dalcetrapib and Atherosclerosis

Atherosclerosis has been effectively avoided with many therapies that lower low-density lipoprotein cholesterol. However, significant cardiovascular burden remains. The effect of raising high-density lipoprotein (HDL) has been confounded by other factors (such as lowering triglycerides or LDL) and unsuccessful when attempting to solely increase HDL. Reviewing the available data, the failures of previous strategies may reflect the complexity of HDL in human metabolism and the heterogeneity of human genetics. dal-GenE (NCT02525939) represents the first large cardiovascular outcomes study to use a selective genomic test to identify the target population most likely to receive therapeutic benefit and uses a cholesterol ester transfer protein inhibitor, dalcetrapib. Both the cholesterol ester transfer protein target and the ADCY9 polymorphism identified by the diagnostic test are based on inheritance and an evolving understanding of inborn risk. Selective treatment of subpopulations may be the key to the conundrum of HDL as an actionable risk factor.

Topics: Adenylyl Cyclases; Amides; Anticholesteremic Agents; Atherosclerosis; Biomarkers; Cholesterol Ester Transfer Proteins; Clinical Decision-Making; Clinical Trials as Topic; Esters; Humans; Lipoproteins, HDL; Pharmacogenetics; Pharmacogenomic Testing; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Predictive Value of Tests; Research Design; Sulfhydryl Compounds; Treatment Failure; Up-Regulation

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.. 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.. 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.. These models are strong indicators that the benefit in preventing atherosclerosis should be earned in cases of hyperlipidemia by CETP inhibitors.

Topics: Amides; Animals; Anticholesteremic Agents; Apolipoproteins B; Atherosclerosis; Benzodiazepines; Cholesterol Ester Transfer Proteins; Esters; Humans; Hypercholesterolemia; Mice; Oxazolidinones; Quinolines; Rabbits; Sulfhydryl Compounds

The cholesteryl ester transfer protein (CETP) plays an integral role in the metabolism of plasma lipoproteins. Despite two failures, CETP inhibitors are still in clinical development. We review the genetics of CETP and coronary disease, preclinical data on CETP inhibition and atherosclerosis, and the effects of CETP inhibition on cholesterol efflux and reverse cholesterol transport. We discuss the two failed CETP inhibitors, torcetrapib and dalcetrapib, and attempt to extract lessons learned. Two CETP inhibitors, anacetrapib and evacetrapib, are in phase III development, and we attempt to differentiate them from the failed drugs. Whether pharmacologic CETP inhibition will reduce the risk of cardiovascular disease is one of the most fascinating and important questions in the field of cardiovascular medicine.

Topics: Amides; Anticholesteremic Agents; Atherosclerosis; Benzodiazepines; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Clinical Trials as Topic; Coronary Disease; Esters; Humans; Oxazolidinones; Quinolines; Sulfhydryl Compounds

How to manage residual atherosclerosis risk after the statin therapy is a major concern in cardiovascular medicine. In addition to life-style modifications, new drugs against atherosclerotic and inflammatory vascular diseases are expected. In current clinical trials, phospholipase A2 inhibitors(darapladib, varespladib), RVX-208, D-4F, CETP inhibitors (anacetrapib, dalcetrapib), succinobucol are investigated. Some has been failed, but others are still promising. On molecular target basis of PAF-AH, CETP, PON, ABC transporters of A1 and G1, SR-BI, HO-1, potential benefits and side effects are discussed.

