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: