CETP Inhibition: Past Failures and Future Hopes

Kosmas, Constantine E.; DeJesus, Eddy; Rosario, Digna; Vittorio, Timothy J.

doi:10.4137/cmc.s32667

Cited by 65 publications

(37 citation statements)

References 55 publications

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“…This relationship has withstood repeated evaluation in large scale population studies; however, there is a great deal of uncertainty about the nature of this relationship and whether HDL is “good” because it is directly protective against CVD or if the cholesterol content of HDL (HDL-C) is simply a biomarker of some other protective process, and in fact, has no direct causal relationship with CVD (2). While there is a great deal of functional data and some clinical data to support the hypothesis that HDL is playing a direct protective role against CVD, several recent studies indicate that pharmacological manipulation (3) or naturally occurring genetic mutations (4), which result in increased HDL-C, do not translate to a reduced risk of cardiovascular events. Many view these studies as a significant blow to the HDL field, suggesting a lack of importance of HDL in CVD; however, there is an alternative interpretation of these results.…”

Section: Our Current Understanding Of Hdl Functionmentioning

confidence: 99%

High density lipoproteins are modulators of protease activity: Implications in inflammation, complement activation, and atherothrombosis

Gordon

Remaley

2017

Atherosclerosis

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High density lipoproteins (HDL) represent a compositionally diverse population of particles in the circulation, containing a wide variety of lipids and proteins. Gene ontology functional analysis of the 96 commonly identified HDL binding proteins reveals that almost half of these proteins are either proteases or have known roles in protease regulation. Here, we discuss the activities of some of these proteins in regard to their roles in regulating proteases involved in inflammation, coagulation, and complement activation, particularly in the context of atherosclerosis. The overall goal of this review is to discuss potential functional roles of HDL in protease regulatory pathways based on current literature and known functions of HDL binding proteins and to promote the consideration of HDL as a global modulator of proteolytic equilibrium.

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Section: Our Current Understanding Of Hdl Functionmentioning

confidence: 99%

High density lipoproteins are modulators of protease activity: Implications in inflammation, complement activation, and atherothrombosis

Gordon

Remaley

2017

Atherosclerosis

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“…32, 33 Failure of CETP inhibitors to reduce cardiovascular events has indicated that it is not sufficient to simply raise HDL cholesterol. 34 The functional capacity of HDL in RCT might be more important mechanistically. Increased fecal cholesterol excretion is a prominent mechanism of action of phytosterols in foods and supplements, 35 but there have been no interventional studies with CVD outcomes to firmly establish the treatment effectiveness.…”

Section: Discussionmentioning

confidence: 99%

Endogenous Cholesterol Excretion Is Negatively Associated With Carotid Intima–Media Thickness in Humans

Lin

Racette

et al. 2017

ATVB

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Objective Epidemiological studies strongly suggest that lipid factors independent of LDL cholesterol contribute significantly to cardiovascular disease (CVD) risk. Because circulating lipoproteins comprise only a small fraction of total body cholesterol, the mobilization and excretion of cholesterol from plasma and tissue pools may be an important determinant of CVD risk. Our hypothesis is that fecal excretion of endogenous cholesterol is protective against atherosclerosis. Approach and Results Cholesterol metabolism and carotid intima-media thickness (CIMT) were quantitated in 86 non-diabetic adults. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d7 solubilized in a lipid emulsion and dietary cholesterol by cholesterol-d5 and the nonabsorbable stool marker sitostanol-d4. Plasma and stool samples were collected while subjects consumed a cholesterol- and phytosterol-controlled metabolic kitchen diet and were analyzed by mass spectrometry. CIMT was negatively correlated with fecal excretion of endogenous cholesterol (r=−0.426, P<0.0001), total cholesterol (r=−0.472, P=<0.0001), and daily percent excretion of cholesterol from the rapidly-mixing cholesterol pool (r=−0.343, P=0.0012), and was positively correlated with percent cholesterol absorption (r=+0.279, P=0.0092). In a linear regression model controlling for age, sex, systolic blood pressure, hemoglobin A1c, LDL, HDL cholesterol, and statin drug use, fecal excretion of endogenous cholesterol remained significant (P=0.0008). Conclusions Excretion of endogenous cholesterol is strongly, independently, and negatively associated with CIMT. The reverse cholesterol transport pathway comprising the intestine and the rapidly-mixing plasma and tissue cholesterol pool could be an unrecognized determinant of CVD risk not reflected in circulating lipoproteins. Further work is needed to relate measures of reverse cholesterol transport to atherosclerotic disease.

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“…The analysis assumes that statin-mediated risk reduction is effective immediately upon the initiation of statin therapy, and that the level of treatment adherence over the course of the VOYAGER studies (typically 4–6 weeks) would be continued over a 10-year period [19]. …”

Section: Discussionmentioning

confidence: 99%

Modeling Statin-Induced Reductions of Cardiovascular Events in Primary Prevention: A VOYAGER Meta-Analysis

et al. 2018

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Objective: We used individual patient data from the VOYAGER database to estimate cardiovascular (CV) risk reduction with commonly used high-intensity statins. Methods: In patients with known atherosclerotic CV disease (ASCVD) treated with high-intensity statin therapy (n = 6,735), the predicted risk reduction was estimated using the Cholesterol Treatment Trialists’ Collaboration meta-analysis, which determined risk reduction per 38.7 mg/dL statin-mediated reduction in low-density lipoprotein cholesterol. Results: The greatest reductions in risk were seen in major vascular events (estimated rate ratios ranged from 0.55 with rosuvastatin [RSV] 40 mg to 0.60 with atorvastatin [ATV] 40 mg) and coronary heart disease death (estimated rate ratios ranged from 0.58 with RSV 40 mg to 0.64 with ATV 40 mg). Conclusions: Our results show that, in individuals without clinical ASCVD, statin therapy has the potential to reduce the frequency of CV events.

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CETP Inhibition: Past Failures and Future Hopes

Cited by 65 publications

References 55 publications

High density lipoproteins are modulators of protease activity: Implications in inflammation, complement activation, and atherothrombosis

High density lipoproteins are modulators of protease activity: Implications in inflammation, complement activation, and atherothrombosis

Endogenous Cholesterol Excretion Is Negatively Associated With Carotid Intima–Media Thickness in Humans

Modeling Statin-Induced Reductions of Cardiovascular Events in Primary Prevention: A VOYAGER Meta-Analysis

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