Cholesteryl ester transfer protein and its inhibitors

Shrestha, Sudichhya; Wu, Ben J.; Guiney, L.; Barter, Philip J.; Rye, Kerry‐Anne

doi:10.1194/jlr.r082735

Cited by 72 publications

(52 citation statements)

References 119 publications

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“…Overall, CETP inhibitors that have reached late stage clinical development are categorized into CETP inhibitors (torcetrapib, evacetrapib and anacetrapib) and modulators (dalcetrapib) (14). Despite the beneficial influence on cholesterol metabolism, off-target effects and lack of reduction in CV events and mortality (with torcetrapib, dalcetrapib and evacetrapib) have highlighted the complex, unclear beneficial mechanism of CETP inhibition (186 Through Lipid-modification) study, demonstrating a significant 9% proportional reduction of major coronary events upon anacetrapib administration (100 mg), reported no data on hsCRP.…”

Section: Cholesteryl Ester Transfer Protein Inhibitorsmentioning

confidence: 99%

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

et al. 2018

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Inflammatory changes are responsible for maintenance of the atherosclerotic process and may underlie some of the most feared vascular complications. Among the multiple mechanisms of inflammation, the arterial deposition of lipids and particularly of cholesterol crystals is the one responsible for the activation of inflammasome NLRP3, followed by the rise of circulating markers, mainly C-reactive protein (CRP). Elevation of lipoproteins, LDL but also VLDL and remnants, associates with increased inflammatory changes and coronary risk. Lipid lowering medications can reduce cholesterolemia and CRP: patients with elevations of both are at greatest cardiovascular (CV) risk and receive maximum benefit from therapy. Evaluation of the major drug series indicates that statins exert the largest LDL and CRP reduction, accompanied by reduced CV events. Other drugs, mainly active on the triglyceride/HDL axis, for example, PPAR agonists, may improve CRP and the lipid pattern, especially in patients with metabolic syndrome. PCSK9 antagonists, the newest most potent medications, do not induce significant changes in inflammatory markers, but patients with the highest baseline CRP levels show the best CV risk reduction. Parallel evaluation of lipids and inflammatory changes clearly indicates a significant link, both guiding to patients at highest risk, and to the best pharmacological approach. Key messages Lipid lowering agents with "pleiotropic" effects provide a more effective approach to CV prevention In CANTOS study, patients achieving on-treatment hsCRP concentrations ≤2 mg/L had a higher benefit in terms of reduction in major CV events The anti-inflammatory activity of PCSK9 antagonists appears to be of a minimal extent.

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Section: Cholesteryl Ester Transfer Protein Inhibitorsmentioning

confidence: 99%

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

et al. 2018

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“…Circulating plasma lipoproteins are remodeled not only by the exchange of their surface components, but also by their core components, mediated by the cholesteryl ester transfer protein (CETP), whose properties are summarized by Rye and her colleagues (7). Thus the triglycerides of the triglyceride rich lipoproteins are exchanged for cholesteryl esters of the smaller lipoproteins, notably HDL.…”

Section: Transfer Of Lipid From Diet To Tissuementioning

confidence: 99%

Lipid Transfer Proteins: Introduction to the Thematic Review Series

Getz

2018

Journal of Lipid Research

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“…Further supporting the hypothesis that CETP inhibition is antiatherogenic came from multiple genetic studies in humans. Large genetic studies consistently showed favorable lipoprotein profiles and lowered ASVD risk in individuals with CETP polymorphisms that reduced CETP activity [6]. Particularly strong evidence was provided in the Copenhagen City Heart Study, in which 10,261 people were followed for up to 34 years [7].…”

mentioning

confidence: 99%

“…With this strong body of evidence for CETP inhibition being athero-protective, what then is the mode of action of CETP such that CETP inhibition should be beneficial? CETP promotes the exchange of neutral lipids between HDL and non-HDL lipoproteins, consisting of lipoprotein particles containing apolipoprotein B100 (apoB100) [6,8]. The non-HDL lipoproteins include VLDL, their remnants, and LDL particles, all of which are pro-atherogenic.…”

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confidence: 99%

“…The non-HDL lipoproteins include VLDL, their remnants, and LDL particles, all of which are pro-atherogenic. The net effect is a mass transport of cholesteryl esters (CE) from HDL to VLDL and LDL, with a reverse movement of triglycerides (TG) to HDL [6,8]. This neutral lipid transfer is most commonly believed to occur by a conformational change in CETP upon CE binding, leading to the formation of a continuous tunnel across CETP through which CE and TG transfers occur [6,8].…”

mentioning

confidence: 99%

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