Effects of the Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib on Apolipoprotein B100 Metabolism in Humans

Abstract

Objective-Cholesteryl ester transfer protein (CETP) inhibition with torcetrapib not only increases high-density lipoprotein cholesterol levels but also significantly reduces plasma triglyceride, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) levels. The goal of the present study was to define the kinetic mechanism(s) by which CETP inhibition reduces levels of apoB-containing lipoproteins. Methods and Results-Nineteen subjects, 9 of whom were pretreated with 20 mg atorvastatin, received placebo for 4 weeks, followed by 120 mg torcetrapib once daily for 4 weeks. Six subjects in the nonatorvastatin group received 120 mg torcetrapib twice daily for an additional 4 weeks. After each phase, subjects underwent a primed-constant infusion of deuterated leucine to endogenously label newly synthesized apoB to determine very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL apoB100 production, and fractional catabolic rates (FCRs). Once-daily 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes by enhancing the FCR of apoB100 within each fraction. On a background of atorvastatin, 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes. The reduction in VLDL apoB100 was associated with an enhanced apoB100 FCR, whereas the decreases in IDL and LDL apoB100 were associated with reduced apoB100 production. Conclusions-These data indicate that when used alone, torcetrapib reduces VLDL, IDL, and LDL apoB100 levels primarily by increasing the rate of apoB100 clearance. In contrast, when added to atorvastatin treatment, torcetrapib reduces apoB100 levels mainly by enhancing VLDL apoB100 clearance and reducing production of IDL and LDL apoB100. Key Words: very low-density lipoproteins Ⅲ triglyceride Ⅲ low-density lipoproteins Ⅲ cholesteryl ester transfer protein Ⅲ CETP inhibition Ⅲ lipoprotein kinetics A n elevated level of plasma cholesterol is a major risk factor for the development of cardiovascular disease. 1 Current treatments to reduce plasma cholesterol levels include diet, exercise, and treatment with cholesterol-lowering medications. 1 Recently, a new class of drug designed to increase high-density lipoprotein (HDL) cholesterol levels through the inhibition of cholesteryl ester transfer protein (CETP) has been developed. 2 CETP mediates the bidirectional exchange of cholesteryl ester and triglyceride between HDL and the apolipoprotein B (apoB)-containing lipoproteins, as well as among the different classes of apoBcontaining lipoproteins. The main result of CETP activity is net transfer of cholesteryl ester from HDL to very lowdensity lipoproteins (VLDLs) and net transfer of triglyceride from VLDL to HDL. Thus, CETP provides a link between the metabolism of apoB-containing lipoproteins and HDL. Expression of CETP in mice, 3 which normally lack CETP, or manipulation of CETP activity in other animals that express CETP 4,5 changes the plasma concentration of apoBcontaining lipoproteins in addition to expected changes in HDL chol...

The inhibition of cholesteryl ester transfer protein: a long and winding road

“…Moreover, this effect was no longer apparent in people that were treated with torcetrapib in combination with atorvastatin. This is the opposite of what the same authors reported previously, where torcetrapib monotherapy lowered the levels of apoB-100-containing lipoproteins by increasing their fractional catabolic rate ( 20 ). As the samples that Diffenderer and colleagues used in the present study were obtained from the same subjects in which apoB-100 kinetics were investigated ( 20 ), this unexpected observation cannot be attributed to a population effect.…”

“…Administration of torcetrapib in combination with atorvastatin also increased the clearance of apoB-100 in VLDL. However, in contrast to what was reported for treatment with torcetrapib alone, administration of torcetrapib in combination with atorvastatin reduced apoB-100 levels by increasing VLDL apoB-100 clearance and by reducing the production of apoB-100 in IDL and LDL ( 20 ).…”

“…Treatment with torcetrapib alone increased the clearance of apoB-100 in intermediate density lipoproteins (IDL) and in LDL, presumably via increased expression of the LDL receptor ( 20 ). VLDL apoB-100 clearance was also increased, possibly because the torcetrapib-mediated reduction in CETP activity inhibited the transfer of triglycerides out of the particles, which converted them into excellent substrates for lipoprotein lipase.…”

Overview of the LDL receptor: relevance to cholesterol metabolism and future approaches for the treatment of coronary heart disease

“…In vivo studies support this model since treatment with a CETP inhibitor was associated with enhanced LDL clearance from plasma, presumably due to upregulation of LDLRs resulting from reduced LDL cholesterol delivery to liver. 110 …”

Anacetrapib reduces (V)LDL cholesterol by inhibition of CETP activity and reduction of plasma PCSK9

“…Although the direct effects of CETP inhibition in humans on lipoprotein remnant clearance have not been described, treatment with the CETP-inhibitor torcetrapib has been shown to increase the fractional catabolic rate of both VLDL-apoE ( 49 ) and VLDL-apoB100 ( 50 ). However, the potentially increased catabolism of (V)LDL and thus antiatherogenic properties were clearly not suffi cient to offset or overrule the adverse side effects of torcetrapib.…”