Anacetrapib lowers lipoprotein(a) by cutting its production rate 41%, not by speeding its clearance (ATVB 2017)

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

Arterioscler Thromb Vasc Biol · 20 July 2017 · 7

Thomas T, Zhou H, Karmally W, Ramakrishnan R, Holleran S, Liu Y, Jumes P, Wagner JA, Hubbard B, Previs SF, Roddy T, Johnson-Levonas AO et al.

Since anacetrapib is known to significantly lower plasma lipoprotein(a), this exploratory study examined the mechanism in 39 participants in a fixed-sequence, double-blind trial (NCT00990808). Twenty-nine subjects received atorvastatin 20 mg/d plus placebo for 4 weeks then atorvastatin plus anacetrapib 100 mg/d for 8 weeks, while 10 received double placebo then placebo plus anacetrapib. In a subset of 12 subjects with baseline Lp(a) above 20 nmol/L and at least 15% Lp(a) reduction, stable-isotope kinetic studies using 2H3-leucine measured apo(a) fractional catabolic and production rates. Anacetrapib lowered Lp(a) by 34.1% (P less than or equal to 0.001) in the full cohort and 39.6% in the kinetic subset, a decrease driven by a 41% reduction in apo(a) production rate with no change in its fractional catabolic rate, establishing that anacetrapib reduces Lp(a) by suppressing its production rather than accelerating its clearance.

Original 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 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.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00990808.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.