High-dose simvastatin exhibits enhanced lipid-lowering effects relative to simvastatin/ezetimibe combination therapy

Stuart G. Snowden, Dmitry Grapov, Magnus Settergren, Fabio Luiz D'Alexandri, Jesper Z. Haeggström, Oliver Fiehn, Tuulia Hyötyläinen, Theresa L. Pedersen, John W. Newman, Matej Orešič, John Pernow, Craig E. Wheelock

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Statins are the frontline in cholesterol reduction therapies; however, their use in combination with agents that possess complimentary mechanisms of action may achieve further reductions in low-density lipoprotein cholesterol. Thirty-nine patients were treated with either 80 mg simvastatin (n=20) or 10 mg simvastatin plus 10 mg ezetimibe (n=19) for 6 weeks. Dosing was designed to produce comparable low-density lipoprotein cholesterol reductions, while enabling assessment of potential simvastatin-associated pleiotropic effects. Baseline and post-treatment plasma were analyzed for lipid mediators (eg, eicosanoids and endocannabinoids) and structural lipids by liquid chromatography tandem mass spectrometry. After statistical analysis and orthogonal projections to latent structures multivariate modeling, no changes were observed in lipid mediator levels, whereas global structural lipids were reduced in response to both monotherapy (R2Y=0.74; Q2=0.66; cross-validated ANOVA P=7.0×10-8) and combination therapy (R2Y=0.67; Q2=0.54; cross-validated ANOVA P=2.6×10-5). Orthogonal projections to latent structures modeling identified a subset of 12 lipids that classified the 2 treatment groups after 6 weeks (R2Y=0.65; Q2=0.61; cross-validated ANOVA P=5.4×10-8). Decreases in the lipid species phosphatidylcholine (15:0/18:2) and hexosyl-ceramide (d18:1/24:0) were the strongest discriminators of lowdensity lipoprotein cholesterol reductions for both treatment groups (q<0.00005), whereas phosphatidylethanolamine (36:3e) contributed most to distinguishing treatment groups (q=0.017). Shifts in lipid composition were similar for high-dose simvastatin and simvastatin/ezetimibe combination therapy, but the magnitude of the reduction was linked to simvastatin dosage. Simvastatin therapy did not affect circulating levels of lipid mediators, suggesting that pleiotropic effects are not associated with eicosanoid production. Only high-dose simvastatin reduced the relative proportion of sphingomyelin and ceramide to phosphatidylcholine (q=0.008), suggesting a pleiotropic effect previously associated with a reduced risk of cardiovascular disease.

Original languageEnglish (US)
Pages (from-to)955-964
Number of pages10
JournalCirculation: Cardiovascular Genetics
Issue number6
StatePublished - Dec 1 2014


  • Eicosanoids
  • Ezetimibe
  • Hydroxymethylglutaryl-CoA reductase inhibitors
  • Lipids
  • Mass spectrometry
  • Simvastatin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics


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