Dalcetrapib and anacetrapib increase apolipoprotein E-containing HDL in rabbits and humans.

The large HDL particles generated by administration of cholesteryl ester transfer protein inhibitors (CETPi) remain poorly characterized, despite their potential importance in the routing of cholesterol to the liver for excretion, which is the last step of the reverse cholesterol transport. Thus, the effects of the CETPi dalcetrapib and anacetrapib on HDL particle composition were studied in rabbits and humans. The association of rabbit HDL to the LDL receptor (LDLr) in vitro was also evaluated. New Zealand White rabbits receiving atorvastatin were treated with dalcetrapib or anacetrapib. A subset of patients from the dal-PLAQUE-2 study treated with dalcetrapib or placebo were also studied. In rabbits, dalcetrapib and anacetrapib increased HDL-C by more than 58% (P < 0.01) and in turn raised large apo E-containing HDL by 66% (P < 0.001) and 59% (P < 0.01), respectively. Additionally, HDL from CETPi-treated rabbits competed with human LDL for binding to the LDLr on HepG2 cells more than control HDL (P < 0.01). In humans, dalcetrapib increased concentrations of large HDL particles (+69%, P < 0.001) and apo B-depleted plasma apo E (+24%, P < 0.001), leading to the formation of apo E-containing HDL (+47%, P < 0.001) devoid of apo A-I. Overall, in rabbits and humans, CETPi increased large apo E-containing HDL particle concentration, which can interact with hepatic LDLr. The catabolism of these particles may depend on an adequate level of LDLr to contribute to reverse cholesterol transport.

Cholesteryl Ester Transfer Protein Inhibitors and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Cholesteryl ester transfer protein (CETP) inhibitors increase serum high-density lipoprotein cholesterol (HDL-c) concentration; however, their impact on cardiovascular outcomes is not clear. This systematic review examines the effect of CETP inhibitors on serum lipid profiles, cardiovascular events, and all-cause mortality. METHODS: We searched MEDLINE, Embase, and the Cochrane Library of Clinical Trials for placebo-controlled randomized controlled trials (RCTs) that examined the effect of a CETP inhibitor (dalcetrapib, anacetrapib, evacetrapib, or TA-8995) on all-cause mortality, major adverse cardiovascular events (MACE), or the components of MACE at ≥6 months. Data were pooled using random-effects models. RESULTS: A total of 11 RCTs (n = 62,431) were included in our systematic review; 4 examined dalcetrapib (n = 16,612), 6 anacetrapib (n = 33,682), and 1 evacetrapib (n = 12,092). Compared to dalcetrapib, ana-cetrapib and evacetrapib were more efficacious at raising HDL-c levels (∼100-130 vs. ∼30%). Anacetrapib and evacetrapib also decreased low-density lipoprotein cholesterol (LDL-c) by approximately 30% while dalcetrapib did not affect the LDL-c level. Overall, CETP inhibitors were not associated with the incidence of MACE (pooled relative risk [RR]: 0.97; 95% confidence interval [CI]: 0.91-1.04). CETP inhibitors may decrease the risks of nonfatal myocardial infarction (MI) (RR: 0.93; 95% CI: 0.87-1.00) and cardiovascular death (RR: 0.92; 95% CI: 0.83-1.01), though these trends did not reach statistical significance. CONCLUSIONS: CETP inhibitors are not associated with an increased risk of MACE or all-cause mortality. There is a trend towards small reductions in nonfatal MI and cardiovascular death, though the clinical im-portance of such reductions is likely modest.

Design and development of novel therapeutics for coronary heart disease treatment based on cholesteryl ester transfer protein inhibition - in silico approach.

Cholesteryl ester transfer protein (CETP) belongs to the group of enzymes which inhibition have the application in the treatment of cardiovascular diseases. This study presents QSAR modeling for a set of compounds acting as CETP inhibitors based on the Monte Carlo optimization with SMILES notation and molecular graph-based descriptors, and field-based 3D modeling. A 3D QSAR model was developed for one random split into the training and test sets, whereas conformation independent QSAR models were developed for three random splits, with the results suggesting there is an excellent correlation between them. Various statistical approaches were used to assess the statistical quality of the developed models, including robustness and predictability, and the obtained results were very good. This study used a novel statistical metric known as the index of ideality of correlation for the final assessment of the model, and the results that were obtained suggested that the model was good. Also, molecular fragments which account for the increases and/or decreases of a studied activity were defined and then used for the computer-aided design of new compounds as potential CETP inhibitors. The final assessment of the developed QSAR model and designed inhibitors was done using molecular docking, which revealed an excellent correlation with the results from QSAR modeling.Communicated by Ramaswamy H. Sarma.

