CETP-Inhibition and HDL-Cholesterol: A Story of CV Risk or CV Benefit, or Both

2018 ◽  
Vol 104 (2) ◽  
pp. 297-300 ◽  
Author(s):  
Stephen J. Nicholls
Keyword(s):  
Hdl Cholesterol ◽  
Cetp Inhibition

Abstract 168: Effects of the CETP Inhibitor Anacetrapib on HDL3-to-HDL2 Transfer: Comparison of in Vitro and in Vivo Methodologies

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Douglas G Johns ◽  
Ying Chen ◽  
Erin D Daniels ◽  
Jose Castro-Perez ◽  
Sheng-Ping Wang ◽  
...  
Keyword(s):  
Lipoprotein Metabolism ◽  
Hdl Cholesterol ◽  
Transfer Protein ◽  
Cetp Inhibitor ◽  
Cetp Inhibition ◽  
Artery Disease ◽  
Maximal Reduction ◽  
Over Time

Cholesteryl ester transfer protein (CETP) is a target for the treatment of dyslipidemia and coronary artery disease. In addition to the well-known effect of CETP to transfer CE from HDL to LDL and to VLDL, in vitro , CETP has been reported to transfer CE between small and large HDL particles (HDL2 and HDL3, respectively). We sought to understand how the CETP inhibitor anacetrapib (ANA) affects HDL3-to-HDL2 transfer under both in vitro and in vivo conditions. In vitro , ANA dose-dependently inhibited transfer of 3 H-CE from total HDL to LDL (IC50 30nM), and from isolated HDL3 to HDL2 particles (IC50 200nM). In human CETP transgenic mice, animals treated with a single dose of ANA (100mg/kg) displayed 80% maximal reduction in plasma CETP activity and a 22% increase in total HDL cholesterol. In animals treated with either vehicle or ANA, 3 H-CE-labeled HDL3 was injected intravenously and 3 H-tracer was monitored in lipoprotein fractions following injection. Animals treated with ANA showed an increase in the amount 3 H-tracer present in HDL2 compared to vehicle over time (20-70% increase across 6 hrs post 3 H-CE-HDL3 injection, P<0.05 vs vehicle). The HDL2 CE pool was also increased with ANA treatment, and 3 H-cholesterol flux into HDL2 was increased with ANA treatment when adjusted to the change in pool size (at 2 and 4 hrs post 3H-CE-HDL3 injection). No change in HDL2 3 H-tracer was seen in C57BL6 mice (lacking CETP) treated with ANA. These results indicate that in contrast to in vitro findings, ANA increases flux of CE into HDL2 in vivo , a process which likely involves multiple pathways. Therefore, the in vitro phenomena of 1) HDL3-to-HDL2 transfer by CETP and 2) inhibition of this transfer by CETP inhibitors are not recapitulated in vivo . It is clear that in vivo approaches are necessary to understand the relevance of HDL3-to-HDL2 transfer in vivo , and to accurately study the effects of CETP inhibition on lipoprotein metabolism.

Abstract 237: Evaluating CETP Inhibition in Context: CETP Inhibition Modifies High-density Lipoprotein Composition in CETP-expressing Transgenic Mice Differently Depending on Diet

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Lin Zhu ◽  
Christopher Emfinger ◽  
Brian Palmisano ◽  
John M Stafford
Keyword(s):  
Clinical Trials ◽  
Transgenic Mice ◽  
Cardiovascular Events ◽  
Cholesterol Metabolism ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Cholesterol Content ◽  
Liver Cholesterol ◽  
Cetp Inhibition ◽  
Lipoprotein Composition

CETP inhibition has been used as a strategy to raise HDL cholesterol, but trials with two CETP inhibitors torcetrapib and dalcetrapib failed to prevent cardiovascular events for high-risk individuals. Of note, approximately 2/3 of patients in these clinical trials were obese. Obesity and fatty liver are known to significantly impact aspects of liver cholesterol metabolism and HDL biology. We propose that high-fat diet feeding (HFD) might adversely impact the effects of CETP inhibition on HDL composition and function. Mice naturally lack CETP expression, so we used CETP transgenic mice to evaluate the effects of administering the CETP inhibitor torcetrapib on HDL composition in chow- and HFD-fed CETP-transgenic mice. Because of the very short half-life of torcetrapib we used acute intravenous infusion of torcetrapib. In both diet groups torcetrapib infusion suppressed plasma CETP activity and raised HDL cholesterol content. In chow-fed CETP mice we found that torcetrapib resulted in changes in HDL composition that would be predicted to be favorable, including increases in apoA1, apoM and apoE protein levels for 2.5-fold ( P <0.01), 1.8-fold ( P <0.05) to 2-fold ( P <0.05), respectively. By contrast, in HFD-fed CETP mice those effects of torcetrapib were diminished, torcetrapib had no effect on apoA1, apoM or apoE. In addition, the acute phase protein SAA1 in HDL was increased significantly by torcetrapib only in HFD-fed mice. Our results show that the effect of pharmacologic CETP inhibition on HDL composition is context-specific to the diet. These findings may be helpful to understanding why CETP inhibition, while beneficial in early animal trials, failed to reduce cardiovascular events in clinical trials where most individuals were obese.

