Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E

Abstract

Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl esters for triglyceride (TG) in VLDL/LDL. CETP inhibition, with anacetrapib, increases HDL-cholesterol, reduces LDL-cholesterol, and lowers TG levels. This study describes the mechanisms responsible for TG lowering by examining the kinetics of VLDL-TG, apoC-II, apoC-III, and apoE. Mildly hypercholesterolemic subjects were randomized to either placebo (N = 10) or atorvastatin 20 mg/qd (N = 29) for 4 weeks (period 1) followed by 8 weeks of anacetrapib, 100 mg/qd (period 2). Following each period, subjects underwent stable isotope metabolic studies to determine the fractional catabolic rates (FCRs) and production rates (PRs) of VLDL-TG and plasma apoC-II, apoC-III, and apoE. Anacetrapib reduced the VLDL-TG pool on a statin background due to an increased VLDL-TG FCR (29%; P = 0.002). Despite an increased VLDL-TG FCR following anacetrapib monotherapy (41%; P = 0.11), the VLDL-TG pool was unchanged due to an increase in the VLDL-TG PR (39%; P = 0.014). apoC-II, apoC-III, and apoE pool sizes increased following anacetrapib; however, the mechanisms responsible for these changes differed by treatment group. Anacetrapib increased the VLDL-TG FCR by enhancing the lipolytic potential of VLDL, which lowered the VLDL-TG pool on atorvastatin background. There was no change in the VLDL-TG pool in subjects treated with anacetrapib monotherapy due to an accompanying increase in the VLDL-TG PR.

Apolipoprotein C-II: New findings related to genetics, biochemistry, and role in triglyceride metabolism

“…To reduce TG synthesis, inhibitors of diacylglycerol O-acyltransferase 1 (DGAT1) may be potential treatment options for FCS 90 . Recently, Millar et al 124 have shown that anacetrapib treatment alone and in conjunction with atorvastatin increased apoC-II but also apoC-III levels and had no effect on direct clearance of VLDL.…”

Anacetrapib-driven triglyceride lowering explained: the fortuitous role of CETP in the intravascular catabolism of triglyceride-rich lipoproteins

“…Although not predicted by in vitro biochemistry studies, CETP inhibitors including anacetrapib modestly lower plasma TG levels (6,7,17). However, the (20). Mechanisms underlying the TG-lowering associated with CETP inhibition were addressed by performing well-controlled stable isotope lipoprotein kinetic studies in subjects treated with anacetrapib monotherapy or anacetrapib plus atorvastatin (20).…”

“…However, the (20). Mechanisms underlying the TG-lowering associated with CETP inhibition were addressed by performing well-controlled stable isotope lipoprotein kinetic studies in subjects treated with anacetrapib monotherapy or anacetrapib plus atorvastatin (20).…”

“…Interestingly, anacetrapib-mediated CETP inhibition increased the fractional catabolic rate (FCR) of VLDL-TG when given either as a monotherapy or in conjunction with atorvastatin (20). In parallel with enhanced FCR, anacetrapib treatment also resulted in the redistribution of several key exchangeable apolipoprotiens including apoC-II, apoC-III, and apoE on circulating lipoproteins (20).…”

“…In parallel with enhanced FCR, anacetrapib treatment also resulted in the redistribution of several key exchangeable apolipoprotiens including apoC-II, apoC-III, and apoE on circulating lipoproteins (20). In subjects treated with anacetrapib plus atorvastatin the pool sizes for apoC-II, apoC-III, and apoE were all elevated (20), which would be expected to alter lipoprotein lipase activity as well as the clearance of remnant lipoproteins (21). However, identical effects on apolipoprotein distribution were not apparent with anacetrapib monotherapy, indicating potential drug-drug interactions that may impact intravascular lipoprotein metabolism (20).…”