title: Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.
abstract: BACKGROUND
  Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease risk is not well-documented.
  
  
  OBJECTIVE
  The aim of this meta-analysis was to evaluate: 1) the interindividual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), or apolipoprotein B (apoB) levels achieved with statin therapy; 2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy; and 3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and cardiovascular disease risk.
  
  
  METHODS
  This meta-analysis used individual patient data from 8 randomized controlled statin trials, in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up.
  
  
  RESULTS
  Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large interindividual variability in the reductions of LDL-C, non-HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target <70 mg/dl. Compared with patients who achieved an LDL-C >175 mg/dl, those who reached an LDL-C 75 to <100 mg/dl, 50 to <75 mg/dl, and <50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval [CI]: 0.46 to 0.67), 0.51 (95% CI: 0.42 to 0.62), and 0.44 (95% CI: 0.35 to 0.55), respectively. Similar associations were observed for non-HDL-C and apoB.
  
  
  CONCLUSIONS
  The reductions of LDL-C, non-HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, >40% did not reach an LDL-C target <70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels.
authors.affiliation: Department of Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: S Matthijs
authors.initials: SM
authors.lastname: Boekholdt
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
authors.affiliation: Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Samia
authors.initials: S
authors.lastname: Mora
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Benoit J
authors.initials: BJ
authors.lastname: Arsenault
authors.affiliation: Department of Neurology and Stroke Center, Bichat University Hospital, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Amarenco
authors.affiliation: Center of Preventive Medicine, Oslo University Hospital, Ulleval and University of Oslo, Oslo, Norway.
authors.forename: Terje R
authors.initials: TR
authors.lastname: Pedersen
authors.affiliation: Health Science Center, State University of New York, Brooklyn, New York.
authors.forename: John C
authors.initials: JC
authors.lastname: LaRosa
authors.affiliation: Division of Cardiology, San Francisco General Hospital and the University of California at San Francisco, San Francisco, California.
authors.forename: David D
authors.initials: DD
authors.lastname: Waters
authors.affiliation: Global Pharmaceuticals, Pfizer Inc., New York, New York.
authors.forename: David A
authors.initials: DA
authors.lastname: DeMicco
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.
authors.forename: R John
authors.initials: RJ
authors.lastname: Simes
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia.
authors.forename: Antony C
authors.initials: AC
authors.lastname: Keech
authors.affiliation: The Wesley Hospital, Brisbane, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Colquhoun
authors.affiliation: Centre for Diabetes, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Graham A
authors.initials: GA
authors.lastname: Hitman
authors.affiliation: Department of Endocrinology and Diabetes, University College Hospital, London, United Kingdom.
authors.forename: D John
authors.initials: DJ
authors.lastname: Betteridge
authors.affiliation: Touro University, Mare Island, California.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Clearfield
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas; VERDICT, South Texas Veterans Health Care System, San Antonio, Texas.
authors.forename: John R
authors.initials: JR
authors.lastname: Downs
authors.affiliation: Medical Research Institute, University of Dundee, Dundee, United Kingdom.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Colhoun
authors.affiliation: Weill Cornell Medical College, New York, New York.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Gotto
authors.affiliation: Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
authors.affiliation: Center for Human Nutrition, Southwestern Medical Center, University of Texas, Dallas, Texas.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Grundy
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. Electronic address: j.j.kastelein@amc.uva.nl.
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
mesh_terms: D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy / Q000453:epidemiology; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000188:drug therapy / Q000517:prevention & control; D014943:Global Health; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D015994:Incidence; D008074:Lipoproteins / Q000097:blood* / Q000187:drug effects; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors
chemical_list: D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins
keywords: LDL-cholesterol; apolipoprotein B; meta-analysis; non–HDL-cholesterol
references.citation: N Engl J Med. 1998 Nov 5;339(19):1349-57
references.pmid: 9841303
references.citation: J Am Coll Cardiol. 2005 Oct 18;46(8):1411-6
references.pmid: 16226163
references.citation: N Engl J Med. 2008 Nov 20;359(21):2195-207
references.pmid: 18997196
references.citation: J Am Coll Cardiol. 2011 Apr 19;57(16):1666-75
references.pmid: 21492764
references.citation: N Engl J Med. 2006 Aug 10;355(6):549-59
references.pmid: 16899775
references.citation: Lancet. 1994 Nov 19;344(8934):1383-9
references.pmid: 7968073
references.citation: Lancet. 2012 Dec 8;380(9858):2007-17
references.pmid: 23141813
references.citation: Arch Intern Med. 2000 Jul 24;160(14):2101-7
references.pmid: 10904452
references.citation: Circ Cardiovasc Genet. 2008 Dec;1(2):100-6
references.pmid: 20031551
references.citation: N Engl J Med. 2012 Nov 15;367(20):1891-900
references.pmid: 23113833
references.citation: JAMA. 2001 May 16;285(19):2486-97
references.pmid: 11368702
references.citation: Am J Cardiol. 2005 Aug 15;96(4):556-63
references.pmid: 16098311
references.citation: Eur Heart J. 2013 Apr;34(13):982-92
references.pmid: 23100282
references.citation: Lancet. 2004 Aug 21-27;364(9435):685-96
references.pmid: 15325833
references.citation: JAMA. 1998 May 27;279(20):1615-22
references.pmid: 9613910
references.citation: Eur Heart J. 2012 Jul;33(13):1635-701
references.pmid: 22555213
references.citation: Circulation. 2002 Mar 12;105(10):1162-9
references.pmid: 11889008
references.citation: Circ Cardiovasc Genet. 2009 Apr;2(2):173-81
references.pmid: 20031582
references.citation: Circulation. 2002 Aug 20;106(8):1024-8
references.pmid: 12186811
references.citation: PLoS Med. 2009 Jul 21;6(7):e1000097
references.pmid: 19621072
references.citation: Am J Med. 2006 Aug;119(8):676-83
references.pmid: 16887414
references.citation: Am J Cardiol. 2006 Mar 15;97(6):843-50
references.pmid: 16516587
references.citation: N Engl J Med. 2005 Apr 7;352(14):1425-35
references.pmid: 15755765
references.citation: Ann Pharmacother. 2007 Nov;41(11):1805-11
references.pmid: 17925498
references.citation: JAMA. 2005 Nov 16;294(19):2437-45
references.pmid: 16287954
references.citation: Circulation. 1998 Apr 21;97(15):1453-60
references.pmid: 9576425
references.citation: Circulation. 1992 Apr;85(4):1293-303
references.pmid: 1555273
references.citation: J Clin Epidemiol. 1998 Dec;51(12):1235-41
references.pmid: 10086815
references.citation: Am J Cardiol. 2007 Sep 1;100(5):747-52
references.pmid: 17719314
references.citation: Ann Intern Med. 2001 May 15;134(10):931-40
references.pmid: 11352694
references.citation: JAMA. 2004 Jun 16;291(23):2821-7
references.pmid: 15199031
references.citation: JAMA. 2012 Mar 28;307(12):1302-9
references.pmid: 22453571
references.citation: Lancet. 2010 Nov 13;376(9753):1670-81
references.pmid: 21067804
references.citation: J Am Coll Cardiol. 2013 Dec 10;62(23):2178-84
references.pmid: 24013058
references.citation: Circ Cardiovasc Genet. 2012 Apr 1;5(2):257-64
references.pmid: 22331829
references.citation: BMJ. 2003 Sep 6;327(7414):557-60
references.pmid: 12958120