Hypercholesterolemia: Difference between revisions

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'''Hypercholesterolemia''' is "a condition with abnormally high levels of [[cholesterol]] in the blood. It is defined as a cholesterol value exceeding the 95th percentile for the population."<ref name="title">{{cite web |url=http://www.nlm.nih.gov/cgi/mesh/2008/MB_cgi?term=Hypercholesterolemia |title=Hypercholesterolemia |accessdate=2008-01-18 |author=Anonymous |authorlink= |coauthors= |date= |format= |work= |publisher=National Library of Medicine }}</ref> It should be differentiated from [[dyslipidemia]], where the total cholesterol may not be abnormally high, but the ratios of lipid components are in an unhealthy reange.
'''Hypercholesterolemia''' is "a condition with abnormally high levels of [[cholesterol]] in the blood. It is defined as a cholesterol value exceeding the 95th percentile for the population."<ref name="title">{{cite web |url=http://www.nlm.nih.gov/cgi/mesh/2008/MB_cgi?term=Hypercholesterolemia |title=Hypercholesterolemia |accessdate=2008-01-18 |author=Anonymous |authorlink= |coauthors= |date= |format= |work= |publisher=National Library of Medicine }}</ref> It should be differentiated from [[dyslipidemia]], where the total cholesterol may not be abnormally high, but the ratios of lipid components are in an unhealthy range.
 
==Prognostication==
Non-HDL cholesterol and [[apolipoprotein]] B levels may better predict subsequent [[vascular disease]] thatn LDL-C levels.<ref name="pmid22453571">{{cite journal| author=Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC, Nestel PJ et al.| title=Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. | journal=JAMA | year= 2012 | volume= 307 | issue= 12 | pages= 1302-9 | pmid=22453571 | doi=10.1001/jama.2012.366 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22453571  }} </ref>According to the Friedewald formula, non-HDL cholesterol is LDL-cholesterol LDL-C and VLDL-C.<ref name="pmid4337382">{{cite journal| author=Friedewald WT, Levy RI, Fredrickson DS| title=Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. | journal=Clin Chem | year= 1972 | volume= 18 | issue= 6 | pages= 499-502 | pmid=4337382 | doi= | pmc= | url= }} </ref> If LDL-C levels are used as goals of therapy:<ref name="pmid12485966">{{cite journal| author=National  Cholesterol Education Program (NCEP) Expert Panel on Detection,  Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult  Treatment Panel III)|  title=Third Report of the National Cholesterol Education Program (NCEP)  Expert Panel on Detection, Evaluation, and Treatment of High Blood  Cholesterol in Adults (Adult Treatment Panel III) final report. | journal=Circulation | year= 2002 | volume= 106 | issue= 25 | pages= 3143-421 | pmid=12485966 | doi= | pmc= | url= }} </ref>
 
:"A 'normal' VLDL cholesterol can be defined as that present when triglycerides are <150 mg/dL; this value typically is ≤30 mg/dL. Conversely, when triglyceride levels are >150 mg/dL, VLDL cholesterol usually is >30 mg/dL. Thus, a reasonable goal for non-HDL cholesterol is one that is 30 mg/dL higher than the LDL-cholesterol goal."
 
Accordingly, the [[U.S. Preventive Services Task Force]] states:<ref name="webPignone">{{cite web |url=http://www.uspreventiveservicestaskforce.org/uspstf/uspschol.htm |title=Screening for Lipid Disorders: Recommendations and Rationale |accessdate=2012-01-05 |format= |work=}}</ref>.
*"The preferred screening tests for dyslipidemia are total cholesterol and HDL-C on non-fasting or fasting samples. There is currently insufficient evidence of the benefit of including TG as a part of the initial tests used to screen routinely for dyslipidemia. Abnormal screening test results should be confirmed by a repeated sample on a separate occasion, and the average of both results should be used for risk assessment."
*"Measuring total cholesterol alone is acceptable for screening if available laboratory services cannot provide reliable measurements of HDL-C; measuring both total cholesterol and HDL-C is more sensitive and specific for assessing coronary heart disease risk than measuring total cholesterol alone. In conjunction with HDL-C, the addition of either LDL-C or total cholesterol would provide comparable information, but measuring LDL-C requires a fasting sample and is more expensive. Direct LDL-C testing, which does not require a fasting sample measurement, is now available; however, calculated LDL (total cholesterol minus HDL minus TG/5) is the validated measurement used in trials for risk assessment and treatment decisions. In patients with dyslipidemia identified by screening, complete lipoprotein analysis is useful."
 
