Evacetrapib alone or in combination with statins lowers lipoprotein(a) and total and small LDL particle concentrations in mildly hypercholesterolemic patients

Nicholls, Stephen J.; Ruotolo, Giacomo; Brewer, H. Bryan; Wang, Ming Dauh; Liu, Liping; Willey, Mark B.; Deeg, Mark A.; Krueger, Kathryn A.; Nissen, Steven E.

doi:10.1016/j.jacl.2015.11.014

Cited by 41 publications

(33 citation statements)

References 40 publications

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“…26 Use of evacetrapib in patients with hypocholesteremia in another phase 2 study resulted in significant placeboadjusted, dose-dependent decreases of sLDL concentration up to 95%. 24 Similarly, improvements in serum Lp(a) compared with placebo that we report are consistent with a separate phase 2 study of 393 patients with hypercholesterolemia in which evacetrapib as monotherapy or with statins, significantly reduced Lp(a) concentration. 24 Gaining an understanding of the causes of these changes, however, will require further study.…”

Section: Discussionsupporting

confidence: 89%

“…24 Similarly, improvements in serum Lp(a) compared with placebo that we report are consistent with a separate phase 2 study of 393 patients with hypercholesterolemia in which evacetrapib as monotherapy or with statins, significantly reduced Lp(a) concentration. 24 Gaining an understanding of the causes of these changes, however, will require further study.…”

Section: Discussionsupporting

confidence: 89%

“…Treatment with evacetrapib resulted in a significant increase in LDL particle size but had no consistent effect on intermediate LDL or large LDL particle concentration. 24 It should be noted, however, that different methods for measuring LDL particle size have produced varied results for LDL particle subfractions. Yamashita et al, using polyacrylamide gel electrophoresis, reported that LDL particles are large in heterozygotes and polydispersed in homozygotes with CETP deficiency; 25 Nicholls et al, using nuclear magnetic resonance spectroscopy, reported reductions of total LDL particle (LDL-P) and small LDL particle (sLDL) concentration with evacetrapib treatment, 24 whereas Krauss et al, using ion mobility for measurement, reported reductions of total LDL-P and sLDL 3a particle as well as increases in very small LDL 4b particle concentration with anacetrapib treatment.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy and Safety of the Cholesteryl Ester Transfer Protein Inhibitor Evacetrapib in Combination With Atorvastatin in Japanese Patients With Primary Hypercholesterolemia

Teramoto

Kiyosue

Iimura

et al. 2018

Circ J

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the hazard ratio for total CAD increases 1.4-, 1.7-, 2.2-, and 2.8-fold when LDL-C is 2.06-2.57, 2.58-3.09, 3.10-3.61, and ≥3.62 mmol/L, respectively, compared with LDL-C <2.06 mmol/L. 5 Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein secreted primarily by the liver that mediates the transfer of cholesteryl ester (CE) from high-density lipoprotein (HDL) to apolipoprotein (apo)B-rich lipoproteins (Lp; i.e., very-low-density lipoprotein [VLDL] and LDL) in exchange for their triglycerides, as well as the transfer of triglycerides/CE between apo-B-rich lipoproteins. Inhibition of CETP represents a potent mechanism for increasing HDL cholesterol (HDL-C) and lowering LDL-C. There is evidence that CETP inhibition prevents transfer of CE from HDL-C to apoB-containing lipoproteins and may increase cholesterol efflux. 6-8 The majority of animal model data indicate that CETP is proatherogenic, supporting an anti-atherogenic effect of CETP inhibitors. 8,9T he use of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) to reduce low-density lipoprotein cholesterol (LDL-C) has resulted in relative reductions in cardiovascular events of 20-30%. As a result, current guidelines for dyslipidemia management and prevention of atherosclerotic cardiovascular diseases recommend reducing LDL-C. 1-3Although LDL-C management has provided significant clinical benefits, atherosclerosis remains a major health burden in Japan, where the relative risk of coronary artery disease (CAD) has been confirmed by epidemiological studies to increase in tandem with LDL-C and total cholesterol (TC). The NIPPON DATA 80 study showed that the relative risk of death due to CAD increases 1.4-, 1.7-, 1.8-, and 3.8-fold when TC is 5.18-5.68, 5.69-6.20, 6.21-6.70, and ≥6.71 mmol/L, respectively, compared with TC 4.14-4.65 mmol/L, for men and women combined. 4 A more recent Japanese epidemiological study reported that

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Efficacy and Safety of the Cholesteryl Ester Transfer Protein Inhibitor Evacetrapib in Combination With Atorvastatin in Japanese Patients With Primary Hypercholesterolemia

Teramoto

Kiyosue

Iimura

et al. 2018

Circ J

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“…2 It is conceivable that mechanisms of reduction in the LDL cholesterol level that are specific to CETP inhibition, in contrast to the LDL cholesterol-receptor up-regulation that is induced by statins and ezetimibe, affect LDL cholesterol in ways that do not influence cardiovascular risk. Although treatment with evacetrapib has resulted in reductions of 60 to 70% in the levels of small dense LDL particles, 29 effects on the total number of LDL particles and on apolipoprotein B levels (reductions of 22% and 20%, respectively) are considerably less pronounced. The effect on the atherogenicity of the polydisperse LDL cholesterol pattern in association with CETP deficiency or inhibition remains unknown.…”

Section: Discussionmentioning

confidence: 95%

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

Lincoff¹,

Nicholls²,

Riesmeyer³

et al. 2017

N Engl J Med

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620

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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“…It should be mentioned that the decrease in LDL cholesterol levels observed with evacetrapib in the ACCELERATE trial (a 37.1% absolute difference compared with placebo) is not mediated by an increased LDL receptors activity known to be associated with a decreased cardiovascular risk, as studies with statins, ezetimibe and PCSK9 inhibitors have shown. Additionally, these reductions in LDL cholesterol were associated with smaller decreases in LDL particles number and apolipoprotein B levels (a decrease of apolipoprotein B by only 15% was noticed in the ACCELERATE trial) (4,18). (II) Off-target adverse effects.…”

Section: Editorialmentioning

confidence: 99%