Topics: Acetates; Amides; Apolipoprotein A-I; Atherosclerosis; Benzaldehydes; Blood Proteins; Cholesterol Ester Transfer Proteins; Clinical Trials as Topic; Drug Design; Esters; Humans; Indoles; Keto Acids; Molecular Targeted Therapy; Oxazolidinones; Oximes; Probucol; Quinazolines; Quinazolinones; Sulfhydryl Compounds

Despite optimal treatment of high low density lipoprotein (LDL) cholesterol with statins many cardiovascular events are not prevented. Additional therapeutic strategies are required to reduce the residual cardiovascular risk. Large epidemiological studies show an inverse correlation between the plasma concentration of high density lipoprotein (HDL) cholesterol and the incidence of cardiovascular events. Under physiological conditions, HDL is vasculoprotective and mediates the reverse cholesterol transport. However, new studies suggest that HDL particles represent a heterogeneous population. Under several pathophysiological conditions, HDL was shown to promote atherogenesis and inflammation. Interventional studies and metaanalyses examining the effect of increasing HDL cholesterol have reported mixed results. Inhibition of cholesteryl ester transfer protein (CETP) is a new and potent strategy to increase HDL concentrations. However, the first CETP-inhibitor torcetrapib increased blood-pressure and increased cardiovascular events despite increasing HDL. The blood-pressure increasing effects are not known for more recently developed CETP inhibitors such as dalcetrapib and anacetrapib nor in patients with genetic CETP deficiency. An increase of HDL cholesterol does not necessarily imply an improvement of the functional properties of HDL such as reverse cholesterol transport. An important open question remains the functional characterization of HDL generated by CETP inhibition. Important current clinical endpoint studies with new CETP inhibitors will elucidate whether increasing HDL by CETP inhibition leads to a reduction of cardiovascular events.

Topics: Amides; Anticholesteremic Agents; Atherosclerosis; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Clofibric Acid; Coronary Artery Disease; Esters; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Life Style; Nicotinic Acids; Oxazolidinones; Quinolines; Randomized Controlled Trials as Topic; Sulfhydryl Compounds; Treatment Outcome

Roche and Japan Tobacco are in a licensing agreement to develop and commercialize dalcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor to slow or prevent atherosclerosis. This drug is currently in phase III development. This review discusses the development history and scientific profile of this new compound.

Topics: Amides; Animals; Anticholesteremic Agents; Atherosclerosis; Cholesterol Ester Transfer Proteins; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Evaluation, Preclinical; Drugs, Investigational; Esters; Humans; Sulfhydryl Compounds

Not only hypercholesterolemia, but also low levels of high-density lipoprotein cholesterol is a critical risk factor for atherosclerosis-related disease. Therefore, there has been great interest in identifying effective and selective cholesteryl ester transfer protein (CETP) inhibitors that can raise high-density lipoprotein. Recently, Phase III clinical studies of torcetrapib, one of the CETP inhibitors developed by researchers at Pfizer, were unexpectedly terminated because of an increase in cardiovascular events and mortality. Torcetrapib has some compound-specific and off-target effects, such as raising blood pressure and aldosterone, which could affect an increase in cardiovascular events and mortality.. The aim of this review is to provide an update (from 2000 to early 2009) on the patenting activity in the field of CETP inhibitors and the status of the most advanced compounds.. Dalcetrapib (JTT-705) and anacetrapib, which have not been reported to have the off-target effects of torcetrapib, are currently in Phase III. They are expected to reveal whether CETP inhibition is beneficial for atherosclerosis-related diseases.

Topics: Amides; Animals; Anticholesteremic Agents; Atherosclerosis; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Clinical Trials, Phase III as Topic; Esters; Humans; Oxazolidinones; Patents as Topic; Quinolines; Sulfhydryl Compounds

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.

Topics: Aldosterone; Amides; Animals; Anticholesteremic Agents; Atherosclerosis; Blood Pressure; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Corticosterone; Esters; Humans; Hydrocortisone; Hypercholesterolemia; Oxazolidinones; Quinolines; Sulfhydryl Compounds

The dramatic failure of clinical trials evaluating the cholesterol ester transfer protein inhibitor torcetrapib has led to considerable doubt about the value of raising high-density lipoprotein cholesterol (HDL-C) as a treatment for cardiovascular disease. These results have underscored the intricacy of HDL metabolism, with functional quality perhaps being a more important consideration than the circulating quantity of HDL. As a result, HDL-based therapeutics that maintain or enhance HDL functionality warrant closer investigation. In this article, we review the complexity of HDL metabolism, discuss clinical-trial data for HDL-raising agents, including possible reasons for the failure of torcetrapib, and consider the potential for future HDL-based therapies.

