Assessment of the clinical effects of cholesteryl ester transfer protein inhibition with evacetrapib in patients at high-risk for vascular outcomes: Rationale and design of the ACCELERATE trial

doi:10.1016/j.ahj.2015.09.007

American Heart Journal

Volume 170, Issue 6, December 2015, Pages 1061-1069

https://doi.org/10.1016/j.ahj.2015.09.007 Get rights and content

Background

Potent pharmacologic inhibition of cholesteryl ester transferase protein by the investigational agent evacetrapib increases high-density lipoprotein cholesterol by 54% to 129%, reduces low-density lipoprotein cholesterol by 14% to 36%, and enhances cellular cholesterol efflux capacity. The ACCELERATE trial examines whether the addition of evacetrapib to standard medical therapy reduces the risk of cardiovascular (CV) morbidity and mortality in patients with high-risk vascular disease.

Study Design

ACCELERATE is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients qualified for enrollment if they have experienced an acute coronary syndrome within the prior 30 to 365 days, cerebrovascular accident, or transient ischemic attack; if they have peripheral vascular disease; or they have diabetes with coronary artery disease. A total of 12,092 patients were randomized to evacetrapib 130 mg or placebo daily in addition to standard medical therapy. The primary efficacy end point is time to first event of CV death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. Treatment will continue until 1,670 patients reached the primary end point; at least 700 patients reach the key secondary efficacy end point of CV death, myocardial infarction, and stroke, and the last patient randomized has been followed up for at least 1.5 years.

Conclusions

ACCELERATE will establish whether the cholesteryl ester transfer protein inhibition by evacetrapib improves CV outcomes in patients with high-risk vascular disease.

Section snippets

Preclinical observations of CETP

First discovered in the 1970s, CETP is a plasma-based factor that facilitates the transfer of esterified cholesterol from high-density lipoproteins (HDLs) to LDL and very low-density lipoprotein particles in exchange for triglycerides. CETP is not ubiquitously expressed in all animal species. In particular, rabbits and humans endogenously express CETP, whereas mice do not. Transgenic expression of CETP in rodents has generated conflicting results, with evidence of protective,3, 4, 5, 6, 7

Population and genetic observations of CETP

Studies have demonstrated that individuals with low levels of CETP activity have higher HDL cholesterol (HDL-C) and lower LDL-C values.17, 18 A number of reports have varied with regard to any potential association with protection from CV risk. Subsequent population studies demonstrated an association between low CETP levels and low rates of CV disease in some,¹⁹ but not all,20, 21 cohorts. Further analysis revealed that the associated lipid state may be critical in determining the influence of

Early experience with torcetrapib

Torcetrapib was the first CETP inhibitor to reach an advanced stage of clinical development. Early studies in humans demonstrated that torcetrapib potently inhibited CETP, resulting in increases in HDL-C by more than 50% and incremental lowering of LDL-C by up to 20% in addition to background statin therapy. These studies also revealed small increases in blood pressure by 2 to 3 mm Hg.²⁵ Supporters of this therapeutic approach felt that any adverse CV effect of this small blood pressure

Modest CETP inhibition with dalcetrapib

Dalcetrapib moved forward in clinical development with evidence of modest CETP inhibition, HDL-C raising by 25% to 30%, no effect on LDL-C levels, and no evidence of torcetrapib-associated off-target toxicity. Early studies with dalcetrapib demonstrated enhanced cholesterol efflux capacity,³⁵ but neither a beneficial nor adverse effect on endothelial function³⁶ or measures of plaque burden and inflammatory activity on carotid imaging.³⁷ The dal-OUTCOMES trial compared the impact of dalcetrapib

Development of potent CETP inhibitors

Evacetrapib and anacetrapib are potent CETP inhibitors, with favorable effects on HDL-C and LDL-C and no evidence of torcetrapib-associated off-target toxicity in early clinical trials. Anacetrapib is a potent and lipophilic CETP inhibitor, increasing HDL-C by more than 130%, decreasing LDL-C by 35% to 40%, and with a 94% probability of lacking torcetrapib adverse effects on CV events on Bayesian analysis.⁴¹ Pharmacologic distribution and accumulation with adipose tissue are likely to

