CETP (Cholesteryl Ester Transfer Protein) Inhibition With Anacetrapib Decreases Production of Lipoprotein(a) in Mildly Hypercholesterolemic Subjects

被引：74

作者：

Thomas, Tiffany ^{[1
]}

Zhou, Haihong ^{[2
]}

Karmally, Wahida ^{[1
]}

Ramakrishnan, Rajasekhar ^{[1
]}

Holleran, Stephen ^{[1
]}

Liu, Yang ^{[2
]}

Jumes, Patricia ^{[2
]}

Wagner, John A. ^{[2
]}

Hubbard, Brian ^{[2
]}

Previs, Stephen F. ^{[2
]}

Roddy, Thomas ^{[2
]}

Johnson-Levonas, Amy O. ^{[2
]}

Gutstein, David E. ^{[2
]}

Marcovina, Santica M. ^{[3
]}

Rader, Daniel J. ^{[4
]}

Ginsberg, Henry N. ^{[1
]}

Millar, John S. ^{[4
]}

Reyes-Soffer, Gissette ^{[1
]}

机构：

[1] Columbia Univ, New York, NY USA

[2] Merck & Co Inc, Kenilworth, NJ USA

[3] Univ Washington, Seattle, WA 98195 USA

[4] Univ Penn, Philadelphia, PA 19104 USA

来源：

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY | 2017年 / 37卷 / 09期

关键词：

anacetrapib; CETP; cysteine; ezetimibe; hypercholesterolemia; inhibitor; kringle; lipoprotein; lipoprotein metabolism; stable isotopes; APOLIPOPROTEIN(A) ALLELES; METABOLISM; DENSITY; APO(A); LP(A); CLEARANCE; KINETICS; RECEPTOR; THERAPY; RISK;

D O I：

10.1161/ATVBAHA.117.309549

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective-Lp(a) [lipoprotein (a)] is composed of apoB (apolipoprotein B) and apo(a) [apolipoprotein (a)] and is an independent risk factor for cardiovascular disease and aortic stenosis. In clinical trials, anacetrapib, a CETP (cholesteryl ester transfer protein) inhibitor, causes significant reductions in plasma Lp(a) levels. We conducted an exploratory study to examine the mechanism for Lp(a) lowering by anacetrapib. Approach and Results-We enrolled 39 participants in a fixed-sequence, double-blind study of the effects of anacetrapib on the I metabolism of apoB and high-density lipoproteins. Twenty-nine patients were randomized to atorvastatin 20 mg/d, plus placebo 6' for 4 weeks, and then atorvastatin plus anacetrapib (100 mg/d) for 8 weeks. The other 10 subjects were randomized to double placebo for 4 weeks followed by placebo plus anacetrapib for 8 weeks. We examined the mechanisms of Lp(a) lowering in a subset of 12 subjects having both Lp(a) levels >20 nmol/L and more than a 15% reduction in Lp(a) by the end of anacetrapib treatment. We performed stable isotope kinetic studies using H-2(3)-leucine at the end of each treatment to measure apo(a) fractional catabolic rate and production rate. Median baseline Lp(a) levels were 21.5 nmol/L (interquartile range, 9.9-108.1 nmol/L) in the complete cohort (39 subjects) and 52.9 nmol/L (interquartile range, 38.4-121.3 nmol/L) in the subset selected for kinetic studies. Anacetrapib treatment lowered Lp(a) by 34.1% (P <= 0.001) and 39.6% in the complete and subset cohort, respectively. The decreases in Lp(a) levels were because of a 41% reduction in the apo(a) production rate, with no effects on apo(a) fractional catabolic rate. Conclusions-Anacetrapib reduces Lp(a) levels by decreasing its production. Visual Overview-An online visual overview is available for this article.

引用

页码：1770 / +

页数：130

共 34 条

[21] Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects [J].