title: High-dose simvastatin exhibits enhanced lipid-lowering effects relative to simvastatin/ezetimibe combination therapy.
abstract: 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 (R(2)Y=0.74; Q(2)=0.66; cross-validated ANOVA P=7.0×10(-8)) and combination therapy (R(2)Y=0.67; Q(2)=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 (R(2)Y=0.65; Q(2)=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 low-density 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.
authors.affiliation: Department of Medical Biochemistry & Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Snowden
authors.affiliation: NIH West Coast Metabolomics Center, University of California.|USDA ARS Western Human Nutrition Research Center, Davis, CA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Grapov
authors.affiliation: Department of Medicine, Unit of Cardiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Settergren
authors.affiliation: Department of Medical Biochemistry & Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Fabio Luiz
authors.initials: FL
authors.lastname: D'Alexandri
authors.affiliation: Department of Medical Biochemistry & Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jesper Z
authors.initials: JZ
authors.lastname: Haeggström
authors.affiliation: NIH West Coast Metabolomics Center, University of California.
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.affiliation: VTT Technical Research Centre of Finland, Espoo, Finland.
authors.forename: Tuulia
authors.initials: T
authors.lastname: Hyötyläinen
authors.affiliation: USDA ARS Western Human Nutrition Research Center, Davis, CA.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Pedersen
authors.affiliation: USDA ARS Western Human Nutrition Research Center, Davis, CA.|Department of Nutrition, University of California.
authors.forename: John W
authors.initials: JW
authors.lastname: Newman
authors.affiliation: VTT Technical Research Centre of Finland, Espoo, Finland.
authors.forename: Matej
authors.initials: M
authors.lastname: Orešič
authors.affiliation: Department of Medicine, Unit of Cardiology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Pernow
authors.affiliation: Department of Medical Biochemistry & Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Wheelock
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001384:Azetidines / Q000627:therapeutic use*; D002518:Ceramides / Q000032:analysis; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D016002:Discriminant Analysis; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004338:Drug Combinations; D000069499:Ezetimibe, Simvastatin Drug Combination; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010713:Phosphatidylcholines / Q000032:analysis; D019821:Simvastatin / Q000627:therapeutic use*; D013109:Sphingomyelins / Q000032:analysis; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D002518:Ceramides; D008078:Cholesterol, LDL; D004338:Drug Combinations; D000069499:Ezetimibe, Simvastatin Drug Combination; D010713:Phosphatidylcholines; D013109:Sphingomyelins; D014280:Triglycerides; D002784:Cholesterol; D019821:Simvastatin
keywords: eicosanoids; ezetimibe; hydroxymethylglutaryl-CoA reductase inhibitors; lipids; mass spectrometry; simvastatin