Selective CETP Inhibition and PPARα Agonism Increase HDL Cholesterol and Reduce LDL Cholesterol in Human ApoB100/Human CETP Transgenic Mice

2010 ◽  
Vol 15 (2) ◽  
pp. 196-202 ◽  
Author(s):  
Michael K. Hansen ◽  
Matthew J. McVey ◽  
Ray F. White ◽  
Jeffrey J. Legos ◽  
Jean-Marie Brusq ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Ldl Cholesterol ◽  
Hdl Cholesterol ◽  
Cetp Inhibition

The evolving role of CETP inhibition: beyond HDL cholesterol

The Lancet ◽  
2015 ◽  
Vol 386 (9992) ◽  
pp. 412-414 ◽  
Author(s):  
Kausik K Ray ◽  
Antonio J Vallejo-Vaz
Keyword(s):  
Hdl Cholesterol ◽  
Cetp Inhibition

scholarly journals CETP inhibition and ADCY9 genotype: evidence of a qualitative pharmacogenetic interaction in cardiovascular disease?

2018 ◽  
Author(s):  
Michael V Holmes ◽  
George Davey Smith
Keyword(s):  
Vascular Disease ◽  
Treatment Response ◽  
Meta Analysis ◽  
Hdl Cholesterol ◽  
Major Adverse Cardiac Events ◽  
Phase Iii ◽  
Cardiac Events ◽  
Adverse Cardiac Events ◽  
Cetp Inhibitor ◽  
Cetp Inhibition

AbstractBackgroundCETP inhibitors raise circulating concentrations of HDL-cholesterol, and potent inhibitors also lower non-HDL-cholesterol and risk of vascular disease. Previous genome-wide pharmacogenetic analysis of a phase III randomized controlled trial (RCT) of the CETP inhibitor, dalcetrapib, found variants in ADCY9 to associate with response to treatment. More recently, findings from a pharmacogenetic analysis of the CETP inhibitor evacetrapib reported a lack of such an association.AimsTo clarify the totality of evidence on whether ADCY9 genotype modifies the treatment response to CETP inhibition on risk of major adverse cardiac events through systematic review and meta-analysis.MethodsWe searched PubMed on 22nd May 2018 to identify RCTs of CETP inhibition that reported vascular disease effect estimates stratified by ADCY9 genotype. Stratum-specific estimates were pooled using fixed effect meta-analysis. Tests of heterogeneity between, and trend across, genotypic strata were assessed using Chi2.ResultsNine studies were identified from PubMed, of which two (dal-OUTCOMES and ACCELERATE) were RCTs reporting the treatment response to CETP inhibition by ADCY9 genotype, and fulfilled the inclusion criteria. In meta-analysis of dal-OUTCOMES and ACCELERATE, treatment with a CETP inhibitor was associated with a relative risk (RR) for major adverse cardiac events of RR 0.80 (95%CI, 0.65-0.99) in carriers of ADCY9 rs1967309 AA. For carriers of AG, the corresponding estimate was a RR of 1.01 (95%CI, 0.89-1.13), and for GG carriers, it was RR 1.21 (95%CI, 1.06-1.40). We identified evidence of heterogeneity (P=0.004) and a trend (P=0.0009) across genotypic groups.ConclusionsIn contrast to the interpretation provided by authors of the analysis based in the ACCELERATE trial, the available evidence lends weak support to a potential interaction of CETP treatment by ADCY9 genotype on risk of major adverse cardiac events. Additional data, e.g. from the ongoing dal-GenE trial focused explicitly on this interaction, should provide further clarity regarding the robustness of this pharmacogenetic effect.

10-Dehydrogingerdione raises HDL-cholesterol through a CETP inhibition and wards off oxidation and inflammation in dyslipidemic rabbits

2013 ◽  
Vol 231 (2) ◽  
pp. 334-340 ◽  
Author(s):  
Mohamed M. Elseweidy ◽  
Fatma R. Abdallah ◽  
Nahla N. Younis ◽  
Sameih Aldohmy ◽  
Haitham M. Kassem
Keyword(s):  
Hdl Cholesterol ◽  
Cetp Inhibition
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