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

Thomas, Tiffany; Zhou, Haihong; Karmally, Wahida; Ramakrishnan, Rajasekhar; Holleran, Stephen F.; 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.; Soffer, Gissette

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 2H3-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.

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More Information

Published In
Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher DOI
https://doi.org/10.1161/ATVBAHA.117.309549
Volume
37
Pages
1770 - 1775
Academic Units
Medicine
Irving Institute for Clinical and Translational Research
Pediatrics
Pathology and Cell Biology
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