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

Arterioscler Thromb Vasc Biol. 2017 Sep;37(9):1770-1775. doi: 10.1161/ATVBAHA.117.309549. Epub 2017 Jul 20.

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.

Keywords: CETP; anacetrapib; cysteine; ezetimibe; hypercholesterolemia; inhibitor; kringle; lipoprotein (a); lipoprotein metabolism; stable isotopes.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anticholesteremic Agents / adverse effects
  • Anticholesteremic Agents / therapeutic use*
  • Biomarkers / blood
  • Cholesterol Ester Transfer Proteins / antagonists & inhibitors*
  • Cholesterol Ester Transfer Proteins / metabolism
  • Chromatography, Liquid
  • Double-Blind Method
  • Down-Regulation
  • Female
  • Humans
  • Hypercholesterolemia / blood
  • Hypercholesterolemia / diagnosis
  • Hypercholesterolemia / drug therapy*
  • Lipoprotein(a) / blood*
  • Male
  • Middle Aged
  • New York City
  • Oxazolidinones / adverse effects
  • Oxazolidinones / therapeutic use*
  • Pennsylvania
  • Severity of Illness Index
  • Tandem Mass Spectrometry
  • Time Factors
  • Treatment Outcome

Substances

  • Anticholesteremic Agents
  • Biomarkers
  • CETP protein, human
  • Cholesterol Ester Transfer Proteins
  • Lipoprotein(a)
  • Oxazolidinones
  • anacetrapib

Associated data

  • ClinicalTrials.gov/NCT00990808