Topics: Amides; Animals; Anticholesteremic Agents; Apolipoprotein A-I; Atherosclerosis; Cholesterol Ester Transfer Proteins; Clinical Trials as Topic; Esters; Humans; Lipoproteins, HDL; Phospholipids; Quinolines; Sulfhydryl Compounds; Treatment Outcome

Coronary arterial diseases are responsible for more deaths than all other associated causes combined. Elevated serum cholesterol levels leading to atherosclerosis can cause coronary heart disease (CHD). Reduction in serum cholesterol levels reduces the risk for CHD, substantially. Medicinal chemists all around the world have been designing, synthesizing, and evaluating a variety of new bioactive molecules for lowering lipid levels. This review summarizes the disorders associated with elevation of lipids in blood and the current strategies to control them. The emphasis has been laid in particular on the new potential biological targets and the possible treatments as well as the current ongoing research status in the field of lipid lowering agents.

Topics: Animals; Atherosclerosis; Biochemical Phenomena; Biochemistry; Disease Progression; Drug Design; Humans; Hyperlipidemias; Lipoproteins

Epidemiologic studies have shown that the concentration of high-density lipoprotein cholesterol (HDL-C) is a strong, independent, inverse predictor of coronary heart disease risk. This identifies HDL-C as a potential therapeutic target. Compared with low-density lipoprotein cholesterol (LDL-C)-lowering agents, however, currently available HDL-raising drugs are relatively ineffective. Consequently, recent years have seen considerable efforts expended on identifying new drugs that can raise HDL-C. Cholesteryl ester transfer protein (CETP) plays an important role in cholesterol metabolism, being responsible for the transfer of cholesteryl esters from HDL to very low-density lipoproteins and LDLs. The observation that Japanese populations with CETP deficiency exhibited high levels of HDL-C has led to the concept that drugs targeting CETP activity may elevate HDL-C levels and potentially decrease cardiovascular risk. Support of this proposition has been obtained in rabbits where inhibition of CETP activity is markedly antiatherogenic. Two CETP inhibitors-torcetrapib and JTT-705-are currently in the preliminary stages of clinical development. Initial studies with these drugs in humans show that they substantially increase HDL-C levels and modestly decrease LDL-C levels. Larger, long-term, randomized, clinical end point trials are required to determine whether the beneficial effects of CETP inhibitors on lipoprotein metabolism can translate into reductions in cardiovascular events.

Topics: Amides; Animals; Atherosclerosis; Cardiovascular Diseases; Carrier Proteins; Cholesterol Ester Transfer Proteins; Cholesterol Esters; Cholesterol, HDL; Cholesterol, LDL; Esters; Glycoproteins; Humans; Quinolines; Risk Factors; Sulfhydryl Compounds; Vaccines

Cholesteryl ester transfer protein (CETP) catalyzes the transfer of cholesteryl ester from high-density lipoprotein (HDL) to apolipoprotein B-containing lipoproteins in exchange for triglyceride, and thereby plays a major role in lipoprotein metabolism. The reciprocal increase in HDL cholesterol (HDL-C) and decrease in low-density lipoprotein cholesterol (LDL-C) associated with CETP deficiency has led to the search for synthetic CETP inhibitors over the past 15 years. Several potent inhibitors have been identified, two of which--JTT-705 and torcetrapib--are undergoing clinical trials. Recent reports that torcetrapib is able to simultaneously raise HDL-C twofold and lower LDL-C by < or = 42% has heightened interest in this new class of agents. Upcoming results from Phase III trials of torcetrapib should provide anatomical measurements of atherosclerosis and thus the first assessment of therapeutic benefit.

