Pharmacological Inhibition of CETP (Cholesteryl Ester Transfer Protein) Increases HDL (High-Density Lipoprotein) That Contains ApoC3 and Other HDL Subspecies Associated With Higher Risk of Coronary Heart Disease

Abstract

Objective: Plasma total HDL (high-density lipoprotein) is a heterogeneous mix of many protein-based subspecies whose functions and associations with coronary heart disease vary. We hypothesize that increasing HDL by CETP (cholesteryl ester transfer protein) inhibition failed to reduce cardiovascular disease risk, in part, because it increased dysfunctional subspecies associated with higher risk such as HDL that contains apoC3. Approach and Results: We studied participants in 2 randomized, double-blind, placebo-controlled trials of a CETP inhibitor on a background of atorvastatin treatment: ACCENTUATE (The Addition of Evacetrapib to Atorvastatin Compared to Placebo, High Intensity Atorvastatin, and Atorvastatin With Ezetimibe to Evaluate LDL-C Lowering in Patients With Primary Hyperlipidemia; 130 mg evacetrapib; n=126) and ILLUMINATE (Phase 3 Multi Center, Double Blind, Randomized, Parallel Group Evaluation of the Fixed Combination Torcetrapib/Atorvastatin, Administered Orally, Once Daily [Qd], Compared With Atorvastatin Alone, on the Occurrence of Major Cardiovascular Events in Subjects With Coronary Heart Disease or Risk Equivalents; 60 mg torcetrapib; n=80). We measured the concentration of apoA1 in total plasma and 17 protein-based HDL subspecies at baseline and 3 months. Both CETP inhibitors increased apoA1 in HDL that contains apoC3 the most of all HDL subspecies (median placebo-adjusted percent increase: evacetrapib 99% and torcetrapib 50%). They also increased apoA1 in other HDL subspecies associated with higher coronary heart disease risk such as those involved in inflammation (α-2-macroglobulin and complement C3) or hemostasis (plasminogen), and in HDL that contains both apoE and apoC3, a complex subspecies associated with higher coronary heart disease risk. ApoA1 in HDL that contains apoC1, associated with lower risk, increased 71% and 40%, respectively. Only HDL that contains apoL1 showed no response to either drug.

Conclusions: CETP inhibitors evacetrapib and torcetrapib increase apoA1 in HDL subspecies that contain apoC3 and other HDL subspecies associated with higher risk of coronary heart disease. Subspecies-specific effects shift HDL subspecies concentrations toward a profile associated with higher risk, which may contribute to lack of clinical benefit from raising HDL by pharmaceutical CETP inhibition.

Keywords: apolipoproteins; cholesterol ester transfer proteins, antagonists & inhibitors; heart diseases; hydroxymethylglutaryl-CoA reductase inhibitors; lipoproteins, HDL.

Figure 1.

Torcetrapib and evacetrapib increase the concentrations of apoA1 in total plasma and in HDL (high-density lipoprotein) that contains apoC3 compared with placebo. Atorvastatin was given as a background medication to all groups to control and equalize LDL (low-density lipoprotein)-cholesterol. Percentages indicated above the bars are median placebo-adjusted changes from baseline. Box plots show median, interquartile range, and mean (indicated by x). P values are for effect of drug compared with placebo and are FDR (false detection rate)-adjusted.

Figure 2.

Both torcetrapib and evacetrapib nominally increased the apoA1 concentrations of all HDL (high-density lipoprotein) subspecies studied, except apoL1, but to different degrees. Bars are median placebo-adjusted percent change. P values are for effect of drug compared with placebo and are FDR (false detection rate)-adjusted. A1AT indicates α-1-antitrypsin; A2M, α-2-macroglobulin; CoC3, complement C3; CP, ceruloplasmin; FBG, fibrinogen; HP, haptoglobin; PLMG, plasminogen; and PON-1, paraoxonase-1.

Figure 3.

Torcetrapib increases the apoA1 concentrations of subspecies of HDL (high-density lipoprotein) that lacks both apoE and apoC3, the subspecies of HDL that contains both apoE and apoC3, and the subspecies of HDL that contains apoC3 but not apoE. Torcetrapib had no effect on the subspecies of HDL that contains apoE but not apoC3. Atorvastatin was given as a background medication to all groups to control and equalize LDL (low-density lipoprotein)-cholesterol. N=14. P values above plots are for change from baseline. P value below bracket compares HDL that contains both apoE and apoC3 to HDL that contains apoE and lacks apoC3.

Figure 4.

Both torcetrapib and evacetrapib increase the proportion of total apoA1 comprised by HDL (high-density lipoprotein) that lacks apoA2 and HDL that contains apoC1, apoC3, or apoE. Both drugs decrease the proportion of total apoA1 that is comprised by HDL that contains apoL1 or haptoglobin (HP). Evacetrapib decreases the proportion of total apoA1 that is comprised by HDL that contains apoC2, apoJ, α-1-antitrypsin (A1AT), α-2-macroglobulin (A2M), ceruloplasmin (CP), complement C3 (CoC3), fibrinogen (FBG), plasminogen (PLMG), or paraoxonase-1 (PON-1). All P values are from Wilcoxon rank-sum test and are FDR (false detection rate)-adjusted.