-atheroclerotic properties (HDL-mediated reverse cholesterol transport, anti-inflammatory and anti oxidant properties). Therapies to raise HDL are therefore of major scientific importance. The most important increase in HDL-cholesterol is presently achieved by inhibition of the cholesterol ester transport protein (CETP), a protein which mediates the transfer of cholesterol esters from HDL to VLDL/LDL and of trigylcerides from VLDL/IDL to HDL. At the present time two inhibitors of CETP are under clinical investigation, Torcetrapib and JTT705. These drugs increase HDL cholesterol by 30 to 100%. They moderately lower VLDL/LDL-cholesterol and they normalize small dense LDL. Raising HDL by CETP inhibition in combination with a statin could prove to be en efficient new approach against atherosclerosis.

Non-HDL-cholesterol is well recognised as a primary causal risk factor in cardiovascular disease. However, despite consistent epidemiological evidence for an inverse association between HDL-C and coronary heart disease, clinical trials aimed at raising HDL-C (AIM-HIGH, HPS2-THRIVE, dal-OUTCOMES) failed to meet their primary goals. This systematic review and meta-analysis investigated the effects of established and novel treatment strategies, specifically targeting HDL, on inhibition of atherosclerosis in cholesteryl ester transfer protein-expressing animals, and the prevention of clinical events in randomised controlled trials. Linear regression analyses using data from preclinical studies revealed associations for TC and non-HDL-C and lesion area (R2=0.258, P=0.045; R2=0.760, P

The failure of the cholesterol ester transfer protein (CETP) inhibitor, torcetrapib, has led to questions regarding whether the molecule itself or the mechanism of CETP inhibition was responsible for the adverse cardiovascular outcomes. Given the association with increases in blood pressure and plasma aldosterone levels, torcetrapib has been postulated to have adverse ‘off-target' effects. In this issue of British Journal of Pharmacology, Forrest and co-workers have elegantly investigated these effects, demonstrating two salient points—(1) the pressor effect of torcetrapib is independent of CETP inhibition and (2) although associated with hyperaldosteronism, the pressor effect is likely not mediated by hyperaldosteronism. Anacetrapib, by contrast, did not demonstrate any pressor or off-target effects. Despite these findings, it remains to be proven whether the adverse cardiovascular outcomes from torcetrapib were indeed related to the pressor effects and whether CETP inhibition by other agents will result in beneficial clinical outcomes. Yet, the studies of Forrest and co-workers do bring us closer to unravelling the reasons behind the failure of torcetrapib.

Raising HDL cholesterol (HDL-C) has become an attractive therapeutic target to lower cardiovascular risk in addition to statins. Inhibition of the cholesteryl ester transfer protein (CETP), which mediates the transfer of cholesteryl esters from HDL to apolipoprotein B-containing particles, leads to a substantial increase in HDL-C levels. Various CETP inhibitors are currently being evaluated in phase II and phase III clinical trials. However, the beneficial effect of CETP inhibition on cardiovascular outcome remains to be established.Torcetrapib, the first CETP inhibitor tested in a phase III clinical trial (ILLUMINATE), failed in 2006 because of an increase in all-cause mortality and cardiovascular events that subsequently were attributed to nonclass-related off-target effects (particularly increased blood pressure and low serum potassium) related to the stimulation of aldosterone production. Anacetrapib, another potent CETP inhibitor, raises HDL-C levels by approximately 138% and decreases LDL cholesterol (LDL-C) levels by approximately 40%, without the adverse off-targets effects of torcetrapib (DEFINE study). The CETP modulator dalcetrapib raises HDL-C levels by approximately 30% (with only minimal effect on LDL-C levels) and proved safety in the dal-VESSEL and dal-PLAQUE trials involving a total of nearly 600 patients. Evacetrapib, a relatively new CETP inhibitor, exhibited favorable changes in the lipid profile in a phase II study.The two ongoing outcome trials, dal-OUTCOMES (dalcetrapib) and REVEAL (anacetrapib), will provide more conclusive answers for the concept of reducing cardiovascular risk by raising HDL-C with CETP inhibition.

OBJECTIVE To assess and validate the application of a non-radioactive assay for cholesteryl ester transfer protein (CETP) activity in clinical samples. DESIGN AND METHODS In this Phase 0 study, CETP activity was measured following addition of the CETP inhibitor JNJ-28545595 to plasma samples from normolipidemic and three subgroups of dyslipidemic subjects with differing lipid profiles. RESULTS CETP activity was elevated in plasma samples from dyslipidemic subjects compared to normolipidemic subjects. Increased triglyceride levels correlated with decreased CETP inhibition. The assay was found to have good analytical precision and high throughput potential as required for clinical trial sample analysis. CONCLUSIONS The results demonstrate that pharmacological inhibition of CETP is affected by the dyslipidemic nature of plasma samples. In addition, since the optimal degree of CETP inhibition for maximal cardiovascular benefit in patients is not known, this assay may be used to help define optimal dosing of CETP inhibitors.

A series of diphenylpyridylethanamine (DPPE) derivatives was identified exhibiting potent CETP inhibition. Replacing the labile ester functionality in the initial lead 7 generated a series of amides and ureas. Further optimization of the DPPE series for potency resulted in the discovery of cyclopentylurea 15d, which demonstrated a reduction in cholesterol ester transfer activity (48% of predose level) in hCETP/apoB-100 dual transgenic mice. The PK profile of 15d was suboptimal, and further optimization of the N-terminus resulted in the discovery of amide 20 with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100 mice and in hamsters. Compound 20 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemeterized rats despite sustained high exposures.

Dalcetrapib increases high-density lipoprotein cholesterol (HDL-C) levels through effects on cholesteryl ester transfer protein (CETP). As part of the dalcetrapib dal-HEART clinical trial programme, the efficacy and safety of dalcetrapib is assessed in coronary heart disease (CHD) patients in the dal-VESSEL study (ClinicalTrials.gov identifier: NCT00655538), the design and methods of which are presented here. RESEARCH DESIGN AND STUDY METHOD: Men and women with CHD or CHD risk equivalent, with HDL-C levels50 mg/dL were recruited for a 36-week, double-blinded, placebo-controlled trial. After a pre-randomisation phase of up to 8 weeks, patients received dalcetrapib 600 mg/day or placebo in addition to their existing treatments. Brachial flow-mediated dilatation (FMD) measured by B-mode ultrasound represents endothelial function and is a validated marker for early atherosclerosis and cardiovascular disease risk.The primary efficacy outcome is change from baseline in brachial FMD after 12 weeks. The primary safety endpoint is 24-hour ambulatory blood pressure monitoring (ABPM) assessed at week 4. Secondary endpoints include brachial FMD at 36 weeks, ABPM at 12 and 36 weeks, lipid profile, CETP mass and activity, and markers of inflammation, oxidation, and cardiovascular risk. Clinical endpoints are assessed as a composite endpoint for the dal-HEART Program.In 19 European clinical centres, 476 subjects met inclusion criteria and have entered the study. In conclusion, the dal-VESSEL study is the largest multicentre trial with brachial FMD ever performed. The study assesses efficacy and safety of dalcetrapib on endothelial function, blood pressure, lipids, and clinical outcomes in CHD patients with below average HDL-C and will therefore provide vital information regarding its potential role in the preventative treatment of CHD risk.

There is overwhelming epidemiologic evidence that increased concentrations of LDL cholesterol (LDL-C)2) and low concentrations of HDL cholesterol (HDL-C) are independently associated with increased cardiovascular risk. Furthermore, the risk associated with low HDL-C concentrations persists even when LDL-C has been reduced to concentrations

Pharmacologic inhibitors of the cholesteryl ester transfer protein (CETP) are capable of increasing HDL cholesterol by 50% to 100% in humans. Despite intriguing antiatherogenic effects of CETP inhibition in animal models of atherosclerosis, the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial investigators observed an excess of cardiovascular and noncardiovascular morbidity and mortality associated with the use of the CETP inhibitor torcetrapib. This review summarizes available clinical and experimental data about potential underlying mechanisms.

Item does not contain fulltext BACKGROUND: Despite reduction in low-density lipoprotein cholesterol, there is still a considerable amount of residual atherosclerosis-related disease. Epidemiological and pathophysiological data strongly favour increasing plasma high-density lipoprotein (HDL) cholesterol levels as antiatherogenic therapy, for example with cholesteryl ester transfer inhibition (CETP). However, negative Phase III studies on clinical end points with the CETP inhibitor torcetrapib challenge the future perspectives of other CETP inhibitors such as JTT-705. OBJECTIVE: Is there potential for CETP inhibition with JTT-705 after torcetrapib's collapse? METHODS: Search of articles in Pubmed citing JTT-705, torcetrapib and anacetrapib, or citing effects of pharmacological HDL-cholesterol raising or CETP inhibition. RESULTS/CONCLUSION: There is possibly a future for HDL-cholesterol raising therapies. Phase III clinical studies with either JTT-705 or anacetrapib will determine whether CETP inhibition is beneficial.

Cholesteryl ester transfer protein (CETP) inhibitors are currently being investigated because of their ability to increase high-density lipoprotein cholesterol levels. In various metabolic settings, the relationship between CETP and lipoprotein metabolism is complex and may depend largely on the concentration of triglyceride-rich lipoproteins. Two CETP inhibitors, JTT-705 and torcetrapib, are in an advanced phase of development. Following hopeful intermediate results, a large endpoint study using torcetrapib has just been discontinued due to increased mortality in torcetrapib-treated subjects. In this review we summarize clinical data on the use of CETP inhibitors.

trapib comes following disappointing earlier trials investigating CETP inhibition, notably with torcetrapib; a trial assessing clinical outcomes of torcetrapib therapy was terminated in 2006 after the drug was shown to cause excess deaths and cardiovascular events. The question was whether the torcetrapib’s poor showing was a class effect or isolated to that specific drug. “We did not know after torcetrapib failed whether the entire strategy would actually achieve success,” said Steven E. Nissen, MD, chairman of the Cleveland Clinic Foundation’s Department of Cardiovascular Medicine and an investigator of torcetrapib. “I believe the failure of torcetrapib was due to an off-target toxicity, that it increased aldosterone, and that offered the possibility of another CETP inhibitor to show success without that offtarget effect.” Nissen said anacetrapib looks promising, but even after the news from the AHA, the drug’s benefit remains a promise only. “The effect on lipids is what caught everyone’s attention, but I would caution everyone that lipid changes are a surrogate end point, and we have come to be suspicious of surrogate end points; there is not a guarantee of success.” Harlan M. Krumholz, MD, professor of medicine at Yale University School of Medicine in New Haven, Conn, and a skeptic of surrogate end points as providing meaningful results that translate to improved hard outcomes, said Merck is doing the DEFINE trial the right way. “DEFINE is a great prelude to a definitive trial to determine the effect on outcomes, but it is not more than that, so it leaves us ready for the next piece of information,” Krumholz said. “I applaud Merck for proceeding to an outcomes trial.”