Study objectives and design

The ACCELERATE trial tests the hypothesis that evacetrapib added to the standard of care reduces CV mortality and morbidity among patients with high-risk vascular disease. This is a phase 3, international multicenter, randomized, double-blind, placebo-controlled event-driven trial. Patients are treated with either evacetrapib 130 mg daily or matching placebo. A total of 12,092 patients have been enrolled from 543 sites in 36 countries. The trial will continue until 1,670 primary end points

Study organization

The ACCELERATE trial is funded by the sponsor, Eli Lilly and Company (Indianapolis, IN), and coordinated by the Cleveland Clinic Coordinating Center for Clinical Research (C5Research; Cleveland, OH). Covance (Princeton, NJ) serves as the contract research organization and provides data and site management. Academic members of the Executive Committee designed the trial in collaboration with the sponsor. The Steering Committee, consisting of the Executive Committee together with the physician

Patient population

The study population consists of patients ≥18 years of age with high-risk vascular disease defined as falling into at least 1 of the following 4 groups:

•
History of ACS, with hospital discharge ≥30 and <365 days prior to randomization. Acute coronary syndrome was defined as UA, non–ST-elevation MI, or ST-elevation MI. Patients were to have undergone coronary revascularization for their ACS event prior to randomization into the ACCELERATE trial or were anticipated to be managed without

Treatment regimen and follow-up

Patients were randomly assigned using an interactive voice response system in a 1:1 ratio to receive evacetrapib 130 mg orally daily or matching placebo, superimposed upon a background of contemporary and guideline-based care for high-risk vascular disease and its risk factors. Patients had initially been evaluated at a screening visit, at which time clinical eligibility criteria were confirmed and central laboratory lipid measurements obtained. Those patients who met all entry criteria

Lipid management

In view of the anticipated effects of evacetrapib on levels of HDL-C and LDL-C, knowledge by the investigator or patient of lipid values during randomized treatment could lead to unmasking of therapy assignment. Therefore, lipid profiles are measured in a central laboratory at randomization, 4 weeks after randomization, and at each subsequent on-site study visit. All members of the study team, including those from the sponsor, academic research organization, and contract research organization,

End points

The primary efficacy measure is the time to first occurrence of any component of the composite of CV death, MI, stroke, coronary revascularization, or hospitalization for UA. Death will be adjudicated as CV unless there is a documented identifiable nonvascular cause. Myocardial infarction includes types 1 to 5 of the Universal Definition (spontaneous or procedure-related MI).⁴⁴ Stroke is defined as an acute episode of neurologic dysfunction caused by vascular injury lasting for longer than 24

Statistical considerations

ACCELERATE is an event-driven clinical trial. The targeted number of primary end points in the original protocol of October 2012 was calculated to detect a 17.5% reduction in hazard for the primary composite end point, with an estimated enrollment of 11,000 patients followed up for an average of 2.5 years. A protocol amendment in September 2013 increased the targeted number of primary end points and increased enrollment to 12,000 patients to detect a smaller reduction in hazard of 15%, given

Trial progress

Enrollment started in October 2012 and ceased in December 2013 when 12,092 patients had been randomized. Baseline characteristics (Table II) show representation throughout the world, with patients entering the trial with excellent control of lipids and with high rates of treatment with contemporary, evidence-based lipid-modifying therapies. Qualifying diagnoses for inclusion are illustrated in Figure; more than 80% of patients have coronary artery disease, and more than 60% have diabetes. The

Summary

ACCELERATE is a phase 3 randomized trial that will define whether evacetrapib, when added to the standard of care of patients with high-risk vascular disease, will reduce the risk of CV ischemic events. This trial will establish whether the beneficial effects of CETP inhibition on HDL-C, LDL-C, and cholesterol efflux will translate to protection against ischemic complications of atherosclerosis.