Topics: Amides; Atherosclerosis; Carrier Proteins; Cholesterol Ester Transfer Proteins; Clinical Trials as Topic; Esters; Female; Glycoproteins; Humans; Lipoproteins, HDL; Male; Quinolines; Sulfhydryl Compounds

Innovative pharmacological approaches to raise anti-atherogenic high-density lipoprotein-cholesterol (HDL-C) are currently of considerable interest, particularly in atherogenic dyslipidemias characterized by low levels of HDL-C, such as type 2 diabetes, the metabolic syndrome, and mixed dyslipidemia, but equally among individuals with or at elevated risk for premature cardiovascular disease (CVD). Epidemiological and observational studies first demonstrated that HDL-C was a strong, independent predictor of coronary heart disease (CHD) risk, and suggested that raising HDL-C levels might afford clinical benefit. Accumulating data from clinical trials of pharmacological agents that raise HDL-C levels have supported this concept. In addition to the pivotal role that HDL-C plays in reverse cholesterol transport and cellular cholesterol efflux, HDL particles possess a spectrum of anti-inflammatory, anti-oxidative, anti-apoptotic, anti-thrombotic, vasodilatory and anti-infectious properties, all of which potentially contribute to their atheroprotective nature. Significantly, anti-atherogenic properties of HDL particles are attenuated in common metabolic diseases that are characterized by subnormal HDL-C levels, such as type 2 diabetes and metabolic syndrome. Inhibition of cholesteryl ester transfer protein (CETP), a key player in cholesterol metabolism and transport, constitutes an innovative target for HDL-C raising. In lipid efficacy trials, 2 CETP inhibitors-JTT-705 and torcetrapib-induced marked elevation in HDL-C levels, with torcetrapib displaying greater efficacy. Moreover, both agents attenuate aortic atherosclerosis in cholesterol-fed rabbits. Clinical trial data demonstrating the clinical benefits of these drugs on atherosclerosis and CHD are eagerly awaited.

Topics: Amides; Animals; Atherosclerosis; Biological Transport; Cholesterol; Cholesterol, HDL; Coronary Disease; Esters; Homeostasis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Oxidative Stress; PPAR alpha; PPAR delta; PPAR gamma; Quinolines; Sulfhydryl Compounds

With the limited effects of low-density lipoprotein-based lipid intervention, more attention is being paid to drugs that augment or mimic high-density lipoprotein's beneficial effects. A thorough understanding of the anti-atherogenic effects of high-density lipoprotein, and the mechanisms of existing or emerging high-density lipoprotein-based therapies, is essential for rational strategy for the prevention of cardiovascular disease.. High-density lipoprotein mediates its beneficial effects through reverse cholesterol transport and direct anti-inflammatory effects of apolipoprotein AI and other component parts. Currently available drugs increase high-density lipoprotein-C through increasing apoAI synthesis (statins, fibrates) and decreasing apolipoprotein AI catabolism (niacin). Cholesteryl ester transfer protein inhibitors dramatically raise high-density lipoprotein-C, but clinical data are still required to verify their cardioprotective effects. Novel therapies such as apolipoprotein AImilano, apolipoprotein AI mimetic peptide, and exogenous phospholipids show tremendous promise as treatments for atherosclerosis.. High-density lipoprotein and its defining functional protein apoAI prevent atherosclerosis through reverse cholesterol transport and other direct effects. Research has led to the development of novel therapies that increase high-density lipoprotein-C or that mimic direct anti-atherogenic effects of apolipoprotein AI. As these emerging therapies find a place in clinical medicine, we can anticipate preventing a much higher degree of cardiovascular events.

