CETP (Cholesteryl Ester Transfer Protein) Inhibition With Anacetrapib Decreases Production of Lipoprotein(a) in Mildly Hypercholesterolemic Subjects. Issue 9 (September 2017)

• Record Type: Journal Article
• Authors: Thomas, Tiffany; Zhou, Haihong; Karmally, Wahida; Ramakrishnan, Rajasekhar; Holleran, Stephen; Liu, Yang; Jumes, Patricia; Wagner, John A.; Hubbard, Brian; Previs, Stephen F.; Roddy, Thomas; Johnson-Levonas, Amy O.; Gutstein, David E.; Marcovina, Santica M.; Rader, Daniel J.; Ginsberg, Henry N.; Millar, John S.; Reyes-Soffer, Gissette
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 37:Issue 9(2017)
• Publication Date: 2017-09
• Subjects: anacetrapib -- CETP -- cysteine -- ezetimibe -- hypercholesterolemia -- inhibitor -- kringle -- lipoprotein (a) -- lipoprotein metabolism -- stable isotopes; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.117.309549
• Languages: English
• ISSNs: 1079-5642

Abstract

Abstract : 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 metabolism of apoB and high-density lipoproteins. Twenty-nine patients were randomized to atorvastatin 20 mg/d, plus placebo 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 2 H3 -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. Clinical Trial Registration—: URL:http://www.clinicaltrials.gov . Unique identifier: NCT00990808. Abstract : Supplemental Digital Content is available in the text.