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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).
Lipoprotein Metabolism and Implications for Atherosclerosis Risk Determination and Treatment Decisions
Published in P. K. Shah, Risk Factors in Coronary Artery Disease, 2006
H. Robert Superko, Szilard Voros, Spencer King III
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).
Treatment of Vulnerable Plaques: Current and Future Strategies
Published in Levon Michael Khachigian, High-Risk Atherosclerotic Plaques, 2004
Leonard Kritharides, David Brieger, S. Benedict Freedman, Harry C. Lowe
The most immediately amenable approach to substantially increasing HDL will involve the use of pharmacological CETP inhibitors currently in Stage II trials.196 CETP promotes the transfer of cholesteryl esters from HDL species to apolipoprotein B-containing lipoproteins including VLDL, remnants, and LDL. A genetic deficiency of CETP is associated with increased HDL levels; thus, inhibition of CETP is considered a reasonable therapeutic strategy for increasing HDL. CETP inhibitors have achieved elevation of HDL in animal studies and results of human intervention trials are awaited with interest. Critical to this evaluation will be the identification of whether all HDL elevation achieved by these agents is beneficial, whether subtypes of HDL must be elevated, or whether hepatic cholesterol clearance mechanisms must also be independently regulated during such treatment.
Novel emerging therapies in atherosclerosis targeting lipid metabolism
Published in Expert Opinion on Investigational Drugs, 2020
Manasvi Gupta, Colin Blumenthal, Subhankar Chatterjee, Dhrubajyoti Bandyopadhyay, Vardhmaan Jain, Carl J Lavie, Salim S. Virani, Kausik K Ray, Wilbert S Aronow, Raktim K Ghosh
Initial attempts at reducing cardiovascular risk by facilitating an increase of plasma HDL-C were unsuccessful, and further investigation revealed that the qualitative increase in HDL-C, measured as cholesterol efflux capacity (CEC), is superior to a quantitative increase in HDL-C for reducing risk of cardiovascular events. Apolipoprotein A-I, a key component of HDL particles that is responsible for CEC is, thus, a potential target. An important enzyme in the HDL metabolism is cholesteryl ester transfer protein (CETP) and is responsible for transfer of cholesteryl ester from HDL to LDL and VLDL and TG transfer from TG-rich lipoproteins to HDL and LDL. The overall effect of CETP is largely considered proatherogenic, forming the basis for the development of CETP inhibitors [5]. The development of CETP inhibitors has failed in multiple major trials with the exception of anacetrapib, which has shown benefits as an add on therapy to statins [6]. Notably, genetic variations in drug targets like CETP and HMG CoA reductase can lead to suboptimal reductions in LDL-C levels [7,8]. Another enzyme called the lecithin cholesterol acyltransferase (LCAT) acts by catalyzing the reaction of the formation of free cholesterol to cholesteryl ester (CE), thereby producing anti-atherogenic and larger mature HDL-C.
Cardiovascular outcomes trial with anacetrapib in subjects with high cardiovascular risk – are major benefits REVEALed?
Published in Expert Opinion on Pharmacotherapy, 2018
Like anacetrapib, torcetrapib [2] and evacetrapib [4] also cause major reductions in LDL-cholesterol, but unlike anacetrapib, they do not cause cardiovascular benefit. Dalcetrapib causes a much lower reduction in LDL-cholesterol than the other CETP inhibitors and is also ineffective in reducing cardiovascular outcomes [3]. It has been postulated that detrimental effects may counter any benefits due to reducing LDL-cholesterol or increasing HDL-cholesterol with the CETP inhibitors. One possible detrimental effect is increased blood pressure as torcetrapib, evacetrapib, and dalcetrapib increase systolic blood pressure by 5.4 mmHg [2], 1.2 mmHg [4], and 0.6 mmHg [3], respectively. Anacetrapib also increased systolic blood pressure by 0.7 mmHg, but does have cardiovascular benefits [7]. Thus, it seems unlikely that increasing blood pressure counters any benefits of lipid modification with evacetrapib and, possibly, dalcetrapib. However, as torcetrapib has a much larger effect on blood pressure than the other CETP inhibitors, the increase in blood pressure may have countered any potential benefits of modifying lipids with this agent.
Advancement in nanotechnology-based approaches for the treatment and diagnosis of hypercholesterolemia
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Nidhi Gupta, Nikita Sharma, Sandeep K. Mathur, Ramesh Chandra, Surendra Nimesh
Cholesteryl ester transfer protein (CETP) plays a key role in transferring the cholesteryl ester group from high-density lipoproteins (HDL) to LDL and very low-density lipoproteins (VLDL). Therefore, CETP inhibitors are believed to raise the level of HDL and indirectly lower the LDL-C levels [25]. Hence, it serves as a therapeutic strategy to reduce the incidence of CVDs. Moreover, there are many CETP inhibitors that are subjected to clinical analysis and are in phase trials such as Torcetrapib, Dalcetrapib, Evacetrapib, Anacetrapib, etc. Furthermore, the full potency of CETP inhibitors still remains to be determined for the decrease in the rate of occurrence of cardiovascular diseases and for the treatment of mild hypercholesterolemia.