dalcetrapib and Coronary-Artery-Disease

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

Lowering low-density lipoprotein cholesterol (LDL-C) levels with statins is a proven strategy for reducing the risk of atherothrombotic cardiovascular disease (CVD). Yet, despite the success of statins in reducing cardiovascular event rates in at-risk patients, many will still experience further events. There is, therefore, a need to develop suitable therapies to reduce this residual risk. Low high-density lipoprotein cholesterol (HDL-C) levels are an important independent risk factor for CVD. Though fibrates, niacin, and statins have been shown to modestly raise HDL-C, there is increasing recognition of the need to develop therapies that can increase HDL-C more robustly. Such therapies may help supplement the LDL-C-lowering benefits of statins. Inhibition of cholesteryl ester transfer protein (CETP) has been identified as a possible strategy for substantially increasing HDL-C levels and CETP inhibitors have demonstrated clinical efficacy, in terms of increasing HDL-C, in preliminary clinical trials, and clinical trials based on outcomes are ongoing. Two CETP inhibitors, JTT-705 and torcetrapib, are now being evaluated more extensively.

Topics: Amides; Cholesterol; Cholesterol Ester Transfer Proteins; Clinical Trials as Topic; Coronary Artery Disease; Esters; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mutation; Risk Factors; Sulfhydryl Compounds

Dalcetrapib modulates cholesteryl ester transfer protein (CETP) activity to raise high-density lipoprotein cholesterol (HDL-C). After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties. dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints.. In this phase 2b, double-blind, multicentre trial, patients (aged 18-75 years) with, or with high risk of, coronary heart disease were randomly assigned (1:1) to dalcetrapib 600 mg/day or placebo for 24 months. Randomisation was done with a computer-generated randomisation code and was stratified by centre. Patients and investigators were masked to treatment. Coprimary endpoints were MRI-assessed indices (total vessel area, wall area, wall thickness, and normalised wall index [average carotid]) after 24 months and (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT assessment of arterial inflammation within an index vessel (right carotid, left carotid, or ascending thoracic aorta) after 6 months, with no-harm boundaries established before unblinding of the trial. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00655473.. 189 patients were screened and 130 randomly assigned to placebo (66 patients) or dalcetrapib (64 patients). For the coprimary MRI and PET/CT endpoints, CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group. MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months; absolute change from baseline relative to placebo was -4·01 mm(2) (90% CI -7·23 to -0·80; nominal p=0·04). The PET/CT measure of index vessel most-diseased-segment target-to-background ratio (TBR) was not different between groups, but carotid artery analysis showed a 7% reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group (-7·3 [90% CI -13·5 to -0·8]; nominal p=0·07). Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups.. Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months. Moreover, this trial suggests possible beneficial vascular effects of dalcetrapib, including the reduction in total vessel enlargement over 24 months, but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed.. F Hoffmann-La Roche Ltd.

Topics: Adolescent; Adult; Aged; Amides; Anticholesteremic Agents; Confidence Intervals; Coronary Artery Disease; Coronary Stenosis; Diagnostic Imaging; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Esters; Female; Follow-Up Studies; Humans; Hypercholesterolemia; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Reference Values; Risk Assessment; Sulfhydryl Compounds; Treatment Outcome; Young Adult

Efficacy and safety data for dalcetrapib (RO4607381/JTT-705) are presented, following a report of increased mortality and cardiac events with another cholesteryl ester transfer protein inhibitor, torcetrapib, associated with off-target adverse effects (hypertension and the activation of the renin-angiotensin-aldosterone system). The efficacy and clinical safety of dalcetrapib 300, 600, and 900 mg or placebo were assessed (n = 838) in 4 pooled 4-week phase IIa trials (1 monotherapy, n = 193; 3 statin combination, n = 353) and 1 12-week phase IIb trial (with pravastatin, n = 292). Nonclinical safety, assessed by the induction of aldosterone production and aldosterone synthase (cytochrome P450 11B2) messenger ribonucleic acid, was measured in human adrenocarcinoma (H295R) cells exposed to dalcetrapib or torcetrapib. Dalcetrapib increased high-density lipoprotein cholesterol by up to 36% and apolipoprotein A-I by up to 16%. The incidence of adverse events (AEs) was similar between placebo (42%) and dalcetrapib 300 mg (50%) and 600 mg (42%), with more events with dalcetrapib 900 mg (58%) (p <0.05, pooled 4-week studies). Six serious AEs (3 with placebo, 1 with dalcetrapib 300 mg, and 2 with dalcetrapib 600 mg) were considered "unrelated" to treatment. Cardiovascular AEs were similar across treatment groups, with no dose-related trends and no clinically relevant changes in blood pressure or electrocardiographic results. Findings were similar in the 12-week study. In vitro, torcetrapib but not dalcetrapib increased aldosterone production and cytochrome P450 11B2 messenger ribonucleic acid levels. In conclusion, dalcetrapib alone or in combination with statins was effective at increasing high-density lipoprotein cholesterol and was well tolerated, without clinically relevant changes in blood pressure or cardiovascular AEs and no effects on aldosterone production as assessed nonclinically.

