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High-dose simvastatin exhibits enhanced lipid-lowering effects relative to simvastatin/ezetimibe combination therapy
Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden.
NIH West Coast Metabolomics Center, University of California, Davis, United States; Department of Nutrition, University of California, Davis, United States.
Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden.
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2014 (English)In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 7, no 6, p. 955-964Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2014. Vol. 7, no 6, p. 955-964
Keyword [en]
eicosanoids, ezetimibe, hydroxymethylglutaryl-CoA reductase inhibitors, lipids, mass spectrometry, simvastatin
National Category
Cardiac and Cardiovascular Systems Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:oru:diva-63700DOI: 10.1161/CIRCGENETICS.114.000606ISI: 000346358800027PubMedID: 25516625Scopus ID: 2-s2.0-84925863928OAI: oai:DiVA.org:oru-63700DiVA, id: diva2:1169265
Funder
Swedish Heart Lung FoundationSwedish Research Council, 10857
Note

Funding agencies:

National Institute of General Medical Sciences-National Institutes of Health T32-GM008799

NIH West Coast Metabolomics Center grant NIH 1 U24 DK097154

US Department of Agriculture (USDA)-Agricultural Research Service Intramural Project 5306-51530-19-00D

Stockholm County Council

Karolinska Institutet/Stockholm County Council Strategic Cardiovascular Program

Gustav V and Queen Victoria Foundation

Available from: 2017-12-22 Created: 2017-12-22 Last updated: 2018-01-30Bibliographically approved

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Hyötyläinen, TuuliaOresic, Matej

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