Molecular lipids identify cardiovascular risk and are efficiently lowered by simvastatin and PCSK9 deficiency

J Clin Endocrinol Metab. 2014 Jan;99(1):E45-52. doi: 10.1210/jc.2013-2559. Epub 2013 Dec 20.


Context: Coronary artery disease (CAD) is among the leading causes of mortality and morbidity worldwide. Traditional risk markers explain only a proportion of total cardiovascular risk. Thus, development and improvement of early diagnostic strategies and targeted initiation of preventive measures would be of great benefit.

Objective: We aimed to identify molecular lipids that are associated with fatal outcome of CAD patients. Furthermore, the effect of different lipid-lowering drugs on novel risk lipids was evaluated.

Methods: Serum samples of 445 CAD subjects participating in a long-term follow-up of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study were analyzed. In addition, samples obtained from a separate randomized parallel three-group study of subjects treated with simvastatin (n=24), ezetimibe (n=24), or their combination (n=24) were studied. Furthermore, samples from the LURIC participants with a loss-of-function mutation (R46L) in the PCSK9 gene (n=19) were analyzed and compared with major allele carriers (n=868).

Results: Distinct ceramide species were significantly associated with the fatal outcome of CAD patients. Simvastatin lowered plasma ceramides broadly by about 25%, but no changes in ceramides were observed in the ezetimibe group. PCSK9 deficiency was significantly associated (-13%) with lowered low-density lipoprotein cholesterol accompanied by a significant 20% reduction in CAD outcome risk-related ceramides.

Conclusions: These data suggest that distinct ceramides associate significantly with CAD outcome independently of traditional risk factors and that the mechanism of lipid lowering is important.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Azetidines / therapeutic use
  • Case-Control Studies
  • Coronary Artery Disease / blood
  • Coronary Artery Disease / drug therapy*
  • Coronary Artery Disease / epidemiology*
  • Ezetimibe
  • Female
  • Follow-Up Studies
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Hypolipidemic Agents / therapeutic use*
  • Lipids / blood*
  • Macromolecular Substances / blood
  • Male
  • Middle Aged
  • Proprotein Convertase 9
  • Proprotein Convertases / deficiency
  • Proprotein Convertases / genetics*
  • Randomized Controlled Trials as Topic
  • Risk Factors
  • Serine Endopeptidases / deficiency
  • Serine Endopeptidases / genetics*
  • Simvastatin / therapeutic use*


  • Azetidines
  • Hypolipidemic Agents
  • Lipids
  • Macromolecular Substances
  • Simvastatin
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases
  • Ezetimibe