A more recent study confirms that non-fasting samples may be accurate.<ref name="pmid23147400">{{cite journal| author=Sidhu D, Naugler C| title=Fasting Time and Lipid Levels in a Community-Based Population: A Cross-sectional Study. | journal=Arch Intern Med | year= 2012 | volume=  | issue=  | pages= 1-4 | pmid=23147400 | doi=10.1001/archinternmed.2012.3708 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23147400  }} </ref>
 
Regarding when to repeat evaluation of risk, "Repeat risk estimation before 8-10 years is not warranted for most people initially not requiring treatment. However, remeasurement within a year seems warranted in those with an initial 15-<20% risk [of cardiovascular disease within ten years]".<ref name="pmid23553971">{{cite journal| author=Bell KJ, Hayen A, Irwig L, Takahashi O, Ohde S, Glasziou P| title=When to remeasure cardiovascular risk in untreated people at low and intermediate risk: observational study. | journal=BMJ | year= 2013 | volume= 346 | issue=  | pages= f1895 | pmid=23553971 | doi=10.1136/bmj.f1895 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23553971  }} </ref>


==Treatment==
==Treatment==
[[Antilipemic agent]]s such as [[hydroxymethylglutaryl-coenzyme A reductase inhibitor]]s (statins) and [[clofibric acid]] derivatives can help.
[[Antilipemic agent]]s such include:
 
* [[Hydroxymethylglutaryl-coenzyme A reductase inhibitor]]s (statins)
A [[meta-analysis]] estimated that after 5 to 7 years of treatment with [[statin]]s, the  [[relative risk reduction]] of coronary heart disease events is decreased by approximately 30%<ref name="pmid11306236">{{cite journal |author=Pignone MP, Phillips CJ, Atkins D, Teutsch SM, Mulrow CD, Lohr KN |title=Screening and treating adults for lipid disorders |journal=American Journal of Preventive Medicine |volume=20 |issue=3 Suppl |pages=77–89 |year=2001 |pmid=11306236 |doi=}}</ref><ref name="webPignone">{{cite web |url=http://www.ahrq.gov/clinic/ajpmsuppl/lipidrr.htm |title=Screening for Lipid Disorders: Recommendations and Rationale |accessdate=2007-10-17 |format= |work=}}</ref>. More recently, a second [[meta-analysis]] reported an almost identical  [[relative risk reduction]] of 29.2% in patients treated for 4.3 years <ref name="pmid17130382">{{cite journal |author=Thavendiranathan P, Bagai A, Brookhart M, Choudhry N |title=Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials |journal=Arch Intern Med |volume=166 |issue=21 |pages=2307-13 |year=2006 |pmid=17130382|doi=10.1001/archinte.166.21.2307}}</ref>. A [[relative risk reduction]] of 19% in coronary mortality was found in a [[meta-analysis]] of patients at all levels of risk.<ref name="pmid16214597">{{cite journal |author=Baigent C, Keech A, Kearney PM, ''et al'' |title=Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins |journal=Lancet |volume=366 |issue=9493 |pages=1267-78 |year=2005 |pmid=16214597 |doi=10.1016/S0140-6736(05)67394-1}}</ref>
* [[Cholesteryl ester transfer protein]] (CETP) inhibitors ([[anacetrapib]], dalcetrapib , [[evacetrapib]], [[torcetrapib]])
* Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 ([[alirocumab]])
* [[Clofibric acid]] derivatives


