Lipidomic analysis of variation in response to simvastatin in the Cholesterol and Pharmacogenetics Study.
Statins are commonly used for reducing cardiovascular disease risk but therapeutic benefit and reductions in levels of low-density lipoprotein cholesterol (LDL-C) vary among individuals. Other effects, including reductions in C-reactive protein (CRP), also contribute to treatment response. Metabolomics provides powerful tools to map pathways implicated in variation in response to statin treatment. This could lead to mechanistic hypotheses that provide insight into the underlying basis for individual variation in drug response. Using a targeted lipidomics platform, we defined lipid changes in blood samples from the upper and lower tails of the LDL-C response distribution in the Cholesterol and Pharmacogenetics study. Metabolic changes in responders are more comprehensive than those seen in non-responders. Baseline cholesterol ester and phospholipid metabolites correlated with LDL-C response to treatment. CRP response to therapy correlated with baseline plasmalogens, lipids involved in inflammation. There was no overlap of lipids whose changes correlated with LDL-C or CRP responses to simvastatin suggesting that distinct metabolic pathways govern statin effects on these two biomarkers. Metabolic signatures could provide insights about variability in response and mechanisms of action of statins. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-010-0207-x) contains supplementary material, which is available to authorized users.
Kaddurah-Daouk
Rima
R
Baillie
Rebecca A
RA
Zhu
Hongjie
H
Zeng
Zhao-Bang
ZB
Wiest
Michelle M
MM
Nguyen
Uyen Thao
UT
Watkins
Steven M
SM
Krauss
Ronald M
RM
Curr Med Chem. 2009;16(16):2021-41
19519379
Am J Clin Nutr. 1997 Feb;65(2):551-9
9022543
Circ Res. 2004 Nov 12;95(10):998-1004
15486318
Pharmacol Rev. 2006 Sep;58(3):591-620
16968951
J Clin Endocrinol Metab. 2006 Feb;91(2):439-46
16234304
N Engl J Med. 2008 Nov 20;359(21):2195-207
18997196
Arterioscler Thromb Vasc Biol. 2005 Sep;25(9):1952-9
16020749
Lancet. 2005 Oct 8;366(9493):1267-78
16214597
Nutr Metab Cardiovasc Dis. 2001 Apr;11(2):88-94
11434193
Circulation. 2003 Mar 25;107(11):1479-85
12654603
J Lipid Res. 1995 Aug;36(8):1813-24
7595102
Arterioscler Thromb Vasc Biol. 1999 Oct;19(10):2431-8
10521373
J Biol Chem. 2006 Jan 13;281(2):775-81
16278219
Circulation. 2004 Jul 13;110(2):227-39
15249516
Am J Cardiol. 2006 Mar 15;97(6):843-50
16516587
Clin Ther. 1994 Mar-Apr;16(2):200-8
8062316
Trans Assoc Am Physicians. 1983;96:1-9
6388097
Diabet Med. 2008 Aug;25(8):909-15
18959603
Atherosclerosis. 1986 Feb;59(2):113-9
3964339
Am Heart J. 2006 Feb;151(2):273-81
16442888
Ann Pharmacother. 2000 Dec;34(12):1432-9
11144702
Bull Exp Biol Med. 2001 Aug;132(2):763-5
11713560
Pharmacol Rep. 2007 Sep-Oct;59(5):483-99
18048949
J Lipid Res. 2007 Nov;48(11):2485-98
17664527
Clin Ther. 2008 Dec;30(12):2298-313
19167589
Am J Clin Nutr. 2005 Dec;82(6):1178-84
16332649
PLoS One. 2006 Dec 20;1:e97
17183729
Int J Circumpolar Health. 1998 Jan;57(1):22-31
9567573
Am J Cardiol. 2001 Oct 11;88(7B):23J-27J
11595195
Circulation. 2001 Feb 13;103(6):836-41
11171792
Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5
12883005
J Lipid Res. 2002 Nov;43(11):1809-17
12401879
Biochem Biophys Res Commun. 1994 Nov 15;204(3):1235-42
7980601
Eur J Pharmacol. 2007 Oct 1;571(2-3):97-105
17655842