title: Fenofibrate and metabolic syndrome.
abstract: The fibric acid derivative, fenofibrate (FF) has been used in the US since 1998 to manage patients with dyslipidemia. Typical changes in serum lipids as result a of FF treatment include clinically important mean reductions of serum triglycerides (TG) by a mean change of -93.7 mg/dL (-39.3%), increases of high density lipoprotein cholesterol (HDLC) by +5.5 mg/dL (+12.4%), and reductions in low density lipoprotein cholesterol (LDLC) by -17.9 mg/dL (-12.3%). The greatest reductions in serum TG are usually observed in subjects with elevated baseline TGs including those with the metabolic syndrome (MetS). Although statins remain the mainstay of therapy for most dyslipidemic patients, their combined use with FF would be expected to address residual risk resulting from less than optimal TG and HDLC levels in such patients. Clinical trials examining the cardiovascular benefits of FF alone or combined with statins have produced mixed results. These observations underscore our lack of understanding of which patients may benefit from FF therapy and which do not. Although FF's basic mechanism of action is known to involve PPAR-alpha agonist activity resulting in altered transcription of several genes, the actual genetic bases for variability in lipid response is poorly understood. Studies, such as our GOLDN study and others designed to better understand the genetic determinants of variability in the response to FF treatment and lipid levels. As a result several important genetic determinants of lipid levels have been identified. For example, in the GOLDN study SNPs from different genes were significantly associated with baseline lipid levels before treatment (APOA5- rs662799, rs3135506; APOC3- rs5128, rs2854117, rs4520); APOA4- rs5104; PPARA- rs9626730, rs135543, rs11703495; LPL- rs1801177), after treatment PPARA- rs11708495; LPL- rs1801177, and appeared to modulate overall response to FF treatment (NOS3- rs1799983). In this article, we will review the literature leading up to the contemporary use of FF as an agent to manage patients with dyslipidemia and focus on emerging understanding of the genetic variability in response to FF treatment. On the basis of the available evidence, we conclude that FF is of benefit in the treatment of dyslipidemia, especially among those with MetS. However, more work is needed to specifically identify which individuals derive a benefit from FF administration in terms of clinical outcomes and which do not - particularly in the context of type 2 diabetes.
authors.affiliation: Division of Statistical Genomics, Washington University School of Medicine, 4444 Forest Park Ave., Campus Box 8506, St. Louis, MO 63110, USA. aldi@wustl.edu
authors.forename: Aldi T
authors.initials: AT
authors.lastname: Kraja
authors.forename: Michael A
authors.initials: MA
authors.lastname: Province
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Straka
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ordovas
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
mesh_terms: D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D011345:Fenofibrate / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D015228:Hypertriglyceridemia / Q000097:blood; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008055:Lipids / Q000627:therapeutic use; D024821:Metabolic Syndrome / Q000188:drug therapy*; D047493:PPAR alpha / Q000819:agonists; D014280:Triglycerides / Q000097:blood
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D008055:Lipids; D047493:PPAR alpha; D014280:Triglycerides; D011345:Fenofibrate
references.citation: Eur Heart J. 2005 May;26(9):897-905
references.pmid: 15781429
references.citation: Am J Cardiol. 2005 Jan 1;95(1):120-2
references.pmid: 15619408
references.citation: Diabetes Care. 2007 Aug;30(8):1945-51
references.pmid: 17483155
references.citation: Circulation. 1998 May 12;97(18):1837-47
references.pmid: 9603539
references.citation: Arch Intern Med. 2002 Dec 9-23;162(22):2597-604
references.pmid: 12456232
references.citation: Am Heart J. 2007 Feb;153(2):335.e1-8
references.pmid: 17239698
references.citation: Prog Clin Biol Res. 1979;32:711-29
references.pmid: 523491
references.citation: Am J Cardiol. 2006 Apr 17;97(8A):89C-94C