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Evolving Therapeutic Targets: Cholesteryl Ester Transfer Protein Inhibition
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Cholesteryl ester transfer protein (CETP) facilitates the exchange of esterified cholesterol from high-density lipoproteins (HDLs) to very-low-density lipoproteins and low-density lipoproteins (LDLs) in exchange for triglycerides. Population and genetic studies demonstrate an inverse association between CETP activity and cardiovascular risk. Preclinical studies have revealed that inhibiting CETP is atheroprotective. However, clinical trials have demonstrated no cardiovascular benefit with most CETP inhibitors and a modest benefit with anacetrapib. Insights from these studies provide the potential to continue development of CETP inhibitors as an approach to reducing cardiovascular risk.
Longitudinal High-Sensitivity C-Reactive Protein and Longer-Term Cardiovascular Outcomes in Optimally-Treated Patients With High-Risk Vascular Disease
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Citation Excerpt :
The ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibitor with Evacetrapib in Patients with High-Risk for Vascular Outcomes) valuated whether evacetrapib, a cholesteryl ester transfer protein inhibitor, would improve cardiovascular outcomes among patients with high-risk vascular disease. Trial design and major findings have been previously described.8,9 Briefly, ACCELERATE was a multicenter, randomized, double-blind, placebo-controlled phase 3 trial that enrolled 12,092 patients with high-risk vascular disease, defined as recent ACS, peripheral artery disease, cerebrovascular disease, and diabetes mellitus, with an established history of coronary artery disease.
The relation between serial high-sensitivity C-reactive protein (hsCRP) and long-term major cardiovascular events (MACEs; cardiovascular death, myocardial infarction, stroke, coronary revascularization, hospitalization for unstable angina) has not been explored in optimally-treated patients with atherosclerotic cardiovascular disease. We tested the hypothesis that longitudinal follow-up hsCRP (repeated measures over time) would associate with 30-month MACE rates. We performed a post hoc analysis of ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibitor with Evacetrapib in Patients with High-Risk for Vascular Outcomes), involving optimally-treated patients with high-risk vascular disease, with available baseline and at least 1 follow-up hsCRP level. Using multivariable Cox proportional hazard models, we determined the association of longitudinal follow-up hsCRP with MACE at 30 months among 8,563 patients (aged 64.6 ± 9 years, 22% women). Patients with incident MACE (n = 961) had higher baseline hsCRP levels (1.77 vs 1.46 mg/L, p <0.0001 for patients with and without MACE, respectively) and showed an upward trajectory during follow-up, whereas median hsCRP levels remained <2 mg/L at all time points (1.83 vs 1.53 mg/L, 1.91 vs 1.53 mg/L, 1.76 vs 1.37 mg/L, at 3, 12, and 24 months, respectively). In a multivariable analysis, higher longitudinal hsCRP levels were independently associated with MACE (hazard ratio [95% confidence interval] per SD 1.19 [1.10 to 1.29], p <0.001), the majority of its individual components and all-cause death. Multivariable models containing longitudinal hsCRP provided improved predictive ability of MACE over baseline hsCRP. In the setting of established medical therapies, longitudinal follow-up hsCRP was independently associated with long-term MACE. In conclusion, these findings suggest that longitudinal hsCRP represents a novel approach of residual cardiovascular risk even when on-treatment hsCRP levels remain <2 mg/L.
The CAP (Controlled attenuation parameter), an indicator of risk and severity of metabolic syndrome?
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Évaluer la relation entre les valeurs du CAP (Controlled Attenuation Parameter) et les différents paramètres du syndrome métabolique.
Il s’agit d’une étude transversale incluant tous les patients âgés de plus de 18 ans et présentant une maladie chronique du foie, adressés à l’hôpital pour une évaluation non invasive de la fibrose hépatique. La mesure de l’élasticité hépatique et du CAP a été réalisée de façon concomitante en utilisant la sonde M ou XL du Fibroscan par des opérateurs entraînés.
La prévalence du syndrome métabolique chez les patients avec un CAP ≥ 238 dB/m était plus élevée que chez les patients avec un CAP < 238 dB/m, et elle augmentait de façon significative avec l’augmentation de la sévérité de la stéatose hépatique (p < 0,001). Les valeurs du CAP étaient significativement plus élevées chez les patients présentant un syndrome métabolique et ces valeurs augmentaient de façon significative avec l’augmentation du nombre de paramètres du syndrome métabolique (p < 0,001). En analyse univariée, il existait une relation linéaire positive statistiquement significative entre le CAP et les paramètres du syndrome métabolique sauf la glycémie et le taux d’HDLc. En analyse multivariée, seuls le tour de taille et le taux de triglycérides étaient significativement liés aux valeurs du CAP.
Cette étude montre qu’il existe une corrélation significative entre le CAP et les différents paramètres du syndrome métabolique. Le CAP pourrait être un indicateur de risque et de sévérité du syndrome métabolique.
The aim of this study is to investigate the relationship between CAP (Controlled Attenuation Parameter) values and the different components of the metabolic syndrome.
This is a cross-sectional study including all patients over 18 years of age with chronic liver disease who were referred to our center for a non-invasive assessment of liver fibrosis. The measurement of hepatic elasticity and CAP was carried out concomitantly using the M or XL probe of Fibroscan® by trained operators.
The prevalence of metabolic syndrome in patients with CAP ≥ 238 dB/m was higher than in patients with CAP < 238 dB/m, and significantly increased with the severity of hepatic steatosis (p < 0.001). CAP values were higher in patients with metabolic syndrome and significantly increased with the increase in the number of metabolic syndrome components (p < 0.001). In univariate analysis, there was a statistically significant positive linear relationship between CAP values and components of metabolic syndrome except for blood glucose and HDLc level. In multivariate analysis, only waist circumference and triglycerides level were significantly related to CAP values.
