Patient considerations and clinical impact of cholesteryl ester transfer protein inhibitors in the management of dyslipidemia: focus on anacetrapib

Abstract

Cardiovascular disease (CVD) is responsible for significant morbidity and mortality within the United States and worldwide. Although targeting low-density lipoprotein cholesterol (LDL-C) in the prevention of CVD has been shown to be effective, evidence exists to indicate that significant cardiovascular (CV) risk remains in patients receiving 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) – a risk that may be correlated with low levels of high-density lipoprotein cholesterol (HDL-C). Among the various tactics under investigation to increase HDL-C, inhibition of cholesteryl ester transfer protein (CETP) appears the most adept to raise these levels. Although torcetrapib, a CETP inhibitor, demonstrated significant beneficial changes in HDL-C and LDL-C after 12 months of therapy when coadministered with atorvastatin, patients in the torcetrapib arm experienced a rise in mortality, including increased risk of death from CV and non-CV causes as well as a significant rise in major CV events. Later studies established that the adverse effects of torcetrapib were produced from molecule-specific off-target effects and not to the mechanism of CETP inhibition. These untoward outcomes have not been detected with anacetrapib, the third of the CETP inhibitors to enter Phase III trials. Furthermore, treatment with anacetrapib revealed both a statistically significant decrease in LDL-C and increase in HDL-C over placebo. While the place in therapy of niacin and fibrates to reduce CV events is currently in question secondary to the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes and the Action to Control CV Risk in Diabetes trials, the ongoing large-scale, randomized–placebo, controlled-outcomes study with anacetrapib coadministered with statin treatment will not only test the hypothesis if CETP inhibition lowers residual CV risk but will also provide insight as to which patient subgroups might benefit the most from anacetrapib despite aggressive therapy with statins.

CETP inhibitors downregulate hepatic LDL receptor and PCSK9 expression in vitro and in vivo through a SREBP2 dependent mechanism

“…Since ANA is a stronger CETP inhibitor than DAL [9, 47], at first, we considered the possible involvement of CETP activity in ANA mediated inhibition of LDLR/PCSK9 expression. By transfection of specific siRNAs to knockdown CETP mRNA expression in HepG2 cells, we observed that ANA produced a similar inhibitory effect on LDLR mRNA expression in si-CETP transfected cells and cells transfected with a nonspecific siRNA control oligonucleotides, thereby suggesting that CETP activity is not required for the observed downregulation of LDLR and PCSK9.…”

“…Thus, inhibition of CETP activity raises plasma HDL-C and lowers LDL-C, which favorably reduces both CVD risk factors simultaneously. Over the last decade, a great deal of efforts has been put into the development of CETP inhibitors as new therapy to raise HDL-C [6–9]. Thus far, four CETP inhibitors have been tested in human clinical studies including torcetrapib (TOR) [7] dalcetrapib (DAL) [10–13], anacetrapib (ANA) [14–17] and evacetrapib (EVA) [18].…”

CETP inhibitors and cardiovascular disease: Time to think again

“…Likewise, the report on Dal-OUTCOMES 15 made no mention of any one of the six observational cohort studies listed in Table 1 , all of which were already in print. The same is true of an article investigating the harm caused by torcetrapib in ILLUMINATE 43 , and of several recent review articles 44 – 48 .…”

Cynanchum wilfordii Etanolic Extract Controls Blood Cholesterol: A Double-blind, Randomized, Placebo-Controlled, Parallel Trial

“…Based on these studies, the significant reduction in apoB level in the treatment groups compared to that in the placebo group was consistent with the effect of CW on blood cholesterol levels. In addition, changes in CETP were concentration-dependent on plasma VLDL levels, and it has been reported that when CETP was inhibited, HDL-C and LDL-C levels changed in a beneficial direction [36,37,38]. These results suggest that CW in the body inhibited the activity of CETP, leading to the inability of VLDL to convert to LDL and consequently to a reduction in the levels of apoB and LDL-C.…”