The Rationale for Intervention to Reduce the Risk of Cardiovascular Disease
James M. Rippe in Lifestyle Medicine, 2019
A number of prospective cohort studies have also demonstrated an inverse relationship between high-density lipoprotein (HDL) cholesterol and risk of CVD. Conversely, low HDL increases the risk of CVD.42 Each increase in HDL cholesterol by 1 mg/dL is associated with a 2–3% decrease in risk of total cardiovascular disease.42 Low HDL cholesterol has been defined as an HDL lower than 40 mg/dL. Levels lower than this are defined as an independent risk factor for CVD in the most recent National Cholesterol Education Program Guidelines. Moreover, the NCEP Adult Treatment Panel (ATP III) Guidelines support an HDL level of > 60 mg/dL as a negative risk factor for CVD.81 It should be noted that several recent trials of novel pharmaceutical agents designed to raise HDL have been somewhat disappointing and have resulted in untoward side effects such as hypertension. Trials such as the “AIM-HIGH” study, which randomly allocated high-risk patients to niacin supplementation, increased HDL cholesterol and reduced triglycerides yet did not yield reductions in clinical events.82 Furthermore, the investigation of lipid-level management to understand its impact on atherosclerotic events (ILLUMINATE), individuals at higher vascular risks who were given a Cholesterylester Transfer Protein (CETP) inhibitor torcetrapib actually showed an unanticipated increase in all-cause mortality.83 Despite these negative results, HDL cholesterol levels as “negative risk factors” for CVD are strongly supported both by cross-sectional and prospective studies which support the continued use in guidelines worldwide.
Pharmacology of p-sitosterol and other Sterols
Amritpal Singh Saroya in 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).
Lipoprotein Metabolism and Implications for Atherosclerosis Risk Determination and Treatment Decisions
P. K. Shah in Risk Factors in Coronary Artery Disease, 2006
Two CETP inhibitor agents have been tried in human subjects: JTT-705, and torce trapib. Initial small human trials with torcetrapib have revealed a 16% to 91% increase in HDL-C when doses of 10 mg to 240 mg/day are utilized (223). In patients with low HDL-C (< 40 mg/dL) 120 mg–240 mg/day resulted in a 46% to 106% increase in HDL-C with an associated increase in mean HDL particle size (224).
Progress and prospects of biological approaches targeting PCSK9 for cholesterol-lowering, from molecular mechanism to clinical efficacy
Published in Expert Opinion on Biological Therapy, 2020
Amir Mohammad Malvandi, Laura Canclini, Anxhela Alliaj, Paolo Magni, Alberto Zambon, Alberico Luigi Catapano
Apart from the mentioned approaches, several different ways are undergoing to develop a new way to block PCSK9 [118]. Small-molecule inhibitors have been developed as a promising therapy to disrupt the interaction of the PCSK9 and LDLR or blocking the gene expression of PCSK9, with the advantage of oral administration and lower production costs than mAbs. A new cholesteryl ester transfer protein (CETP) inhibitor, K-312, reduces the PCSK9 expression and LDL-C level via a mechanism independent of CETP inhibition. Based on experimental data, in vivo, K-312 administered to rabbits after two weeks led to a 63% reduction of PCSK9’s transcript levels in the liver and increased the high-density lipoproteins- cholesterol levels [119]. Another molecule PF846 has been proposed to block PCSK9 by interfering with the elongation phase of translation. The ribosome profiling showed that PF846 is a highly selective inhibitor of PCSK9 translation with no sign of toxicity in vivo [23]; however, the product was discontinued. Other known small molecules can reduce the PCSK9 synthesis or its function. Among them, only O-304 (an activator of 5′ adenosine monophosphate-activated protein kinases (AMPK) developed by Betagenon) is in clinical trials for type 2 diabetes treatment; however, it can reduce the PCSK9 level significantly as well [120].
The influence of multiple oral administration on the pharmacokinetics and distribution profile of dalcetrapib in rats
Published in Xenobiotica, 2021
Hiroaki Takubo, Tomohiro Ishikawa, Toshio Taniguchi, Kazunori Iwanaga, Yukihiro Nomura
Dalcetrapib (JTT-705/RO4607381, S-{2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl} 2-methylpropanethioate; see Figure 1), which is metabolized to its active form with a sulfhydryl group, is a cholesteryl ester transfer protein (CETP) inhibitor with the expected clinical benefit of increasing HDL-C. Dalcetrapib is known to undergo rapid hydrolysis by non-specific esterases and lipases (Bentley et al., 2012; Gross et al., 2012) in the intestine and liver to generate dalcetrapib-SH (Figure 1). It has the potential to inhibit CETP by forming a disulfide bond with the cysteine of CETP (Okamoto et al., 2000; Takubo et al., 2014). This pharmacologically active thiol was found to be the main component in human plasma (Derks et al., 2009, 2010). Based on our previous study, dalcetrapib-SH binds with low-molecular weight thiols such as cysteine and glutathione and high-molecular weight thiols such as peptides and proteins via disulfide bonds (Takubo et al., 2014). The reversibility of the disulfide bond and a high excretion ratio from the body have been demonstrated by studies of single oral administration of 14 C-dalcetrapib to rats and monkeys.
Lower LDL is better – can this be achieved with CETP inhibition therapy?
Published in Expert Review of Cardiovascular Therapy, 2020
What were the mechanisms of action through which anacetrapib reduced CVD? Prior studies show that increased catabolism and clearance of LDL particles through the hepatic LDL receptor pathway, causing reductions in plasma LDL-C and apoB levels, plays a major role [16]. This effect may be due to the increased affinity of LDL particles to LDL receptors upon remodeling of their lipid components and size by CETP [12]. It may also be due to an increase in hepatic LDL receptor numbers, although this has not specifically been tested [12]. An additional CETP inhibitor-mediated decrease in LDL formation, either as a result of decreased hepatic production of precursor VLDL particles or from decreased lipolytic conversion of VLDL to LDL, has not been demonstrated but cannot be ruled out.
Related Knowledge Centers
- Anacetrapib
- Dalcetrapib
- Cardiovascular Disease
- Atherosclerosis
- Cholesteryl Ester Transfer Protein
- Torcetrapib
- Evacetrapib
- Obicetrapib
- High-Density Lipoprotein
- Low-Density Lipoprotein