This study shows that there is a significant correlation between CAP and the different components of the metabolic syndrome. CAP could be an indicator of risk and severity of metabolic syndrome.
Lipid-lowering therapy: Guidelines to precision medicine
2021, Clinica Chimica Acta
Dyslipidemia is correlated with a series of health problems, such as obesity, insulin resistance, and the development of cardiovascular disease (CVD). Currently, accumulating evidence sheds light on the fact that β-hydroxy β-methylglutaryl-CoA reductase inhibitors, named statins, could lower circulating lipid-density lipoprotein cholesterol (LDL-C) and represent a revolution for the prevention of metabolic disorder diseases. In addition, statins remain the cornerstone of LDL-C-lowering treatments, together with ezetimibe and bile acid sequestrants, which are used either in combination with statins or as monotherapies in the case of statin intolerance or side effects. On the other hand, other medicines that reduce circulating LDL-C have also been researched, including inhibitors of protein convertase subtilisin/kexin type 9 (PCSK9). More recently, PCSK9 inhibitors have been approved for the secondary prevention of CVD and for the atherogenic dyslipidemia therapy. Here, we summarize the latest guidelines for the management of dyslipidemia and its relation to CVD, focusing on LDL-C-lowering medicines that are either available in daily clinical practice or under investigation. In addition, we also discuss the “who, when, and how” with respect to treating patients with dyslipidemia according to LDL-C reduction as an individualized clinical precision medicine.
Cholesteryl ester transfer protein inhibitors in precision medicine
2020, Clinica Chimica Acta
Dyslipidemia is associated with atherosclerosis and cardiovascular disease development, posing serious risks to human health. Cholesteryl ester transfer protein (CETP) is responsible for exchange of neutral lipids, such as cholesteryl ester and TG, between plasma high density lipoprotein (HDL) particles and Apolipoprotein B-100 (ApoB-100) containing lipoprotein particles. Genetic studies suggest that single-nucleotide polymorphism (SNPs) with loss of activity CETP is associated with increased HDL-C, reduced LDL-C, and cardiovascular risk. In animal studies, mostly in rabbits, which have similar CETP activity to humans, inhibition of CETP through antisense oligonucleotides reduced aortic arch atherosclerosis. Concerning this notion, inhibiting the CETP is considered as a promise approach to reduce cardiovascular events, and several CETP inhibitors have been recently studied as a cholesterol modifying agent to reduce cardiovascular mortality in high risk cardiovascular disease patients. However, in Phase III cardiovascular outcome trials, three CETP inhibitors, named Torcetrapib, Dalcetrapib, and Evacetrapib, did not provide expected cardiovascular benefits and failed to improve outcomes of patient with cardiovascular diseases (CVD). Although REVEAL trail has recently shown that Anacetrapib could reduce major coronary events, it was also shown to induce excessive lipid accumulation in adipose tissue; thereby, the further regulatory approval will not be sought. On the other hand, growing evidence indicated that the function of CETP inhibitors on modulating the cardiovascular events are determined by correlated single nucleotide polymorphism (SNP) in the ADCY9 gene. However, the underlying mechanisms whereby CETP inhibitors interact with the genotype are not yet elucidated, which could potentially be related to the genotype-dependent cholesterol efflux capacity of HDL particles. In the present review, we summarize the current understanding of the functions of CETP and the outcomes of the phase III randomized controlled trials of CETP inhibitors. In addition, we also put forward the implications from results of the trials which potentially suggest that the CETP inhibitors could be a promising precise therapeutic medicine for CVD based on genetic background.
Present therapeutic role of cholesteryl ester transfer protein inhibitors
2018, Pharmacological Research
Citation Excerpt :
In experimental models, anacetrapib alone or in combination with atorvastatin reduced the atherosclerotic lesion area and severity and increased the plaque stability index [70]. The recently completed ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High-Risk for Vascular Outcomes; NCT01687998) study was aimed at evaluating whether the addition of evacetrapib to standard medical therapy reduced the risk of CV morbidity and mortality in patients with high-risk vascular disease [92]. 12,092 patients (mean age, 64.9), only in secondary prevention, were randomized to either evacetrapib (130 mg; n = 6038) or matching placebo (n = 6054), administered daily for up to 4 years, in addition to standard medications (eg, any statin, high-intensity statin, medication to treat high-blood pressure and aspirin).
Therapeutic interventions aimed at increasing high-density lipoprotein (HDL) levels in order to reduce the residual cardiovascular (CV) risk of optimally drug treated patients have not provided convincing results, so far. Transfer of cholesterol from extrahepatic tissues to the liver appears to be the major atheroprotective function of HDL, and an elevation of HDL levels could represent an effective strategy. Inhibition of the cholesteryl ester transfer protein (CETP), raising HDL-cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) levels, reduces low-density lipoprotein-cholesterol (LDL-C) and apoB levels, thus offering a promising approach. Despite the beneficial influence on cholesterol metabolism, off-target effects and lack of reduction in CV events and mortality (with torcetrapib, dalcetrapib and evacetrapib) highlighted the complex mechanism of CETP inhibition. After the failure of the above mentioned inhibitors in phase III clinical development, possibly due to the short duration of the trials masking benefit, the secondary prevention REVEAL trial has recently shown that the inhibitor anacetrapib significantly raised HDL-C (+104%), reduced LDL-C (−18%), with a protective effect on major coronary events (RR, 0.91; 95%CI, 0.85–0.97; p = 0.004). Whether LDL-C lowering fully accounts for the CV benefit or if HDL-C-rise is a crucial factor still needs to be determined, although the reduction of non-HDL (−18%) and Lp(a) (−25%), should be also taken into account. In spite of the positive results of the REVEAL Study, Merck decided not to proceed in asking regulatory approval for anacetrapib. Dalcetrapib (Dal-GenE study) and CKD-519 remain the two molecules within this area still in clinical development.

