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Berries and Lipids in Cardiovascular Health
Published in Catherina Caballero-George, Natural Products and Cardiovascular Health, 2018
Arpita Basu, Nancy Betts, Paramita Basu, Timothy J. Lyons
In addition to measuring lipid outcomes related to conventional lipids, findings reported by Qin et al. (2009) and Zhu et al. (2015) provide further mechanistic insights on the hypolipidemic effects of purified berry extracts in adults with independent cardiovascular risks such as dyslipidemia/hyperlipidemia and type 2 diabetes. In a 12-week randomized placebo-controlled trial in adults with dyslipidemia, purified anthocyanins derived from bilberries and black currants were shown to decrease the mass and activity of cholesteryl ester transfer protein (CETP) (Qin et al., 2009). CETP is a plasma protein that mediates the removal of cholesteryl esters from HDL in exchange for a triglyceride molecule derived primarily from either LDL, VLDL or chylomicrons. Thus, CETP inhibition has been shown to be a possible mechanism for the elevation of HDL cholesterol and decrease of LDL cholesterol (Inazu et al., 1990). In another study in participants with type 2 diabetes, supplementation of a similar berry anthocyanin extract was shown to decrease specific plasma apolipoproteins, especially apolipoprotein B and CIII that have been associated with increased risks of atherosclerotic CVD in epidemiological observations (Jiang et al., 2004; Wyler von Ballmoos et al., 2015; Zhu et al., 2015).
Lipid disorders and emerging risk factors for cardiovascular disease
Published in Clive Handler, Gerry Coghlan, Marie-Anne Essam, Preventing Cardiovascular Disease in Primary Care, 2018
Clive Handler, Gerry Coghlan, Marie-Anne Essam
There may be risks associated with increasing HDL cholesterol levels. The torcetrapib trial – torcetrapib is a cholesterylester transfer protein inhibitor – was stopped prematurely due to increased mortality in the torcetrapib and atorvastatin arm of the study in comparison with those using atorvastatin alone.
Pharmacology of p-sitosterol and other Sterols
Published in Amritpal Singh Saroya, Contemporary Phytomedicines, 2017
A recent trial with dalcetrapib (Fig. 19.7), a cholesteryl esterase transport protein (CETP) inhibitor. Cholesteryl esterase transport protein inhibitor is a new class of cholesterol lowering medications currently in development. It showed that this agent may have the potential to increase levels of campesterol through increasing intestinal absorption. Dalcetrapib specifically increased markers of cholesterol absorption, most likely reflecting nascent HDL lipidation by intestinal ABCA1, without affecting markers of synthesis (Niesor et al. 2011).
An update on emerging drugs for the treatment of hypercholesterolemia
Published in Expert Opinion on Emerging Drugs, 2021
Adam J Nelson, Kristen Bubb, Stephen J Nicholls
Cholesteryl ester transfer protein (CETP) plays an important role in the regulation of lipid metabolism, promoting transfer of esterified cholesterol from HDL to VLDL and LDL particles, in exchange for triglycerides [62]. CETP inhibitors were originally developed on the basis of their ability to raise HDL cholesterol levels [62] and atheroprotective properties of CETP inhibition in rabbit models [63–66]. However, the clinical development of small molecule CETP inhibitors has proven challenging. The first agent, torcetrapib, was demonstrated to produce an increase cardiovascular events and all-cause mortality [67]. Subsequent analyses revealed that torcetrapib possessed a number of off-target toxicities, including elevation of blood pressure, adrenal synthesis of cortisol and aldosterone and aortic wall expression of endothelin [67–69]. The ability to demonstrate a lack of such effects would permit other CETP inhibitors to proceed in development. However, outcomes trials of the modest CETP inhibitor, dalcetrapib, and the potent CETP inhibitor, evacetrapib, demonstrated clinical futility with no impact on cardiovascular events [70,71]. Anacetrapib, an additional potent CETP inhibitor, was demonstrated to produce a significant reduction in cardiovascular events, with the degree of benefit directly proportional to the extent of lowering levels of atherogenic lipoproteins [72]. Clinical development of this agent was halted due to the finding of adipose tissue accumulation.
The mystery of evacetrapib - why are CETP inhibitors failing?
Published in Expert Review of Cardiovascular Therapy, 2020
Stephen J. Nicholls, Kristen Bubb
Cholesteryl ester transfer protein (CETP) plays a pivotal role in lipoprotein metabolism, primarily by virtue of its ability to facilitate transfer of esterified cholesterol from high-density lipoproteins (HDL) to very low-density lipoproteins (VLDL) and low-density lipoprotein (LDL) [1]. There has been considerable interest in pharmacological approaches to CETP inhibition on the basis of observations from both population studies [2] and cohorts with genetic polymorphisms [1,3,4] demonstrating low CETP activity to associate with high levels of HDL cholesterol and low rates of cardiovascular disease. A range of CETP inhibitory strategies including small molecule inhibitors, antisense oligonucleotides, and vaccination have proven to be atheroprotective in rabbit models [5–8]. Accordingly, CETP inhibition attracted considerable interest as a pharmacological approach to raising HDL cholesterol and potentially reducing cardiovascular risk.
HDL therapy today: from atherosclerosis, to stent compatibility to heart failure
Published in Annals of Medicine, 2019
C.R. Sirtori, M. Ruscica, L. Calabresi, G. Chiesa, R. Giovannoni, J.J. Badimon
Recent approaches aiming to elevate HDL-C levels have mostly shown unsatisfactory results [32,33]. Well established drugs, such as fenofibrate and extended release nicotinic acid (ER-NA) were not associated with decreased CV risk in patients on statin treatment [34,35], even though several authors have highlighted some issues affecting the design of the studies [36]. Fenofibrate, in particular, did reduce CV risk in hypertriglyceridemic patients with low HDL-C levels [37], probably indicating the importance of a targeted selection of patients. Among cholesteryl ester transfer protein (CETP) inhibitors, markedly raising HDL-C, only anacetrapib in the large REVEAL study did reduce CV risk by approximately 10%, but certain safety concerns associated to the drug [38]. in particular a very long half-life and prolonged permanence in tissues, consequent to a direct uptake by the adipocytes [39], led to drug discontinuation. Trials with this drug class well support the notion of quality vs quantity of HDL particle levels [40]. The HDL infusion therapy has been tested in different conditions with initially very positive results, particularly with the mutant apoA-IMilano [41]. However, more recent investigations with this and other HDL formulations did not confirm the initial positive findings, for reasons needing further evaluation (see below).