Effects of CETP inhibition on triglyceride-rich lipoprotein composition and apoB-48 metabolism

Abstract

Cholesteryl ester transfer protein (CETP) facilitates the transfer of HDL cholesteryl ester to triglyceride-rich lipoproteins (TRL). This study aimed to determine the effects of CETP inhibition with torcetrapib on TRL composition and apoB-48 metabolism. Study subjects with low HDL cholesterol (<40 mg/dl), either untreated (n = 9) or receiving atorvastatin 20 mg daily (n = 9), received placebo for 4 weeks, followed by torcetrapib 120 mg once daily for the next 4 weeks. A subset of the subjects not treated with atorvastatin participated in a third phase (n = 6), in which they received torcetrapib 120 mg twice daily for an additional 4 weeks. At the end of each phase, all subjects received a primed-constant infusion of [5,5,5-(2)H(3)]L-leucine, while in the constantly fed state, to determine the kinetics of TRL apoB-48 and TRL composition. Relative to placebo, torcetrapib markedly reduced TRL CE levels in all groups (≥-69%; P < 0.005). ApoB-48 pool size (PS) and production rate (PR) decreased in the nonatorvastatin once daily (PS: -49%, P = 0.007; PR: -49%, P = 0.005) and twice daily (PS: -30%, P = 0.01; PR: -27%, P = 0.13) cohorts. In the atorvastatin cohort, apoB-48 PS and PR, which were already lowered by atorvastatin, did not change with torcetrapib. Our findings indicate that CETP inhibition reduced plasma apoB-48 concentrations by reducing apoB-48 production but did not have this effect in subjects already treated with atorvastatin.

Fig. 1.

Effect of torcetrapib on the nonfasting plasma concentration of TRL apoB-48 in subjects with low HDL cholesterol. Relative to placebo, torcetrapib decreased apoB-48 levels by 49 ± 9% (from 0.47 ± 0.10 to 0.23 ± 0.08 mg/dl) in the torcetrapib 120 mg once daily group (n = 9), by 31 ± 6% (from 0.57 ± 0.15 to 0.40 ± 0.12 mg/dl) in the torcetrapib 120 mg twice daily group (n = 6), and by 2 ± 14% (from 0.19 ± 0.04 to 0.16 ± 0.04 mg/dl) in the atorvastatin group (n = 9). The effects on apoB-100, apoA-I, apoA-II, and apoE are shown in the supplementary data. Data are expressed as mean ± SEM. *P < 0.01 for comparison with the placebo phase. QD, once daily; BID, twice daily.

Fig. 2.

The relationship between the torcetrapib-mediated percent change in nonfasting TRL TG concentration and the percent change in TRL apoB-48 PS (A), FCR (B), and PR (C) and between the percent change in nonfasting TRL CE concentration and the percent change in TRL apoB-48 PS (D), FCR (E), and PR (F), compared with placebo. In the nonatorvastatin cohort, the percent change in TRL TG concentration correlated positively with the percent change in apoB-48 PS and inversely with the percent change in apoB-48 FCR, whereas in the atorvastatin cohort, the percent change in TRL TG concentration was associated with the percent change in apoB-48 PS and PR. The percent change in TRL CE concentration correlated positively with the percent change in apoB-48 PS and inversely with the percent change in apoB-48 FCR in the nonatorvastatin cohort, but only with the percent change in apoB-48 PS in the atorvastatin cohort. Closed square and bold line indicate the nonatorvastatin group (n = 9); open circle and dotted line indicate the atorvastatin group (n = 9).

Fig. 3.

The relationship between the percent change in nonfasting TRL apoB-48 PS and in TRL apoE PS (A) and between the percent change in TRL apoB-48 PS and in TRL apoE FCR (B) compared with placebo. The relationship between the percent change in TRL apoB-48 PS and in TRL apoE PS was significant in both the nonatorvastatin and the atorvastatin groups, but only the nonatorvastatin group showed a significant relationship between the percent change in TRL apoB-48 PS and the percent change in TRL apoE FCR. Closed square and bold line indicate the nonatorvastatin group (n = 9); open circle and dotted line indicate the atorvastatin group (n = 9).