View all citing articles on Scopus

: Conflict of interest: The ACCELERATE trial is funded by the sponsor, Eli Lilly and Company (Indianapolis, IN).

: John K. French, MB, PhD served as guest editor for this article.

: RCT No. NCT01687998.

^l: Contributed equally to this manuscript.

View full text

Trial DesignAssessment of the clinical effects of cholesteryl ester transfer protein inhibition with evacetrapib in patients at high-risk for vascular outcomes: Rationale and design of the ACCELERATE trial

Background

Study Design

Conclusions

Section snippets

Preclinical observations of CETP

Population and genetic observations of CETP

Early experience with torcetrapib

Modest CETP inhibition with dalcetrapib

Development of potent CETP inhibitors

Study objectives and design

Study organization

Patient population

Treatment regimen and follow-up

Lipid management

End points

Statistical considerations

Trial progress

Summary

J Am Coll Cardiol

J Biol Chem

J Lipid Res

J Lipid Res

J Biol Chem

J Lipid Res

Lancet

Lancet

Am J Cardiol

Am J Cardiol

Lancet

Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials

Lancet

Cholesteryl ester transfer protein expression prevents diet-induced atherosclerotic lesions in male db/db mice

Arterioscler Thromb Vasc Biol

Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene

J Clin Invest

Restoration of high-density lipoprotein levels by cholesteryl ester transfer protein expression in scavenger receptor class B type I (SR-BI) knockout mice does not normalize pathologies associated with SR-BI deficiency

Arterioscler Thromb Vasc Biol

Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein

Nature

Increased atherosclerosis in ApoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression

Arterioscler Thromb Vasc Biol

Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice

Arterioscler Thromb Vasc Biol

Spontaneous combined hyperlipidemia, coronary heart disease and decreased survival in Dahl salt-sensitive hypertensive rats transgenic for human cholesteryl ester transfer protein

Nat Med

Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis

Arterioscler Thromb Vasc Biol

A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits

Nature

Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins

Nature

Trial Design
Assessment of the clinical effects of cholesteryl ester transfer protein inhibition with evacetrapib in patients at high-risk for vascular outcomes: Rationale and design of the ACCELERATE trial