Therapy with cholesteryl ester transfer protein (CETP) inhibitors and diabetes risk.

BACKGROUND: Cholesteryl ester transfer protein (CETP) inhibitors are a class of drugs that targets the CETP enzyme to significantly increase serum high-density lipoprotein cholesterol (HDL-C) and decrease low-density lipoprotein cholesterol (LDL-C) levels. As HDL-C has potential antidiabetic properties, and the beneficial effects of CETP drugs on glucose homoeostasis have not been sufficiently studied, the aims of this study were: (1) to evaluate the effect of CETP inhibitors on the incidence of diabetes; and (2) to assess the association between CETP inhibitor-induced changes in HDL-C levels and incidence of diabetes. METHODS: A meta-analysis was performed of randomized controlled clinical trials of CETP inhibitor therapy, either alone or combined with other lipid-lowering drugs, reporting data from new cases of diabetes with a minimum of 6 months of follow-up, after searching the PubMed/MEDLINE, Embase and Cochrane Controlled Trials databases. A fixed-effects meta-regression model was then applied. RESULTS: Four eligible trials of CETP inhibitors, involving a total of 73,479 patients, were considered for the analyses, including 960 newly diagnosed cases of diabetes in the CTEP inhibitor group vs 1086 in the placebo group. CETP inhibitor therapy was associated with a significant 12% reduction in incidence of diabetes (OR: 0.88, 95% CI: 0.81-0.96; P=0.005). Assessment of the relationship between on-treatment HDL-C and the effect of CETP inhibitors showed a statistically non-significant trend (Z=-1.13, P=0.26). CONCLUSION: CETP inhibitors reduced the incidence of diabetes. The improvement in glucose metabolism may have been related, at least in part, to the increase in HDL-C concentration.

Cholesteryl ester transfer protein inhibitors: challenges and perspectives.

INTRODUCTION: Cholesteryl ester transfer protein (CETP) inhibitors substantially increase the concentration of high-density lipoprotein cholesterol (HDL-C), which may have a possible beneficial effect for cardiovascular disease risk reduction. AREAS COVERED: Current data regarding the effects of CETP inhibitors on cardiovascular disease risk and possible mechanisms for their effects and safety are presented in this review. Expert commentary: The first CETP inhibitor, torcetrapib, was discontinued because of increased off-target adverse effects (increased serum aldosterone and blood pressure levels). The development program of dalcetrapib and evacetrapib, which were not associated with increased blood pressure, was terminated due to futility (insufficient efficacy) concerning cardiovascular outcomes. Although the failure of torcetrapib has been attributed to specific off-target effects, there are some common characteristics between CETP inhibitors pointing to the possibility that certain adverse effects may be class-specific. The newer CETP inhibitors anacetrapib and TA-8995 have promising effects on lipid profile and metabolism (increase of HDL-C and reduction of both low-density lipoprotein cholesterol and lipoprotein (a) levels), but their cardiovascular effects and safety profile have not yet been confirmed in large outcome trials.

Anacetrapib for the treatment of dyslipidaemia: the last bastion of the cholesteryl ester transfer protein inhibitors?

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Effects of anacetrapib on plasma lipids in specific patient subgroups in the DEFINE (Determining the Efficacy and Tolerability of CETP INhibition with AnacEtrapib) trial.

