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Title:   Author  item
                                            SNOWDEN, STUART - Karolinska Instituteitem
                                            GRAPOV, DMITRY - University Of Californiaitem
                                            NYGREN, HELI - Vtt Technical Research Centre Of Finlanditem
                                            SETTERGREN, MAGNUS - Karolinska Instituteitem
                                            D'ALEXANDRI, FABIO - Karolinska Instituteitem
                                            HAEGGSTROM, JESPER - Karolinska Instituteitem
                                            HYOTYLAINEN, TUULIA - Vtt Technical Research Centre Of Finlanditem
                                            ORESIC, MATEJ - Vtt Technical Research Centre Of Finlanditem
                                            Pedersen, Theresaitem
                                            Newman, Johnitem
                                            PERNOW, JOHN - Karolinska Instituteitem
                                            WHEELOCK, CRAIG - Karolinska Institute
  Submitted to: Circulation: Cardiovascular Genetics
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 5/28/2013
                                    Publication  Date: 12/1/2014
                                    Citation: Snowden, S.G., Grapov, D., Nygren, H., Settergren, M., D'Alexandri, F.L., Haeggstrom, J.Z., Hyotylainen, T., Oresic, M., Pedersen, T.L., Newman, J.W., Pernow, J., Wheelock, C.E. 2014. High dose simvastatin exhibits enhanced lipid lowering effects relative to simvastatin/ezetimibe combination therapy. Circulation: Cardiovascular Genetics. 7:955-964. doi: 10.1161/CIRCGENETICS.114.000606.Interpretive Summary: 

Cholesterol reduction is associated with a reduction of cardiovascular risk however therapies which reduce cholesterol may affect other aspects of metabolism through either direct or indirect mechanisms.    Statin type drugs interfere with cholesterol synthesis and are the most commonly used cholesterol reduction therapy while ezatimibe reduces cholesterol absorption in the intestine.   By comparing changes in lipid metabolism associated with either stain only or statin/ezatimibe co-therapy, the metabolic improvements associated with statin treatment that are independent of cholesterol concentrations themselves (i.e. pleiotropic effect) may be revealed.   In this 6 week study, 20 patients were treated with 80mg simvastatin and 19 subjects were treated with 10mg simvastatin + 10 mg of ezatimibe.  Dosing was designed to achieve equivalent reductions in low density lipoprotein cholesterol (LDL-C) levels, while enabling the assessment of sivastain-associated changes in lipids other than cholesterol.  Baseline and post-treatment plasma were analyzed for a range of lipid mediators of inflammation, vascular function, and energy balance, along with broad profiles of structural lipids. Following statistical analysis, no changes were observed in lipid mediator levels with either treatment.  However, significant reductions in structural lipids were produced by both mono- and combination therapy.  The majority of changes were associated with simvastatin in a dose-dependent manner. Decreases in the phosphotidylcholine containing on saturated 15 carbon fatty acid and one 18 carbon ppolyunsaturated fatt acid (i.e. PC(15:0/18:2) and the monoglycosylated ceramide with one 18 carbon monounsaturated fatty acid and one 24 carbon unsaturated fatty acid (i.e. HexCer(d18:1/24:0)) were the strongest discriminators of LDL-C reductions for both treatment groups.  Both high-dose simvastatin and simvastatin/ezetimibe therapy shifted lipid composition in a similar manner, with the magnitude of reduction being linked to the simvastatin dose. Simvastatin therapy did not affect circulating levels of lipid mediators, suggesting that reported anti-inflammatory effects do not influence the production of eicosanoids, potent and well studied inflammatory and vascular mediators. Only high-dose simvastatin reduced the relative proportion of sphingomyelin and ceramide to phosphatidylcholine (p=0.03), an effect previously associated with a reduced risk of cardiovascular disease.
                                Technical Abstract: 
Technical Abstract:
Background: Statins are the frontline in cholesterol reduction therapies; however use in combination with agents that possess complimentary mechanisms of action may achieve further reduce in LDL-C.

Methods and Results: Thirty-nine patients were treated with either 80mg simvastatin (n=20) or 10mg simvastatin plus 10mg ezetimibe (n=19) for 6 weeks. Dosing was designed to produce comparable LDL-C reductions, while enabling assessment of potential simvastatinassociated pleiotropic effects. Baseline and post-treatment plasma were analyzed for lipid mediators (e.g., eicosanoids, endocannabinoids) and structural lipids by liquid chromatography tandem mass spectrometry. Following statistical analysis and orthogonal projections to latent structures (OPLS) multivariate modeling, no changes were observed in lipid mediator levels, while global structural lipids were reduced in response to both mono- (R2Y=0.74, Q2=0.66, CV-ANOVA p=7.0×10-8) and combination therapy (R2Y=0.67,Q2=0.54, CV-ANOVA p=2.6×10-5). The majority of changes were associated with simvastatin in a dose-dependent manner. Decreases in the lipid species PC(15:0/18:2) and HexCer(d18:1/24:0) were the strongest discriminators of LDL-C reductions for both treatment groups (q<0.00005). LysoPC(20:4) and PE(36:6) were the only lipids that increased in response to both treatments (q<0.01). 

Conclusions: 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 highdose simvastatin reduced the relative proportion of sphingomyelin and ceramide to phosphatidylcholine (p=0.03), suggesting a pleiotropic effect that has been previously associated with a reduced risk of cardiovascular disease.


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