Anacetrapib, but not evacetrapib, impairs endothelial function in CETP-transgenic mice in spite of marked HDL-C increase

Simić, B; Mocharla, Pavani; Crucet, Margot; Osto, Elena; Kratzer, Adelheid; Stivala, Simona; Kühnast, Susan; Speer, Thimoteus; Doycheva, Petia; Princen, H.M.G.; Hoorn, José W. van der; Jukema, J. Wouter; Giral, Héctor; Tailleux, Anne; Landmesser, Ulf; Staels, Bart; Lüscher, Thomas F.

doi:10.1016/j.atherosclerosis.2017.01.011

Cited by 18 publications

(10 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A post-hoc analysis of 2 large prospective study, however, suggested that very large HDL particles, which are formed upon CETP inhibition, are associated with higher risk of cardiovascular events despite apoA-I remains negatively associated to CAD risk [29]. Recently it has been shown that, in CETP transgenic mice, cholesterol efflux as well as PON1 activity were significantly increased and reactive oxygen species decreased by evacetrapib, while anacetrapib had no effect, despite similar effects on lipids [133]. As a result, anacetrapib worsened endothelium-dependent acetylcoline-induced vasorelaxation while evacetrapib had no effect [133].…”

Section: Defective Hdl Remodellingmentioning

confidence: 99%

“…Recently it has been shown that, in CETP transgenic mice, cholesterol efflux as well as PON1 activity were significantly increased and reactive oxygen species decreased by evacetrapib, while anacetrapib had no effect, despite similar effects on lipids [133]. As a result, anacetrapib worsened endothelium-dependent acetylcoline-induced vasorelaxation while evacetrapib had no effect [133]. Furthermore, the ACCENTUATE study with evacetrapib [134] showed that, although the treatment increased cholesterol efflux capacity, it also generated HDL particles with increased apoC-III content.…”

Section: Defective Hdl Remodellingmentioning

confidence: 99%

See 1 more Smart Citation

Biological Consequences of Dysfunctional HDL

Pirillo

Catapano

Norata

2019

CMC

View full text Add to dashboard Cite

Epidemiological studies have suggested an inverse correlation between high density lipoprotein (HDL) cholesterol levels and the risk of cardiovascular disease. HDLs promote reverse cholesterol transport (RCT) and possess several putative atheroprotective functions, associated to the anti-inflammatory, anti-thrombotic and anti-oxidant properties as well as to the ability to support endothelial physiology. The assumption that increasing HDL-C levels would be beneficial on cardiovascular disease (CVD), however, has been questioned as, in most clinical trials, HDL-C-raising therapies did not result in improved cardiovascular outcomes. These findings, together with the observations from Mendelian randomization studies showing that polymorphisms mainly or solely associated with increased HDL-C levels did not decrease the risk of myocardial infarction, shift the focus from HDL-C levels toward HDL functional properties. Indeed, HDL from atherosclerotic patients not only exhibit impaired atheroprotective functions but also acquire pro-atherogenic properties and are referred to as "dysfunctional" HDL; this occurs even in the presence of normal or elevated HDL-C levels. Pharmacological approaches aimed at restoring HDL functions may therefore impact more significantly on CVD outcome than drugs used so far to increase HDL-C levels. Aims of this review is to discuss the pathological conditions leading to the formation of dysfunctional HDL and their role in atherosclerosis and beyond.

show abstract

Section: Defective Hdl Remodellingmentioning

confidence: 99%

Section: Defective Hdl Remodellingmentioning

confidence: 99%

Biological Consequences of Dysfunctional HDL

Pirillo

Catapano

Norata

2019

CMC

View full text Add to dashboard Cite

show abstract

“…In a recent study in mice, anacetrapib and evacetrapib were analyzed for their influence on HDL function, HDL subclass distribution and endothelial function. Expectantly, treatment with both drugs raised HDL-C levels while only evacetrapib increased PON1 activity and RCT ( Simic et al, 2017 ). Similarly to human studies, treatment with both drugs showed increases in large HDL subclasses quantified by nuclear magnetic resonance spectroscopy ( Simic et al, 2017 ).…”

Section: Selective Hdl Subclass May Explain Discrepancies In Therapiementioning

confidence: 99%

Pharmacological Intervention to Modulate HDL: What Do We Target?

et al. 2018

View full text Add to dashboard Cite

The cholesterol concentrations of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) have traditionally served as risk factors for cardiovascular disease. As such, novel therapeutic interventions aiming to raise HDL cholesterol have been tested in the clinical setting. However, most trials led to a significant increase in HDL cholesterol with no improvement in cardiovascular events. The complexity of the HDL particle, which exerts multiple physiological functions and is comprised of a number of subclasses, has raised the question as to whether there should be more focus on HDL subclass and function rather than cholesterol quantity. We review current data regarding HDL subclasses and subclass-specific functionality and highlight how current lipid modifying drugs such as statins, cholesteryl ester transfer protein inhibitors, fibrates and niacin often increase cholesterol concentrations of specific HDL subclasses. In addition this review sets out arguments suggesting that the HDL3 subclass may provide better protective effects than HDL2.

show abstract

“… 26 This was observed, despite additional reports that anacetrapib treatment was associated with impairment in endothelial function in this model. 27 More recent examinations have revealed prolonged storage of anacetrapib within white adipose tissue, with only minimal reduction in adipose concentrations more than 1 year following administration. 28 This has been important to understand as there has been ongoing work to study the long-term disposition of anacetrapib following administration.…”

Section: Experience From Animal Studiesmentioning

confidence: 99%

Anacetrapib as a potential cardioprotective strategy

Bartolo

Nicholls

2017

DDDT

View full text Add to dashboard Cite

Cholesteryl ester transfer protein (CETP) facilitates movement of esterified cholesterol between high-density lipoproteins (HDLs) and apolipoprotein B-containing lipoproteins. By virtue of their ability to raise HDL cholesterol and lower low-density lipoprotein cholesterol, pharmacological inhibitors of CETP have received considerable attention as potential new agents in cardiovascular prevention. While early studies of CETP inhibitors have demonstrated a lack of clinical efficacy and potential toxicity, development of the potent CETP inhibitor, anacetrapib, has moved forward, with emerging evidence suggesting a role in reducing cardiovascular events. The experience with anacetrapib and its potential for use in clinical practice are reviewed here.

show abstract

Anacetrapib, but not evacetrapib, impairs endothelial function in CETP-transgenic mice in spite of marked HDL-C increase

Cited by 18 publications

References 49 publications

Biological Consequences of Dysfunctional HDL

Biological Consequences of Dysfunctional HDL

Pharmacological Intervention to Modulate HDL: What Do We Target?

Anacetrapib as a potential cardioprotective strategy

Contact Info

Product

Resources

About