Topics: Amides; Animals; Apolipoprotein A-I; Atherosclerosis; Cardiovascular Diseases; Carrier Proteins; Cholesterol Ester Transfer Proteins; Clofibric Acid; Esters; Glycoproteins; Humans; Hypolipidemic Agents; Lipoproteins, HDL; Sulfhydryl Compounds; Thiazolidinediones

Over the past decades, lowering of LDL-cholesterol (LDL-c) levels has been established as the foundation for preventing atherosclerotic disease. It is, however, widely accepted that additional risk reduction has to come from modifying other risk factors than LDL-c. In this context, increasing HDL-cholesterol (HDL-c) levels by pharmacological inhibition of the cholesteryl ester transfer protein (CETP) is currently under intense investigation. Two small-molecule compounds, JTT-705 and Torcetrapib, have been shown to effectively increase HDL-c levels in humans, without inducing clinically significant side effects when used as monotherapy or combined with statins. Whether this approach will translate into a reduction in risk of atherosclerotic disease has not yet been established. Data from studies focusing on genetic CETP deficiency as well as those studying the relationship between CETP plasma levels and risk of atherosclerosis do not provide clear answers. Several long-term clinical studies addressing this crucial issue have recently been initiated, results of which will follow within the next few years. This review focuses on CETP, its role in human lipid metabolism and its relation to atherosclerotic disease. Furthermore, it summarizes the currently available data regarding pharmacological CETP inhibition. Finally, it will highlight a number of issues basic to the considerations of whether CETP inhibition will fulfill its promises.

Topics: Amides; Atherosclerosis; Carrier Proteins; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Esters; Glycoproteins; Humans; Models, Biological; Quinolines; Sulfhydryl Compounds

The objectives of precision medicine are to better match patient characteristics with the therapeutic intervention to optimize the chances of beneficial actions while reducing the exposure to unneeded adverse drug experiences. In a retrospective genome-wide association study of the overall neutral placebo-controlled dal-Outcomes trial, the effect of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on the composite of cardiovascular death, myocardial infarction or stroke was found to be influenced by a polymorphism in the adenylate cyclase type 9 (ADCY9) gene. Whereas patients with the AA genotype at position rs1967309 experienced fewer cardiovascular events with dalcetrapib, those with the GG genotype had an increased rate and the heterozygous AG genotype exhibited no difference from placebo. Measurements of cholesterol efflux and C-reactive protein (CRP) offered directionally supportive genotype-specific findings. In a separate, smaller, placebo-controlled trial, regression of ultrasonography-determined carotid intimal-medial thickness was only observed in dalcetrapib-treated patients with the AA genotype. Collectively, these observations led to the hypothesis that the cardiovascular effects of dalcetrapib may be pharmacogenetically determined, with a favorable benefit-risk ratio only for patients with this specific genotype. We describe below the design of dal-GenE, a precision medicine, placebo-controlled clinical outcome trial of dalcetrapib in patients with a recent acute myocardial infarction with the unique feature of selecting only those with the AA genotype at rs1967309 in the ADCY9 gene.

Topics: Adenylyl Cyclases; Amides; Anticholesteremic Agents; Atherosclerosis; Dose-Response Relationship, Drug; Double-Blind Method; Esters; Female; Follow-Up Studies; Genetic Testing; Genome-Wide Association Study; Genotype; Global Health; Humans; Incidence; Male; Middle Aged; Pharmacogenetics; Polymorphism, Genetic; Precision Medicine; Prognosis; Prospective Studies; Retrospective Studies; Sulfhydryl Compounds

Atherosclerosis is an inflammatory condition with calcification apparent late in the disease process. The extent and progression of coronary calcification predict cardiovascular events. Relatively little is known about noncoronary vascular calcification.. This study investigated noncoronary vascular calcification and its influence on changes in vascular inflammation.. A total of 130 participants in the dal-PLAQUE (Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging) study underwent fluorodeoxyglucose positron emission tomography/computed tomography at entry and at 6 months. Calcification of the ascending aorta, arch, carotid, and coronary arteries was quantified. Cardiovascular risk factors were related to arterial calcification. The influences of baseline calcification and drug therapy (dalcetrapib vs. placebo) on progression of calcification were determined. Finally, baseline calcification was related to changes in vascular inflammation.. Age >65 years old was consistently associated with higher baseline calcium scores. Arch calcification trended to progress more in those with calcification at baseline (p = 0.055). There were no significant differences between progression of vascular calcification with dalcetrapib compared to that with placebo. Average carotid target-to-background ratio indexes declined over 6 months if carotid calcium was absent (single hottest slice [p = 0.037], mean of maximum target-to-background ratio [p = 0.010], and mean most diseased segment [p < 0.001]), but did not significantly change if calcification was present at baseline.. Across multiple arterial regions, higher age is consistently associated with higher calcium scores. The presence of vascular calcification at baseline is associated with progressive calcification; in the carotid arteries, calcification appears to influence vascular inflammation. Dalcetrapib therapy did not affect vascular calcification.

