Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects

Abstract

Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma protein that promotes the bidirectional transfer of cholesteryl esters (CE) and triglycerides (TG) between and among HDL particles and atherogenic apolipoprotein B-containing (ApoB-containing) lipoproteins, including the predominantly TG-rich VLDL, intermediate-density lipoprotein (IDL), and LDL particles (1-3). Genetic deficiency of CETP is associated with elevated HDL cholesterol (HDL-C) and reduced LDL-C (1), and common variants at the CETP locus are associated with HDL-C and LDL-C in inverse directions (3). Pharmacologic inhibition of CETP activity in humans raises HDL-C levels and generally reduces LDL-C levels (4-7).The mechanism by which CETP inhibition reduces LDL-C remains unknown. A study of ApoB kinetics during administration of the CETP inhibitor torcetrapib (120 mg), with or without atorvastatin (ATV), to subjects with dyslipidemia (8) suggested that in dyslipidemic subjects, torcetrapib monotherapy reduced LDL ApoB by increasing the fractional catabolic rate (FCR) and that torcetrapib administered with ATV may have reduced production of LDL ApoB. However, none of these changes were statistically significant. Thus, the study was underpowered for detecting changes in many of the ApoB kinetic parameters and led to no firm conclusions regarding the mechanisms responsible for the lowering of ApoB.BACKGROUND. Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib. METHODS.We performed a trial of the effects of anacetrapib on ApoB kinetics. Mildly hypercholesterolemic subjects were randomized to background treatment of either placebo (n = 10) or 20 mg atorvastatin (ATV) (n = 29) for 4 weeks. All subjects then added 100 mg anacetrapib to background treatment for 8 weeks. Following each study period, subjects underwent a metabolic study to determine the LDL-ApoB-100 and proprotein convertase subtilisin/kexin type 9 (PCSK9) production rate (PR) and fractional catabolic rate (FCR). RESULTS.Anacetrapib markedly reduced the LDL-ApoB-100 pool size (PS) in both the placebo and ATV groups. These changes in PS resulted from substantial increases in LDL-ApoB-100 FCRs in both groups. Anacetrapib had no effect on LDL-ApoB-100 PRs in either treatment group. Moreover, there were no changes in the PCSK9 PS, FCR, or PR in either group. Anacetrapib treatment was associated with considerable increases in the LDL triglyceride/cholesterol ratio and LDL size by NMR. CONCLUSION.These data indicate that anacetrapib, given alone or in combination with a statin, reduces LDL-ApoB-100 levels by increasing the rate of ApoB-100 fractional clearance. TRIAL REGISTRATION. ClinicalTrials.gov NCT00990808.

Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol

“…For instance, anacetrapib increases levels of HDL-C and decreases levels of both LDL-C and apoB-100 (89,90), and, when added to statin treatment, results in further reductions in LDL-C (91,92). Anacetrapib treatment also increases the LDL TG/cholesterol ratio and LDL size and increases LDL-apoB-100 clearance (93). CETP inhibitors that more potently lower atherogenic, apoB-containing lipoproteins, and that lack off-target adverse effects on blood pressure, may reduce the number of CVD events.…”

Reduction in PCSK9 levels induced by anacetrapib: an off-target effect?

“…Treatment with the CETP inhibitors, torcetrapib, anacetrapib, evacetrapib, and TA-8995, reduces the plasma concentration of apoB ( 12 -15 ). In the case of both torcetrapib ( 18 ) and anacetrapib ( 19 ), this is the consequence of an enhanced clearance from plasma of the apoB contained in both the VLDL and LDL fractions, and most likely refl ects an increase in the number of cell surface LDL receptors.…”

“…However, activation of SREBP-2 is also known to increase the synthesis of PCSK9 ( 23 ). It was therefore quite unexpected to fi nd that treatment with anacetrapib (given as monotherapy) decreased rather than increased plasma levels of PCSK9 in rhesus macaques ( 24 ) and humans ( 19 ). However, when given to humans who were also taking atorvastatin, anacetrapib reduced the concentration of LDL apoB, but had no effect on the level of PCSK9 ( 19 ).…”

“…It was therefore quite unexpected to fi nd that treatment with anacetrapib (given as monotherapy) decreased rather than increased plasma levels of PCSK9 in rhesus macaques ( 24 ) and humans ( 19 ). However, when given to humans who were also taking atorvastatin, anacetrapib reduced the concentration of LDL apoB, but had no effect on the level of PCSK9 ( 19 ). The explanation for any anacetrapib-induced reduction in PCSK9 is unclear because, whether given as monotherapy or as add-on therapy in people treated with atorvastatin, anacetrapib had no effect on either the production rate or the fractional catabolic rate of PCSK9 ( 19 ).…”

CETP Deficiency and Concerns in CETP Inhibitor Development

“…Anacetrapib reduced plasma PCSK9 levels by -19% (37). It appears to be mediated by reduced levels of mature form of SREBP2 (38).…”