references.pmid: 16581336
references.citation: Int J Clin Pharmacol Ther. 2006 Feb;44(2):64-70
references.pmid: 16502765
references.citation: Diabetes Care. 2009 Mar;32(3):493-8
references.pmid: 18984774
references.citation: Cell Mol Life Sci. 2004 Feb;61(4):393-416
references.pmid: 14999402
references.citation: Curr Opin Lipidol. 2009 Dec;20(6):505-11
references.pmid: 19829109
references.citation: EMBO J. 1992 Feb;11(2):433-9
references.pmid: 1537328
references.citation: Clin Pharmacol Ther. 2003 Sep;74(3):236-44
references.pmid: 12966367
references.citation: Circulation. 2004 Sep 7;110(10):1245-50
references.pmid: 15326067
references.citation: Diabetologia. 2007 Oct;50(10):2067-75
references.pmid: 17653691
references.citation: Pharmacotherapy. 2007 Mar;27(3):412-24
references.pmid: 17316152
references.citation: Diabetes Obes Metab. 2008 Jun;10(6):476-83
references.pmid: 17459096
references.citation: Atherosclerosis. 2007 May;192(1):204-10
references.pmid: 16781717
references.citation: Arch Intern Med. 2006 Apr 10;166(7):743-8
references.pmid: 16606810
references.citation: J Am Coll Cardiol. 2008 Jan 29;51(4):459-65
references.pmid: 18222357
references.citation: Clin Drug Investig. 2008;28(10):625-34
references.pmid: 18783301
references.citation: Diabetes Care. 2002 Mar;25(3):627-8
references.pmid: 11874962
references.citation: Proc Natl Acad Sci U S A. 1986 Mar;83(6):1747-51
references.pmid: 3456610
references.citation: Manag Care Interface. 2000 Mar;13(3):52-8
references.pmid: 11066277
references.citation: Diabetes Care. 2005 Jul;28(7):1769-78
references.pmid: 15983333
references.citation: Clin Ther. 2004 Oct;26(10):1599-607
references.pmid: 15598476
references.citation: Endocr Metab Immune Disord Drug Targets. 2010 Jun;10(2):109-23
references.pmid: 20384572
references.citation: Diabetes Care. 2008 Jul;31(7):1405-9
references.pmid: 18375418
references.citation: J Mol Cell Cardiol. 2004 Feb;36(2):295-304
references.pmid: 14871557
references.citation: N Engl J Med. 2010 Apr 29;362(17):1563-74
references.pmid: 20228404
references.citation: Clin Cardiol. 2006 Jun;29(6):268-73
references.pmid: 16796078
references.citation: Am J Med. 1987 Nov 27;83(5B):9-20
references.pmid: 3318457
references.citation: Drugs Aging. 2001;18(9):665-83
references.pmid: 11599634
references.citation: J Cardiovasc Pharmacol. 2003 Jan;41(1):60-7
references.pmid: 12500022
references.citation: Clin Ther. 2004 Sep;26(9):1456-69
references.pmid: 15531008
references.citation: Eur J Hum Genet. 2008 May;16(5):603-13
references.pmid: 18212815
references.citation: Diabetes Care. 2008 May;31(5):910-5
references.pmid: 18285551
references.citation: Science. 2001 Oct 5;294(5540):169-73
references.pmid: 11588264
references.citation: Lancet. 1984 Sep 15;2(8403):600-4
references.pmid: 6147641
references.citation: J Hum Genet. 2008;53(8):709-717
references.pmid: 18542840
references.citation: Atherosclerosis. 2003 Oct;170(2):315-23
references.pmid: 14612213
references.citation: Drugs. 2007;67(1):121-53
references.pmid: 17209672
references.citation: Ann Med. 1991 Apr;23(2):155-9
references.pmid: 2069792
references.citation: Arterioscler Thromb. 1992 Mar;12(3):286-94
references.pmid: 1547188
references.citation: N Engl J Med. 1999 Aug 5;341(6):410-8
references.pmid: 10438259
references.citation: J Am Coll Cardiol. 2005 Jan 18;45(2):185-97
references.pmid: 15653014
references.citation: Mol Cell Biol. 1995 Jun;15(6):3012-22
references.pmid: 7539101
references.citation: Lancet. 2005 Nov 26;366(9500):1849-61
references.pmid: 16310551
references.citation: Hum Genet. 2004 Nov;115(6):468-74
references.pmid: 15375693
references.citation: Lancet. 2005 Oct 8;366(9493):1267-78
references.pmid: 16214597
references.citation: BMC Med Genet. 2009 May 09;10:39
references.pmid: 19426517
references.citation: Biochim Biophys Acta. 1996 Jul 26;1302(2):93-109
references.pmid: 8695669
references.citation: Eur Heart J. 2010 Jan;31(1):92-9
references.pmid: 19797259
references.citation: Drugs. 2004;64(11):1181-96
references.pmid: 15161326
references.citation: Atherosclerosis. 2007 Dec;195(2):385-91
references.pmid: 17109866
references.citation: Metabolism. 2007 Nov;56(11):1534-41
references.pmid: 17950105
references.citation: Atherosclerosis. 2002 Jun;162(2):363-71