Studies of drugs other than statins show other drugs can lower the cholesterol, but without definite benefit on clinical events. Examples include [[randomized controlled trial]]s of [[fenofibrate]]<ref name="pmid20228404">{{cite journal| author=ACCORD Study Group. Ginsberg HN, Elam MB, Lovato LC, Crouse JR, Leiter LA et al.| title=Effects of combination lipid therapy in type 2 diabetes mellitus. | journal=N Engl J Med | year= 2010 | volume= 362 | issue= 17 | pages= 1563-74 | pmid=20228404 | doi=10.1056/NEJMoa1001282 | pmc=PMC2879499 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20228404  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20922178 Review in: J Fam Pract. 2010 Oct;59(10):582-4]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20643983 Review in: Ann Intern Med. 2010 Jul 20;153(2):JC1-5] </ref>, [[ezetimibe]], [[torcetrapib]]<ref name="pmid17984165">{{cite journal| author=Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M et al.| title=Effects of torcetrapib in patients at high risk for coronary events. | journal=N Engl J Med | year= 2007 | volume= 357 | issue= 21 | pages= 2109-22 | pmid=17984165 | doi=10.1056/NEJMoa0706628 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17984165  }} </ref>, and [[niacin]].
Studies of drugs other than statins show other drugs can lower the cholesterol, but without definite benefit on clinical events.<ref name="pmid25038074">{{cite journal| author=Keene D, Price C, Shun-Shin MJ, Francis DP| title=Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117 411 patients. | journal=BMJ | year= 2014 | volume= 349 | issue=  | pages= g4379 | pmid=25038074 | doi=10.1136/bmj.g4379 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25038074  }} </ref> Examples include [[randomized controlled trial]]s of:
* [[fenofibrate]] (fenofibric acid) Fibrates may reduce [[myocardial infarction]], but not mortality according to a [[meta-analysis]].<ref name="pmid19698935">{{cite journal| author=Abourbih S, Filion KB, Joseph L, Schiffrin EL, Rinfret S, Poirier P et al.| title=Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review. | journal=Am J Med | year= 2009 | volume= 122 | issue= 10 | pages= 962.e1-8 | pmid=19698935 | doi=10.1016/j.amjmed.2009.03.030 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19698935  }} </ref> The more recent ACCORD [[randomized controlled trial]] of patients with [[diabetes mellitus type 2]] and with triglyceride levels less than 750 mg per deciliter (8.5 mmol per liter) found no reduction in [[myocardial infarction]] or mortality.<ref name="pmid20228404">{{cite journal| author=ACCORD Study Group. Ginsberg HN, Elam MB, Lovato LC, Crouse JR, Leiter LA et al.| title=Effects of combination lipid therapy in type 2 diabetes mellitus. | journal=N Engl J Med | year= 2010 | volume= 362 | issue= 17 | pages= 1563-74 | pmid=20228404 | doi=10.1056/NEJMoa1001282 | pmc=PMC2879499 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20228404  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20922178 Review in: J Fam Pract. 2010 Oct;59(10):582-4]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20643983 Review in: Ann Intern Med. 2010 Jul 20;153(2):JC1-5] </ref> However, among the diabetics with [[triglyceride]]s about 204 and [[HDL cholesterol]] less than 34, there was significant better (primary outcome over 5 years reduced from 17% to 12%).<ref name="pmid20228404"/> The FIELD [[randomized controlled trial]] of patients with [[diabetes mellitus type 2]] also found no reduction in primary outcomes.<ref name="pmid16310551">{{cite journal| author=Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR et al.| title=Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. | journal=Lancet | year= 2005 | volume= 366 | issue= 9500 | pages= 1849-61 | pmid=16310551 | doi=10.1016/S0140-6736(05)67667-2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16310551  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17213107 Review in: Evid Based Med. 2006 Jun;11(3):86]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16646609 Review in: ACP J Club. 2006 May-Jun;144(3):65] </ref>
* [[ezetimibe]]<ref name="pmid18398080">{{cite journal |author=Howard BV, Roman MJ, Devereux RB, ''et al'' |title=Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: the SANDS randomized trial |journal=JAMA |volume=299 |issue=14 |pages=1678–89 |year=2008 |month=April |pmid=18398080 |doi=10.1001/jama.299.14.1678 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=18398080 |issn=}}</ref><ref name="pmid19915217">{{cite journal| author=Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M et al.| title=Extended-release niacin or ezetimibe and carotid intima-media thickness. | journal=N Engl J Med | year= 2009 | volume= 361 | issue= 22 | pages= 2113-22 | pmid=19915217 | doi=10.1056/NEJMoa0907569 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19915217  }} </ref><ref name="pmid18376000">{{cite journal |author=Kastelein JJ, Akdim F, Stroes ES, ''et al'' |title=Simvastatin with or without ezetimibe in familial hypercholesterolemia |journal=N. Engl. J. Med. |volume=358 |issue=14 |pages=1431–43 |year=2008 |month=April |pmid=18376000 |doi=10.1056/NEJMoa0800742 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=18376000&promo=ONFLNS19 |issn=}}</ref><ref name="pmid18765433">{{cite journal| author=Rossebø AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K et al.| title=Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. | journal=N Engl J Med | year= 2008 | volume= 359 | issue= 13 | pages= 1343-56 | pmid=18765433 | doi=10.1056/NEJMoa0804602 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18765433  }} </ref>, a cholesterol-absorption inhibitor
* [[niacin]]<ref name="pmid22085343">{{cite journal| author=AIM-HIGH Investigators. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P et al.| title=Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. | journal=N Engl J Med | year= 2011 | volume= 365 | issue= 24 | pages= 2255-67 | pmid=22085343 | doi=10.1056/NEJMoa1107579 | pmc= | url= }} </ref><ref name="pmid17239888">{{cite journal |author=McKenney JM, Jones PH, Bays HE, ''et al'' |title=Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study) |journal=Atherosclerosis |volume=192 |issue=2 |pages=432–7 |year=2007 |month=June |pmid=17239888 |doi=10.1016/j.atherosclerosis.2006.11.037 |url=http://linkinghub.elsevier.com/retrieve/pii/S0021-9150(06)00733-7 |issn=}}</ref> <ref name="pmid19915217"/> <ref name="pmid11757504">{{cite journal |author=Brown BG, Zhao XQ, Chait A, ''et al.''  |title=Simvastatin and niacin, antioxidant vitamins, or the combination  for the prevention of coronary disease |journal=N. Engl. J. Med.  |volume=345 |issue=22 |pages=1583–92 |year=2001 |month=November  |pmid=11757504 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=11757504&promo=ONFLNS19 |issn=}}</ref><ref name="pmid15537681">{{cite journal |author=Taylor  AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA |title=Arterial Biology  for the Investigation of the Treatment Effects of Reducing Cholesterol  (ARBITER) 2: a double-blind, placebo-controlled study of  extended-release niacin on atherosclerosis progression in secondary  prevention patients treated with statins |journal=Circulation  |volume=110 |issue=23 |pages=3512–7 |year=2004 |month=December  |pmid=15537681 |doi=10.1161/01.CIR.0000148955.19792.8D |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=15537681 |issn=}}</ref> A meta-analysis reported reduce in cardiac events with niacin, but the choice of trails in the meta-analysis is not clear.<ref name="pmid23168285">{{cite journal| author=Phan BA, Muñoz L, Shadzi P, Isquith D, Triller M, Brown BG et al.| title=Effects of Niacin on Glucose Levels, Coronary Stenosis Progression, and Clinical Events in Subjects With Normal Baseline Glucose Levels (<100 mg/dl): A Combined Analysis of the Familial Atherosclerosis Treatment Study (FATS), HDL-Atherosclerosis Treatment Study (HATS), Armed Forces Regression Study (AFREGS), and Carotid Plaque Composition by MRI During Lipid-lowering (CPC) Study. | journal=Am J Cardiol | year= 2012 | volume=  | issue=  | pages=  | pmid=23168285 | doi=10.1016/j.amjcard.2012.09.034 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23168285  }} </ref>
* [[Cholesteryl ester transfer protein]] (CETP) inhibitors
** [[torcetrapib]]<ref name="pmid17984165">{{cite journal| author=Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M et al.| title=Effects of torcetrapib in patients at high risk for coronary events. | journal=N Engl J Med | year= 2007 | volume= 357 | issue= 21 | pages= 2109-22 | pmid=17984165 | doi=10.1056/NEJMoa0706628 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17984165  }} </ref>
** [[Dalcetrapib]]<ref name="pmid23126252">{{cite journal| author=Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J et al.| title=Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome. | journal=N Engl J Med | year= 2012 | volume=  | issue=  | pages=  | pmid=23126252 | doi=10.1056/NEJMoa1206797 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23126252  }} </ref>
* Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors
** [[Alirocumab]]<ref name="pmid25687353">{{cite journal| author=Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R et al.| title=Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. | journal=Eur Heart J | year= 2015 | volume=  | issue=  | pages=  | pmid=25687353 | doi=10.1093/eurheartj/ehv028 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25687353  }} </ref>
* [[eicosapentaenoic acid]] (fish oil)<ref name="pmid17398308">{{cite journal |author=Yokoyama M, Origasa H, Matsuzaki M, ''et al''  |title=Effects of eicosapentaenoic acid on major coronary events in  hypercholesterolaemic patients (JELIS): a randomised open-label, blinded  endpoint analysis |journal=Lancet |volume=369 |issue=9567 |pages=1090–8  |year=2007 |month=March |pmid=17398308  |doi=10.1016/S0140-6736(07)60527-3 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(07)60527-3 |issn=}}</ref>


