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

Nicholls, Stephen J.; Lincoff, A. Michael; Barter, Philip J.; Brewer, H. Bryan; Fox, Keith A.A.; Gibson, C. Michael; Grainger, Christopher M.; Menon, Venugopal P.; Montalescot, Gilles; Rader, Daniel J.; Tall, Alan R.; McErlean, Ellen; Riesmeyer, Jeffrey S.; Vangerow, Burkhard; Ruotolo, Giacomo; Weerakkody, Govinda J.; Nissen, Steven E.

doi:10.1016/j.ahj.2015.09.007

Cited by 81 publications

(36 citation statements)

References 44 publications

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“…8 In dal-OUTCOMES, dalcetrapib, which did not have off-target effects and raised HDL-C about 30%, there was no effect on CVD. 9 More recently, ACCELERATE, a CVD outcome study with evacetrapib, 10 another CETP inhibitor without off-target effects, was stopped early due to apparent insufficient efficacy of the drug, although no specific data has been presented yet. Two additional CETP inhibitors under development, anacetrapib and TA-8995, do not appear to have the off target effects of torcetrapib and increase HDL-C by up to 140 – 180%.…”

Section: Introductionmentioning

confidence: 99%

Cholesteryl Ester Transfer Protein Inhibition With Anacetrapib Decreases Fractional Clearance Rates of High-Density Lipoprotein Apolipoprotein A-I and Plasma Cholesteryl Ester Transfer Protein

Reyes‐Soffer

Millar

Ngai

et al. 2016

ATVB

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Objective Anacetrapib, an inhibitor of cholesteryl ester transfer protein (CETP) activity, increases plasma concentrations of HDL-C, apoA-I, apoA-II, and CETP. The mechanisms responsible for these treatment-related increases in apolipoproteins and plasma CETP are unknown. We performed a randomized, placebo-controlled, double-blind, fixed-sequence study to examine the effects of anacetrapib on the metabolism of HDL apoA-I and apoA-II and plasma CETP. Approach and Results Twenty-nine participants received atorvastatin 20mg/day plus placebo for four weeks, followed by atorvastatin plus anacetrapib 100 mg/day for 8 weeks (ATV-ANA). Ten participants received double placebo for four weeks followed by placebo plus anacetrapib for 8 weeks (PBO-ANA). At the end of each treatment, we examined the kinetics of HDL apoA-I, HDL apoA-II and plasma CETP after D3-leucine administration as well as 2D gel analysis of HDL subspecies. In the combined ATV-ANA and PBO-ANA groups, anacetrapib treatment increased plasma HDL-C (63.0%, P < 0.001) and apoA-I levels (29.5%, P < 0.001). These increases were associated with reductions in HDL apoA-I fractional clearance rate (FCR) (18.2%, P = 0.002) without changes in production rate (PR). Although the apoA-II levels increased by 12.6% (P < 0.001), we could not discern significant changes in either apoA-II FCR or PR. CETP levels increased 102% (P < 0.001) on anacetrapib due to a significant reduction in the FCR of CETP (57.6%, P < 0.001) with no change in CETP PR. Conclusion Anacetrapib treatment increases HDL apoA-I and CETP levels by decreasing the fractional clearance rate of each protein. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00990808

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Section: Introductionmentioning

confidence: 99%

Cholesteryl Ester Transfer Protein Inhibition With Anacetrapib Decreases Fractional Clearance Rates of High-Density Lipoprotein Apolipoprotein A-I and Plasma Cholesteryl Ester Transfer Protein

Reyes‐Soffer

Millar

Ngai

et al. 2016

ATVB

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“…The trial design has been described previously. 12 The trial was sponsored by Eli Lilly and was coordinated by the Cleveland Clinic Coordinating Center for Clinical Research (C5Research) and Covance (Princeton, NJ). The trial protocol, which is available with the full text of this article at NEJM.org, was designed by the sponsor and the executive committee.…”

Section: Trial Design and Organizationmentioning

confidence: 99%

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

Lincoff¹,

Nicholls²,

Riesmeyer³

et al. 2017

N Engl J Med

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641

357

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BACKGROUNDThe cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODSIn a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTSAt 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P = 0.91). CONCLUSIONSAlthough the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998.)

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“…The validity of HDL as a surrogate for cardiovascular risk has recently been questioned (Tuteja and Rader, 2014), and initial efforts to develop CETP inhibitors for increasing HDL levels clinically have been hampered either by unwanted side effects, such as blood pressure increases caused by Pfizer's torcetrapib (Barter et al, 2007), or by lack of efficacy, as was the case for Roche's dalcetrapib (Schwartz et al, 2012) and Lilly's evacetrapib (Nicholls et al, 2015). Nonetheless, pharmaceutical companies continue to invest significant resources into the development of safe and effective CETP inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Disposition into Adipose Tissue Determines Accumulation and Elimination Kinetics of the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Mice

Hartmann

Kumar

Johns

et al. 2015

Drug Metabolism and Disposition

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The cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibits a long terminal half-life (t ½ ) in humans; however, the dispositional mechanisms that lead to this long t ½ are still being elucidated. As it is hypothesized that disposition into adipose tissue and binding to CETP might play a role, we sought to delineate the relative importance of these factors using a preclinical animal model. A multiple-dose pharmacokinetic study was conducted in C57BL6 wild-type (WT) lean, WT diet-induced obese (DIO), natural flanking region (NFR) CETP-transgenic lean, and NFR-DIO mice. Mice were dosed orally with 10 mg/kg anacetrapib daily for 42 days. Drug concentrations in blood, brown and white adipose tissue, liver, and brain were measured up to 35 weeks postdose. During dosing, a 3-to 9-fold accumulation in 72-hour postdose blood concentrations of anacetrapib was observed. Drug concentrations in white adipose tissue accumulated ∼20-to 40-fold, whereas 10-to 17-fold accumulation occurred in brown adipose and approximately 4-fold in liver. Brain levels were very low (<0.1 mM), and a trend of accumulation was not seen. The presence of CETP as well as adiposity seems to play a role in determining the blood concentrations of anacetrapib. The highest blood concentrations were observed in NFR DIO mice, whereas the lowest concentrations were seen in WT lean mice. In adipose and liver tissue, higher concentrations were seen in DIO mice, irrespective of the presence of CETP. This finding suggests that white adipose tissue serves as a potential depot and that disposition into adipose tissue governs the long-term kinetics of anacetrapib in vivo.

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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

Cited by 81 publications

References 44 publications

Cholesteryl Ester Transfer Protein Inhibition With Anacetrapib Decreases Fractional Clearance Rates of High-Density Lipoprotein Apolipoprotein A-I and Plasma Cholesteryl Ester Transfer Protein

Cholesteryl Ester Transfer Protein Inhibition With Anacetrapib Decreases Fractional Clearance Rates of High-Density Lipoprotein Apolipoprotein A-I and Plasma Cholesteryl Ester Transfer Protein

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

Disposition into Adipose Tissue Determines Accumulation and Elimination Kinetics of the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Mice

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