references.pmid: 11996956
references.citation: J Clin Invest. 1995 Feb;95(2):705-12
references.pmid: 7860752
references.citation: Ann Med. 2006;38(7):522-8
references.pmid: 17101543
references.citation: Arterioscler Thromb Vasc Biol. 2007 Jun;27(6):1417-25
references.pmid: 17431185
references.citation: Toxicol Lett. 1998 Sep 1;98(1-2):13-23
references.pmid: 9776557
references.citation: Am Heart J. 2008 Mar;155(3):499.e9-16
references.pmid: 18294485
references.citation: Arterioscler Thromb Vasc Biol. 2002 May 1;22(5):717-26
references.pmid: 12006382
references.citation: Drugs. 1990 Aug;40(2):260-90
references.pmid: 2226216
references.citation: Circulation. 2004 Jun 15;109(23 Suppl 1):III50-7
references.pmid: 15198967
references.citation: J Lipid Res. 2004 Nov;45(11):2096-105
references.pmid: 15342688
references.citation: Thromb Haemost. 2005 Jul;94(1):193-9
references.pmid: 16113803
references.citation: Am J Med. 1987 Nov 27;83(5B):21-5
references.pmid: 3318449
references.citation: Diabetes Res Clin Pract. 2003 Jul;61 Suppl 1:S27-34
references.pmid: 12880692
references.citation: FEBS Lett. 1992 Aug 31;309(1):37-40
references.pmid: 1324848
references.citation: Atherosclerosis. 2007 Oct;194(2):e123-30
references.pmid: 17145061
references.citation: Vasc Health Risk Manag. 2005;1(3):209-15
references.pmid: 17319106
references.citation: N Engl J Med. 2010 Apr 22;362(16):1477-90
references.pmid: 20228403
references.citation: Arterioscler Thromb Vasc Biol. 2004 Apr;24(4):658-63
references.pmid: 14751809
references.citation: Metabolism. 1965 Sep;14:966-75
references.pmid: 14327273
references.citation: J Lipid Res. 2006 Jul;47(7):1339-51
references.pmid: 16585781
references.citation: Expert Opin Pharmacother. 2006 Sep;7(13):1701-14
references.pmid: 16925498
references.citation: Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2160-4
references.pmid: 8384714
references.citation: Endocr Metab Immune Disord Drug Targets. 2008 Sep;8(3):198-207
references.pmid: 18782016
references.citation: JAMA. 2001 May 16;285(19):2486-97
references.pmid: 11368702
references.citation: Clin Chem. 2006 Nov;52(11):2036-42
references.pmid: 16990410
references.citation: Hypertension. 2007 Jun;49(6):1285-90
references.pmid: 17404185
references.citation: Endocr Metab Immune Disord Drug Targets. 2010 Jun;10(2):124-37
references.pmid: 20088815
references.citation: Lancet. 2007 Nov 17;370(9600):1687-97
references.pmid: 17988728
references.citation: Curr Opin Lipidol. 2006 Dec;17(6):653-8
references.pmid: 17095910
references.citation: Am J Epidemiol. 1996 Jun 15;143(12):1219-28
references.pmid: 8651220
references.citation: Biometrics. 1997 Sep;53(3):983-97
references.pmid: 9333350
references.citation: Am J Cardiol. 2005 Feb 15;95(4):462-8
references.pmid: 15695129
references.citation: Ann Pharmacother. 1999 Oct;33(10):1083-103
references.pmid: 10534222
references.citation: J Atheroscler Res. 1963 Sep-Dec;3:427-44
references.pmid: 14100884
references.citation: Genomics. 2007 Dec;90(6):674-9
references.pmid: 17936576
references.citation: Circulation. 2005 Oct 25;112(17):2735-52
references.pmid: 16157765
references.citation: Curr Opin Cardiol. 2009 Jul;24(4):372-9
references.pmid: 19424060
references.citation: Cardiology. 2004;102(2):61-6
references.pmid: 15103174
references.citation: Metab Syndr Relat Disord. 2007 Dec;5(4):305-14
references.pmid: 18370800
references.citation: Obes Res. 2005 Nov;13(11):1885-90
references.pmid: 16339118
references.citation: Cardiovasc Diabetol. 2005 Aug 22;4:13
references.pmid: 16111499
references.citation: Diabetes Metab Res Rev. 1999 Nov-Dec;15(6):395-9
references.pmid: 10634964
references.citation: Endocr Metab Immune Disord Drug Targets. 2010 Jun;10(2):86-108
references.pmid: 20406164
references.citation: Curr Pharm Des. 2009;15(5):537-52
references.pmid: 19199980
references.citation: Curr Med Res Opin. 2004;20(2):241-7
references.pmid: 15006019
references.citation: Nat Genet. 2008 Feb;40(2):161-9
references.pmid: 18193043
references.citation: Pharmacogenet Genomics. 2005 May;15(5):287-93
references.pmid: 15864129
references.citation: Expert Opin Drug Saf. 2006 Jan;5(1):145-56
references.pmid: 16370963
references.citation: Cardiovasc Res. 2007 Jul 15;75(2):398-407
references.pmid: 17412316