Topics: Aged; Amides; Anticholesteremic Agents; Atherosclerosis; Esters; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multimodal Imaging; Positron-Emission Tomography; Risk Factors; Sulfhydryl Compounds; Tomography, X-Ray Computed; Vascular Calcification; Vasculitis

Dalcetrapib effects on cardiovascular outcomes are determined by adenylate cyclase 9 gene polymorphisms. Our aim was to determine whether these clinical end point results are also associated with changes in reverse cholesterol transport and inflammation.. Participants of the dal-OUTCOMES and dal-PLAQUE-2 trials were randomly assigned to receive dalcetrapib or placebo in addition to standard care. High-sensitivity C-reactive protein was measured at baseline and at end of study in 5243 patients from dal-OUTCOMES also genotyped for the rs1967309 polymorphism in adenylate cyclase 9. Cholesterol efflux capacity of high-density lipoproteins from J774 macrophages after cAMP stimulation was determined at baseline and 12 months in 171 genotyped patients from dal-PLAQUE-2. Treatment with dalcetrapib resulted in placebo-adjusted geometric mean percent increases in high-sensitivity C-reactive protein from baseline to end of trial of 18.1% (P=0.0009) and 18.7% (P=0.00001) in participants with the GG and AG genotypes, respectively, but the change was -1.0% (P=0.89) in those with the protective AA genotype. There was an interaction between the treatment arm and the genotype groups (P=0.02). Although the mean change in cholesterol efflux was similar among study arms in patients with GG genotype (mean: 7.8% and 7.4%), increases were 22.3% and 3.5% with dalcetrapib and placebo for those with AA genotype (P=0.005). There was a significant genetic effect for change in efflux for dalcetrapib (P=0.02), but not with placebo.. Genotype-dependent effects on C-reactive protein and cholesterol efflux are supportive of dalcetrapib benefits on atherosclerotic cardiovascular outcomes in patients with the AA genotype at polymorphism rs1967309.. ClinicalTrials.gov; Unique Identifiers: NCT00658515 and NCT01059682.

Topics: Adenylyl Cyclases; Aged; Amides; Animals; Anticholesteremic Agents; Atherosclerosis; Biomarkers; C-Reactive Protein; Cell Line; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Dyslipidemias; Esters; Female; Humans; Inflammation; Macrophages; Male; Mice; Middle Aged; Pharmacogenetics; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Sulfhydryl Compounds; Time Factors; Treatment Outcome

Dalcetrapib did not improve clinical outcomes, despite increasing high-density lipoprotein cholesterol by 30%. These results differ from other evidence supporting high-density lipoprotein as a therapeutic target. Responses to dalcetrapib may vary according to patients' genetic profile.. We conducted a pharmacogenomic evaluation using a genome-wide approach in the dal-OUTCOMES study (discovery cohort, n=5749) and a targeted genotyping panel in the dal-PLAQUE-2 imaging trial (support cohort, n=386). The primary endpoint for the discovery cohort was a composite of cardiovascular events. The change from baseline in carotid intima-media thickness on ultrasonography at 6 and 12 months was evaluated as supporting evidence. A single-nucleotide polymorphism was found to be associated with cardiovascular events in the dalcetrapib arm, identifying the ADCY9 gene on chromosome 16 (rs1967309; P=2.41×10(-8)), with 8 polymorphisms providing P<10(-6) in this gene. Considering patients with genotype AA at rs1967309, there was a 39% reduction in the composite cardiovascular endpoint with dalcetrapib compared with placebo (hazard ratio, 0.61; 95% confidence interval, 0.41-0.92). In patients with genotype GG, there was a 27% increase in events with dalcetrapib versus placebo. Ten single-nucleotide polymorphism in the ADCY9 gene, the majority in linkage disequilibrium with rs1967309, were associated with the effect of dalcetrapib on intima-media thickness (P<0.05). Marker rs2238448 in ADCY9, in linkage disequilibrium with rs1967309 (r(2)=0.8), was associated with both the effects of dalcetrapib on intima-media thickness in dal-PLAQUE-2 (P=0.009) and events in dal-OUTCOMES (P=8.88×10(-8); hazard ratio, 0.67; 95% confidence interval, 0.58-0.78).. The effects of dalcetrapib on atherosclerotic outcomes are determined by correlated polymorphisms in the ADCY9 gene.. URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00658515 and NCT01059682.

Topics: Adenylyl Cyclases; Aged; Amides; Atherosclerosis; Carotid Intima-Media Thickness; Chromosomes, Human, Pair 16; Esters; Female; Humans; Linkage Disequilibrium; Male; Middle Aged; Pharmacogenetics; Polymorphism, Genetic; Sulfhydryl Compounds

Topics: Amides; Anticholesteremic Agents; Atherosclerosis; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Clinical Trials, Phase II as Topic; Endothelium, Vascular; Esters; Evidence-Based Medicine; Female; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Sulfhydryl Compounds; Treatment Outcome; Vasodilation

Topics: Acute Coronary Syndrome; Amides; Anticholesteremic Agents; Atherosclerosis; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Early Termination of Clinical Trials; Esters; Humans; Oxazolidinones; Quinolines; Randomized Controlled Trials as Topic; Sulfhydryl Compounds

The excessive proliferation and migration of vascular smooth muscle cells (SMCs) participate in the growth and instability of atherosclerotic plaque. We examined the direct role of a newly developed chemical inhibitor of cholesteryl ester transfer protein, JTT-705, on SMC proliferation and angiogenesis in endothelial cells (ECs). JTT-705 inhibited human coronary artery SMC proliferation. JTT-705 induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular-signal-regulated kinases (ERK) in SMCs. In addition, the anti-proliferative effects of JTT-705 in SMCs were blocked by p38 MAPK inhibitor. JTT-705 induced the upregulation of p-p21(waf1), and this effect was blocked by dominant-negative Ras (N17), but not by inhibitors of p38 MAPK or ERK. In addition, JTT-705 also induced the upregulation of p27(kip1), and this effect was blocked by p38 MAPK inhibitor. Interestingly, culture medium from JTT-705-treated SMCs blocked human coronary artery EC tube formation in an in vitro model of angiogenesis indirectly via a decrease in vascular endothelial growth factor (VEGF) from SMCs and directly via an anti-proliferative effect in ECs. JTT-705 blocked the proliferation of SMCs through the activation of p38 kinase/p27(kip1) and Ras/p21(waf1) pathways, and simultaneously blocked EC tube formation associated with a decrease in VEGF production from SMCs and an anti-proliferative effect in ECs. Our results indicate that JTT-705 may induce a direct anti-atherogenic effect in addition to its inhibitory effect of CETP activity.

Topics: Amides; Atherosclerosis; Cell Division; Cells, Cultured; Coronary Vessels; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Endothelium, Vascular; Enzyme Inhibitors; Esters; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Humans; Imidazoles; Intracellular Signaling Peptides and Proteins; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Muscle, Smooth, Vascular; Neovascularization, Pathologic; p38 Mitogen-Activated Protein Kinases; Pyridines; ras Proteins; Sulfhydryl Compounds; Up-Regulation; Vascular Endothelial Growth Factor A