Topics: Amides; Anticholesteremic Agents; Cholesterol Ester Transfer Proteins; Coronary Artery Disease; Double-Blind Method; Dyslipidemias; Esters; Female; Humans; Incidence; Male; Middle Aged; Quinolines; Risk Assessment; Risk Factors; Sulfhydryl Compounds

Baseline predictors of response to treatment of patients with coronary heart disease (CHD) with respect to vascular inflammation and atherosclerotic plaque burden are poorly understood. From post hoc analysis of the dal-PLAQUE study (NCT00655473), 18F-fluorodeoxyglucose-positron emission tomography (18-FDG-PET) imaging and carotid black blood magnetic resonance imaging (MRI) were used to track changes in these vascular parameters. Baseline demographics, imaging, and biomarkers were collected/measured in 130 patients with CHD or CHD risk-equivalents, and imaging follow-up at 6 months (PET) and 24 months (MRI) was performed. Using stepwise linear regression, predictors of change in carotid plaque inflammation by PET [target-to-background ratio (TBR), n = 92] and plaque burden by MRI [wall area (WA) and total vessel area (TVA), n = 89] were determined. Variables with p < 0.05 in multivariable models were considered independently significant. Interleukin-6, systolic blood pressure and standard deviation of wall thickness (WT) at baseline were independently positively associated with 18-FDG uptake (mean of maximum [MeanMax] TBR change over 6 months). Mean of mean TBR, phospholipase A2, apolipoprotein A-I, and high-sensitivity C-reactive protein at baseline were independently negatively associated with MeanMax TBR change over 6 months. Mean WT and plasminogen activator inhibitor-1 (PAI-1) activity at baseline, and age, were independently associated with change in WA over 24 months. For TVA changes; mean WA and PAI-1 activity at baseline, age, and female gender were independent predictors. These findings may help determine patients most suitable for clinical trials employing plaque inflammation or burden changes as endpoints.

Topics: Amides; Anticholesteremic Agents; Coronary Artery Disease; Esters; Female; Fluorodeoxyglucose F18; Follow-Up Studies; Humans; Inflammation; Magnetic Resonance Imaging; Male; Middle Aged; Plaque, Atherosclerotic; Positron-Emission Tomography; Predictive Value of Tests; Radiopharmaceuticals; Sulfhydryl Compounds; Tomography, X-Ray Computed; Treatment Outcome

In almost 30 years since the introduction of HMG-CoA reductase inhibitors (statins), no other class of lipid modulators has entered the market. Elevation of high-density lipoprotein-cholesterol (HDL-C) via inhibiting cholesteryl ester transfer protein (CETP) is an attractive strategy for reducing the risk of cardiovascular events in high-risk patients. Transfer of triglyceride and cholesteryl ester (CE) between lipoproteins is mediated by CETP; thus inhibition of this pathway can increase the concentration of HDL-C. Torcetrapib was the first CETP inhibitor evaluated in phase III clinical trials. Because of off-target effects, torcetrapib raised blood pressure and increased the concentration of serum aldosterone, leading to higher cardiovascular events and mortality. Torcetrapib showed positive effects on cardiovascular risk especially in patients with a greater increase in HDL-C and apolipoprotein A-1 (apoA-1) levels. The phase III clinical trial of dalcetrapib, the second CETP inhibitor that has entered clinical development, was terminated because of ineffectiveness. Dalcetrapib is a CETP modulator that elevated HDL-C levels but did not reduce the concentration of low-density lipoprotein cholesterol (LDL-C). Both heterotypic and homotypic CE transfer between lipoproteins are mediated by some CETP inhibitors, including torcetrapib, anacetrapib, and evacetrapib, while dalcetrapib only affects the heterotypic CE transfer. Dalcetrapib has a chemical structure that is distinct from other CETP inhibitors, with a smaller molecular weight and a lack of trifluoride moieties. Moreover, dalcetrapib is a pro-drug that must be hydrolyzed to a pharmacologically active thiol form. Two other CETP inhibitors, anacetrapib and evacetrapib, are currently undergoing evaluation in phase III clinical trials. Both molecules have shown beneficial effects by increasing HDL-C and decreasing LDL-C concentration. The success of anacetrapib and evacetrapib remains to be confirmed upon the completion of phase III clinical trials in 2017 and 2015, respectively. Generally, the concentration of HDL-C has been considered a biomarker for the activity of CETP inhibitors. However, it is not clear whether a fundamental relationship exists between HDL-C levels and the risk of coronary artery diseases. The most crucial role for HDL is cholesterol efflux capacity in which HDL can reverse transport cholesterol from foam cells in atherosclerotic plaques. In view of the heterogeneity in HDL particl

Topics: Amides; Animals; Anticholesteremic Agents; Benzodiazepines; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Coronary Artery Disease; Esters; Humans; Oxazolidinones; Quinolines; Sulfhydryl Compounds

Topics: Amides; Anticholesteremic Agents; Coronary Artery Disease; Coronary Stenosis; Diagnostic Imaging; Esters; Female; Humans; Hypercholesterolemia; Male; Sulfhydryl Compounds

Topics: Amides; Cholesterol Ester Transfer Proteins; Coronary Artery Disease; Diabetes Mellitus; Drug Therapy, Combination; Esters; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Niacin; Randomized Controlled Trials as Topic; Sulfhydryl Compounds

Topics: Amides; Animals; Anticholesteremic Agents; Apolipoprotein A-I; Biological Transport; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Coronary Artery Disease; Esters; Heterozygote; Humans; Hyperlipoproteinemias; Lipoproteins, HDL; Lipoproteins, LDL; Liver; Middle Aged; Mutation; Randomized Controlled Trials as Topic; Sulfhydryl Compounds; Tomography, X-Ray Computed; Triglycerides