BACKGROUND: In the Determining the Efficacy and Tolerability of cholesteryl ester transfer protein (CETP) INhibition with AnacEtrapib (DEFINE) trial, anacetrapib added to statin produced robust low-density lipoprotein cholesterol (LDL-C)-lowering and high-density lipoprotein cholesterol (HDL-C)-raising vs placebo in patients with coronary heart disease (CHD). Predictors of the degree of LDL-C and HDL-C responses to anacetrapib, however, are poorly understood. OBJECTIVE: Lipid effects of anacetrapib in patient subgroups within the DEFINE trial (clinicaltrials.gov: NCT00685776) are reported. METHODS: The percent of placebo-corrected changes from baseline for LDL-C (estimated by Friedewald calculation [Fc-LDL-C]) and HDL-C after 24 weeks of anacetrapib 100 mg/day were compared among patients by age, gender, race, diabetes status, type of concomitant statin with or without other lipid therapies, and baseline HDL-C, Fc-LDL-C, and triglyceride (TG) levels. RESULTS: Percent decreases in Fc-LDL-C and increases in HDL-C with anacetrapib were similar (magnitude of difference generally <1/5 of the overall treatment effect) across subgroups by age, gender, diabetes status, lipid-modifying regimen, and baseline Fc-LDL-C, HDL-C, or TG. On the other hand, anacetrapib effects on Fc-LDL-C (-24% vs -41%) and HDL-C (+75% vs +139%) appeared to be less in black vs white patients, respectively. CONCLUSION: Effects of anacetrapib on Fc-LDL-C and HDL-C were generally comparable across subgroups, including being relatively independent of baseline Fc-LDL-C, HDL-C, or TG levels. The clinical impact of the lipid-modifying effects of anacetrapib is being evaluated in the cardiovascular disease outcomes trial, Randomized EValuation of the Effects of Anacetrapib though Lipid-modification (REVEAL).

Lipoprotein apheresis and new therapies for severe familial hypercholesterolemia in adults and children.

Familial hypercholesterolemia (FH), the most common and severe monogenic form of hypercholesterolemia, is an autosomal co-dominant disease characterized by an increased plasma low density lipoprotein (LDL)-cholesterol concentration and premature coronary heart disease (CHD). The clinical phenotype depends on the gene involved and severity of mutation (or mutations) present. Patients with homozygous or compound heterozygous FH have severe hypercholesterolemia (LDL-cholesterol >13 mmol/L) due to a gene dosing effect and without treatment have accelerated atherosclerotic CHD from birth, and frequently die of CHD before age 30. Cholesterol-lowering therapies have been shown to reduce both mortality and major adverse cardiovascular events in individuals with FH. Lipoprotein apheresis concomitant with lipid-lowering therapy is the treatment of choice for homozygous FH. This article describes the rationale and role of lipoprotein apheresis in the treatment of severe FH and outlines the recent advances in new pharmacotherapies for this condition.

High density lipoprotein and cardiovascular diseases.

Several epidemiological studies have clearly shown that low plasma levels of high density lipoprotein cholesterol (HDL-C) represent a cardiovascular disease (CVD) risk factor. However, it is unclear if there is a causal association between HDL-C concentration and CVD. A recent study published in the Lancet, which performed two Mendelian randomization analyses, showed that increased HDL-C levels were not associated with a decreased risk of myocardial infarction. These findings, together with the termination of the niacin-based AIM-HIGH trial and the discontinuation of cholesteryl ester transfer protein inhibitor dalcetrapib, challenge the concept that raising of plasma HDL-C will uniformly translate into reductions in CVD risk. HDL particles exhibit several anti-atherosclerotic properties, such as anti-inflammatory and anti-oxidative activities and cellular cholesterol efflux activity. Furthermore, HDL particles are very heterogeneous in terms of size, structure, composition and metabolism. HDL functionality may be associated more strongly with CVD risk than the traditional HDL-C levels. More research is needed to assess the association of the structure of HDL particle with its functionality and metabolism.

High-density lipoprotein cholesterol: How High.

The high-density lipoprotein cholesterol (HDL-C) is considered anti-atherogenic good cholesterol. It is involved in reverse transport of lipids. Epidemiological studies have found inverse relationship of HDL-C and coronary heart disease (CHD) risk. When grouped according to HDL-C, subjects having HDL-C more than 60 mg/dL had lesser risk of CHD than those having HDL-C of 40-60 mg/dL, who in turn had lesser risk than those who had HDL-C less than 40 mg/dL. No upper limit for beneficial effect of HDL-C on CHD risk has been identified. The goals of treating patients with low HDL-C have not been firmly established. Though many drugs are known to improve HDL-C concentration, statins are proven to improve CHD risk and mortality. Cholesteryl ester transfer protein (CETP) is involved in metabolism of HDL-C and its inhibitors are actively being screened for clinical utility. However, final answer is still awaited on CETP-inhibitors.