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

• Main Authors: Carvajal-Gonzalez, S. (Author), Dullea, R. (Author), Furtado, J.D (Author), Nicholls, S.J (Author), Ruotolo, G. (Author), Sacks, F.M (Author)
• Format: Article
• Language: English
• Published: Lippincott Williams and Wilkins 2022
• Subjects: aged; Aged; Antagonists & inhibitors; Anticholesteremic Agents; apolipoprotein C3; Apolipoprotein C-III; Apolipoproteins; atorvastatin; Atorvastatin; benzodiazepine derivative; Benzodiazepines; blood; CETP protein, human; cholesterol ester transfer protein; Cholesterol ester transfer proteins; Cholesterol Ester Transfer Proteins; clinical trial; complication; controlled study; coronary artery disease; Coronary Disease; evacetrapib; ezetimibe; Ezetimibe; female; Female; HDL; Heart Disease Risk Factors; Heart diseases; high density lipoprotein; human; Humans; Hydroxymethylglutaryl-CoA reductase inhibitors; hyperlipidemia; Hyperlipidemias; hypocholesterolemic agent; Lipoproteins; Lipoproteins, HDL; male; Male; middle aged; Middle Aged; multicenter study; phase 3 clinical trial; randomized controlled trial
• Online Access: View Fulltext in Publisher

 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. © 2021 The Authors. Arteriosclerosis, Thrombosis, and Vascular Biology is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.