It is not clear whether to treat to LDL targets. Studies are currently evaluating this.<ref>[http://clinicaltrials.gov/ct2/show/NCT00202878 IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs Simvastatin (Study P04103AM3)] Clinical Trials.gov</ref><ref>[http://clinicaltrials.gov/ct2/show/NCT01252875 Treat Stroke to Target (TST)] ClinicalTrials.gov <!-- search for cholesterol AND (target OR goal) AND (mortality OR death) AND random*--></ref>
It is not clear whether to treat to LDL targets. Studies are currently evaluating this.<ref>[http://clinicaltrials.gov/ct2/show/NCT00202878 IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs Simvastatin (Study P04103AM3)] Clinical Trials.gov</ref><ref>[http://clinicaltrials.gov/ct2/show/NCT01252875 Treat Stroke to Target (TST)] ClinicalTrials.gov <!-- search for cholesterol AND (target OR goal) AND (mortality OR death) AND random*--></ref>


===Clinical practice guidelines===
===Clinical practice guidelines===
Various [[clinical practice guideline]]s have addressed the treatment of [[hypercholesterolemia]].  
Various [[clinical practice guideline]]s have addressed the treatment of hypercholesterolemia.
 
[[U.S. Preventive Services Task Force]] published in 2012 guidelines about screening. <ref name="webPignone">{{cite web |url=http://www.uspreventiveservicestaskforce.org/uspstf/uspschol.htm |title=Screening for Lipid Disorders: Recommendations and Rationale |accessdate=2012-01-05 |format= |work=}}</ref>.


[[Clinical practice guideline]]s by the [[National Institute for Health and Clinical Excellence]] in 2008 recommend treatment if the estimated 10 year risk of cardiovascular disease is at least 20%.<ref name="pmid">{{cite journal |author=Cooper A, O'Flynn N |title=Risk assessment and lipid modification for primary and secondary prevention of cardiovascular disease: summary of NICE guidance |journal=BMJ |volume= |issue= |pages= |year=2008 |pmid=18511800 |pmc=2405875 |doi= |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=18511800 |issn=}}</ref><ref name="urlNICE guidance by type">{{cite web |url=http://www.nice.org.uk/guidance/index.jsp?action=byID |title=Lipid modification |author=Anonymous |authorlink= |coauthors= |date=2008 |format= |work= |publisher=National Institute for Health and Clinical Excellence |pages= |language= |archiveurl= |archivedate= |quote= |accessdate=2008-08-26}}</ref>
[[Clinical practice guideline]]s by the [[National Institute for Health and Clinical Excellence]] in 2008 recommend treatment if the estimated 10 year risk of cardiovascular disease is at least 20%.<ref name="pmid">{{cite journal |author=Cooper A, O'Flynn N |title=Risk assessment and lipid modification for primary and secondary prevention of cardiovascular disease: summary of NICE guidance |journal=BMJ |volume= |issue= |pages= |year=2008 |pmid=18511800 |pmc=2405875 |doi= |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=18511800 |issn=}}</ref><ref name="urlNICE guidance by type">{{cite web |url=http://www.nice.org.uk/guidance/index.jsp?action=byID |title=Lipid modification |author=Anonymous |authorlink= |coauthors= |date=2008 |format= |work= |publisher=National Institute for Health and Clinical Excellence |pages= |language= |archiveurl= |archivedate= |quote= |accessdate=2008-08-26}}</ref>
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The [[National Cholesterol Education Program]] revised their 2001 guidelines<ref name="pmid11368702">{{cite journal| author=Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults| title=Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). | journal=JAMA | year= 2001 | volume= 285 | issue= 19 | pages= 2486-97 | pmid=11368702 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11368702 }} </ref> in 2004 to include goal LDL values.<ref name="pmid15358046">{{cite journal |author=Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Stone NJ |title=Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines |journal=J. Am. Coll. Cardiol. |volume=44 |issue=3 |pages=720-32 |year=2004 |pmid=15358046 |doi=10.1016/j.jacc.2004.07.001}}</ref>; however, their 2004 revisions have been criticized for use of nonrandomized, observational data.<ref name="pmid17015870">{{cite journal |author=Hayward RA, Hofer TP, Vijan S |title=Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem |journal=Ann. Intern. Med. |volume=145 |issue=7 |pages=520-30 |year=2006 |pmid=17015870 |doi=}}</ref> A [[decision analysis]] found that treating to targets is not efficient.<ref name="pmid20083825">{{cite journal| author=Hayward RA, Krumholz HM, Zulman DM, Timbie JW, Vijan S| title=Optimizing statin treatment for primary prevention of coronary artery disease. | journal=Ann Intern Med | year= 2010 | volume= 152 | issue= 2 | pages= 69-77 | pmid=20083825  
The [[National Cholesterol Education Program]] revised their 2001 guidelines<ref name="pmid11368702">{{cite journal| author=Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults| title=Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). | journal=JAMA | year= 2001 | volume= 285 | issue= 19 | pages= 2486-97 | pmid=11368702 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11368702 }} </ref> in 2004 to include goal LDL values.<ref name="pmid15358046">{{cite journal |author=Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Stone NJ |title=Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines |journal=J. Am. Coll. Cardiol. |volume=44 |issue=3 |pages=720-32 |year=2004 |pmid=15358046 |doi=10.1016/j.jacc.2004.07.001}}</ref>; however, their 2004 revisions have been criticized for use of nonrandomized, observational data.<ref name="pmid17015870">{{cite journal |author=Hayward RA, Hofer TP, Vijan S |title=Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem |journal=Ann. Intern. Med. |volume=145 |issue=7 |pages=520-30 |year=2006 |pmid=17015870 |doi=}}</ref> A [[decision analysis]] found that treating to targets is not efficient.<ref name="pmid20083825">{{cite journal| author=Hayward RA, Krumholz HM, Zulman DM, Timbie JW, Vijan S| title=Optimizing statin treatment for primary prevention of coronary artery disease. | journal=Ann Intern Med | year= 2010 | volume= 152 | issue= 2 | pages= 69-77 | pmid=20083825  
| url=http://www.annals.org/content/152/2/69.full5 | doi=10.1059/0003-4819-152-2-201001190-00004 }}</ref>
| url=http://www.annals.org/content/152/2/69.full5 | doi=10.1059/0003-4819-152-2-201001190-00004 }}</ref> However, in this analysis, an older version of the Framingham was used which incorporated EKG findings and included diabetics.<ref>Matheny M, McPheeters ML, Glasser A, Mercaldo N, Weaver RB, Jerome RN, Walden  R, McKoy JN, Pritchett J, Tsai C. Systematic Review of Cardiovascular Disease Risk Assessment Tools [Internet]. Rockville (MD): Agency for Healthcare Research  and Quality (US); 2011 May. Available from http://www.ncbi.nlm.nih.gov/books/NBK56166/ PubMed PMID: http://pubmedogv/21796824.</ref>


===Primary prevention===
===Meta-analyses and trials===
In 2012,  a [[meta-analysis]] of 27 [[randomized controlled trial]]s  of patients, including some at low risk of vascular disease and some  with prior vascular disease, reported reduced vascular  events, "statins  reduced the risks of vascular (RR per 1.0 mmol/L LDL  cholesterol  reduction 0.85, 95% CI 0.77—0.95) and all-cause mortality  (RR 0.91,  95% CI 0.85—0.97)".<ref name="pmid22607822">{{cite journal| author=| title=The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. | journal=Lancet | year= 2012 | volume=  | issue=  | pages=  | pmid=22607822 | doi=10.1016/S0140-6736(12)60367-5 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22607822  }} </ref>
 
====Primary prevention====
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Two [[meta-analysis|meta-analyses]] found that overall mortality is ''insignificantly'' reduced.<ref name="pmid20585067">{{cite journal| author=Ray KK, Seshasai SR, Erqou S, Sever P, Jukema JW, Ford I et al.| title=Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. | journal=Arch Intern Med | year= 2010 | volume= 170 | issue= 12 | pages= 1024-31 | pmid=20585067 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20585067 | doi=10.1001/archinternmed.2010.182 }} </ref><ref name="pmid17130382">{{cite journal |author=Thavendiranathan P, Bagai A, Brookhart MA, Choudhry NK |title=Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials |journal=Arch. Intern. Med. |volume=166 |issue=21 |pages=2307–13 |year=2006 |pmid=17130382 |doi=10.1001/archinte.166.21.2307}}</ref>
Several [[meta-analysis|meta-analyses]], summarizing the [[randomized controlled trial]]s, have been published.
 
* In 2011,  a [[meta-analysis]] of 29 [[randomized controlled trial]]s, 16 of which examined mortality found reduced mortality (especially among the trials that used high potency statins) and reduced vascular events.<ref name="pmid21989464">{{cite journal| author=Tonelli M, Lloyd A, Clement F, Conly J, Husereau D, Hemmelgarn B et al.| title=Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis. | journal=CMAJ | year= 2011 | volume= 183 | issue= 16 | pages= E1189-202 | pmid=21989464 | doi=10.1503/cmaj.101280 | pmc=PMC3216447 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21989464  }} </ref>
However, two [[meta-analysis|meta-analyses]] have reported that statins can significantly help in the primary prevention of [[coronary heart disease]]<ref name="pmid16214597">{{cite journal |author=Baigent C, Keech A, Kearney PM, ''et al'' |title=Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins |journal=Lancet |volume=366 |issue=9493 |pages=1267-78 |year=2005 |pmid=16214597 |doi=10.1016/S0140-6736(05)67394-1}}</ref><ref name="pmid19567909">{{cite journal |author=Brugts JJ, Yetgin T, Hoeks SE, ''et al.'' |title=The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials |journal=BMJ |volume=338 |issue= |pages=b2376 |year=2009 |pmid=19567909 |doi= |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=19567909 |issn=}}</ref> However, one of these meta-analyses focused on patients at risk.<ref name="pmid19567909"/> while the other did not stratify results based on underlying risk.<ref name="pmid16214597"/>
* In 2010, a [[meta-analysis]] of 11 [[randomized controlled trial]]s of patients at increased risk found that overall mortality is ''insignificantly'' reduced.<ref name="pmid20585067">{{cite journal| author=Ray KK, Seshasai SR, Erqou S, Sever P, Jukema JW, Ford I et al.| title=Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. | journal=Arch Intern Med | year= 2010 | volume= 170 | issue= 12 | pages= 1024-31 | pmid=20585067 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20585067 | doi=10.1001/archinternmed.2010.182 }} </ref>
* In 2006, a [[meta-analysis]] reported a [[relative risk reduction]] in major vascular events of 29.2% in patients treated for 4.3 years. There was no decrease in overall mortality.<ref name="pmid17130382">{{cite journal |author=Thavendiranathan P, Bagai A, Brookhart M, Choudhry N |title=Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials |journal=Arch Intern Med |volume=166 |issue=21 |pages=2307-13 |year=2006 |pmid=17130382|doi=10.1001/archinte.166.21.2307}}</ref>.
* In 2005, a [[meta-analysis]] of 10 [[randomized controlled trial]]s of patients at risk of [[coronary heart disease]] found reduced mortality and vascular events.<ref name="pmid19567909">{{cite journal |author=Brugts JJ, Yetgin T, Hoeks SE, ''et al.'' |title=The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials |journal=BMJ |volume=338 |issue= |pages=b2376 |year=2009 |pmid=19567909 |doi= |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=19567909 |issn=}}</ref>
* In 2005, a [[meta-analysis]] by the Cholesterol Treatment Trialists' (CTT) Collaborators of 14 [[randomized controlled trial]]s found reduction in vascular events and a 19% [[relative risk reduction]] in coronary mortality.<ref name="pmid16214597">{{cite journal |author=Baigent C, Keech A, Kearney PM, ''et al'' |title=Efficacy  and safety of cholesterol-lowering treatment: prospective meta-analysis  of data from 90,056 participants in 14 randomised trials of statins |journal=Lancet |volume=366 |issue=9493 |pages=1267-78 |year=2005 |pmid=16214597 |doi=10.1016/S0140-6736(05)67394-1}}</ref>


An important [[randomized controlled trial]] included in the meta-analyses is the AFCAPS/TexCAPS.<ref name="pmid9613910">{{cite journal| author=Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA et al.| title=Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. | journal=JAMA | year= 1998 | volume= 279 | issue= 20 | pages= 1615-22 | pmid=9613910 | doi=10.1001/jama.279.20.1615
Older [[meta-analysis|meta-analyses]] report similar results:
| pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9613910 }} </ref> The 10 year risk of [[coronary heart disease]] among an average patient in this study ((age 57, male, non-smoker, total and HDL cholesterol values of 221 mg/dL and 36 mg/dL, respectively, SBP 138 mm/Hg with medications for hypertension) was 12%.
* In 2001, a [[meta-analysis]] estimated that after 5 to 7 years of treatment with [[statin]]s, the  [[relative risk reduction]] of coronary heart disease events is decreased by approximately 30%<ref name="pmid11306236">{{cite journal |author=Pignone MP, Phillips CJ, Atkins D, Teutsch SM, Mulrow CD, Lohr KN |title=Screening and treating adults for lipid disorders |journal=American Journal of Preventive Medicine |volume=20 |issue=3 Suppl |pages=77–89 |year=2001 |pmid=11306236 |doi=}}</ref>
* In 2000, a [[meta-analysis]] concluded "treatment with lipid lowering drugs lasting five to seven years reduces coronary heart disease events but not all cause mortality in people with no known cardiovascular disease."<ref name="pmid11039962">{{cite journal| author=Pignone M, Phillips C, Mulrow C| title=Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials. | journal=BMJ | year= 2000 | volume= 321 | issue= 7267 | pages= 983-6 | pmid=11039962 | doi= | pmc=PMC27504 | url= }} </ref>


Treating based on risk factors is probably better than treating to a specific target [[LDL cholesterol]].<ref name="pmid20083825">{{cite journal| author=Hayward RA, Krumholz HM, Zulman DM, Timbie JW, Vijan S| title=Optimizing statin treatment for primary prevention of coronary artery disease. | journal=Ann Intern Med | year= 2010 | volume= 152 | issue= 2 | pages= 69-77 | pmid=20083825 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=20083825 | doi=10.1059/0003-4819-152-2-201001190-00004 }}</ref> Using a calculator such as the [http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof NIH calculator]:
Treating based on risk factors is probably better than treating to a specific target [[LDL cholesterol]].<ref name="pmid20083825"/> Using a calculator such as the [http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof NIH calculator]:
* 5% to 15% risk or [[coronary heart disease]] in ''5'' years, use simvastatin 40 mg
* 5% to 15% risk or [[coronary heart disease]] in ''5'' years, use simvastatin 40 mg
* >15% risk or [[coronary heart disease]] in ''5'' years, use atorvastatin, 40 mg
* >15% risk or [[coronary heart disease]] in ''5'' years, use atorvastatin, 40 mg


For primary prevention in [[diabetes mellitus]], the [[American College of Physicians]] states:<ref name="pmid15096336">{{cite journal |author=Snow  V, Aronson M, Hornbake E, Mottur-Pilson C, Weiss K |title=Lipid control in the management of type 2 diabetes mellitus: a clinical practice  guideline from the American College of Physicians |journal=Ann Intern Med |volume=140 |issue=8 |pages=644-9 |year=2004 |pmid=15096336 | url=http://www.annals.org/cgi/content/full/140/8/644}}</ref><ref  name="pmid15096337">{{cite journal| author=Vijan S, Hayward RA, American College of Physicians| title=Pharmacologic lipid-lowering  therapy in type 2 diabetes mellitus: background paper for the American  College of Physicians. | journal=Ann Intern Med | year= 2004 | volume= 140 | issue= 8 | pages= 650-8 | pmid=15096337 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15096337  }}   [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15518449  Review in: ACP J Club. 2004 Nov-Dec;141(3):65] </ref>
Important [[randomized controlled trial]]s included in the meta-analyses are:
* Recommendation 2: Statins should be used for primary prevention against macrovascular complications in patients (both men and women) with type 2  diabetes and other cardiovascular risk factors.
* AFCAPS/TexCAPS.<ref name="pmid9613910">{{cite journal| author=Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA  et al.| title=Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of  AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. | journal=JAMA | year= 1998 | volume= 279 | issue= 20 | pages= 1615-22 | pmid=9613910 | doi=10.1001/jama.279.20.1615
*  Recommendation 3: Once lipid-lowering therapy is initiated, patients  with type 2 diabetes mellitus should be taking at least moderate doses of a statin (the accompanying evidence report states "simvastatin, 40  mg/d; pravastatin, 40 mg/d; lovastatin, 40 mg/d; atorvastatin, 20 mg/d;  or an equivalent dose of another statin")<ref name="pmid15096337">{{cite journal |author=Vijan  S, Hayward RA |title=Pharmacologic lipid-lowering therapy in type 2  diabetes mellitus: background paper for the American College of  Physicians |journal=Ann. Intern. Med. |volume=140 |issue=8 |pages=650-8  |year=2004 |pmid=15096337 |doi=|url=http://www.annals.org/cgi/content/full/140/8/650}}</ref>.
| pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9613910 }} </ref> The 10 year risk of [[coronary heart disease]] among an average patient in this study ((age 57, male, non-smoker,  total and HDL cholesterol values of 221 mg/dL and 36 mg/dL, respectively, SBP 138 mm/Hg with medications for hypertension) was 12%.
 
* JUPITER which found that yreating patients with normal cholesterol level may benefit patients if their high sensitivity [[c-reactive protein]] is elevated according to the Jupiter [[randomized controlled trial]].<ref name="pmid18997196">{{cite journal| author=Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ et al.| title=Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. | journal=N Engl J Med | year= 2008 | volume= 359 | issue= 21 | pages= 2195-207 | pmid=18997196 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=18997196 | doi=10.1056/NEJMoa0807646 }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=19172709 Review in: Ann Intern Med. 2009 Jan 20;150(2):JC1-4]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=19332604 Review in: Evid Based Med. 2009 Apr;14(2):48]</ref> However, the Jupiter trial was stopped early, the subjects had a projected [http://sumsearch.org/fram/default.aspx?todo=search&age=66&gender=1&tobacco=0&diabetes=0&hypertension=0&sbp=134&totalcholesterol=186&hdlcholesterol=49&ekglvh=0&timeframe=5 6.3% risk] of coronary events over 5 years and only 17% of patients were taking aspirin.<ref  name="pmid18997196"/>
Treating patients with normal cholesterol level may benefit patients if their high sensitivity [[c-reactive protein]] is elevated according to the Jupiter [[randomized controlled trial]].<ref name="pmid18997196">{{cite journal| author=Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ et al.| title=Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. | journal=N Engl J Med | year= 2008 | volume= 359 | issue= 21 | pages= 2195-207 | pmid=18997196  
* Excel studied low risk patients.<ref name="pmid1985608">{{cite journal| author=Bradford RH, Shear CL, Chremos AN, Dujovne C, Downton M, Franklin FA et al.| title=Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. | journal=Arch Intern Med | year= 1991 | volume= 151 | issue= 1 | pages= 43-9 | pmid=1985608 | doi= | pmc= | url= }} </ref>
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=18997196 | doi=10.1056/NEJMoa0807646 }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=19172709 Review in: Ann Intern Med. 2009 Jan 20;150(2):JC1-4]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=19332604 Review in: Evid Based Med. 2009 Apr;14(2):48]</ref> However, in the Jupiter trial, only 16% of patients were taking aspirin.<ref  name="pmid18997196"/>
* Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study). These subjects had a [http://sumsearch.org/fram/default.aspx?todo=search&age=58&gender=0&tobacco=0&diabetes=0&hypertension=0&sbp=132&totalcholesterol=242&hdlcholesterol=58&ekglvh=0&timeframe=5 3% risk] of coronary events in 5 years.<ref name="pmid17011942">{{cite journal| author=Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T et al.| title=Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. | journal=Lancet | year= 2006 | volume= 368 | issue= 9542 | pages= 1155-63 | pmid=17011942 | doi=10.1016/S0140-6736(06)69472-5 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17011942  }} </ref>


;Combination treatment
;Combination treatment
It is not clear that combination therapy is better than high dose [[hydroxymethylglutaryl-coenzyme A reductase inhibitor]]s.<ref name="pmid19884623">{{cite journal| author=Sharma M, Ansari MT, Abou-Setta AM, Soares-Weiser K, Ooi TC, Sears M et al.| title=Systematic review: comparative effectiveness and harms of combination therapy and monotherapy for dyslipidemia. | journal=Ann Intern Med | year= 2009 | volume= 151 | issue= 9 | pages= 622-30 | pmid=19884623  
It is not clear that combination therapy is better than high dose [[hydroxymethylglutaryl-coenzyme A reductase inhibitor]]s.<ref name="pmid19884623">{{cite journal| author=Sharma M, Ansari MT, Abou-Setta AM, Soares-Weiser K, Ooi TC, Sears M et al.| title=Systematic review: comparative effectiveness and harms of combination therapy and monotherapy for dyslipidemia. | journal=Ann Intern Med | year= 2009 | volume= 151 | issue= 9 | pages= 622-30 | pmid=19884623  
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19884623 | doi=10.1059/0003-4819-151-9-200911030-00144 }}</ref>
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19884623 | doi=10.1059/0003-4819-151-9-200911030-00144 }}</ref>


If treatment with a [[hydroxymethylglutaryl-coenzyme A reductase inhibitor]] does not achieve a desirable cholesterol, other drugs that have been studied include [[eicosapentaenoic acid]] which is a metabolite of [[fish oil]].<ref name="pmid17398308">{{cite journal |author=Yokoyama M, Origasa H, Matsuzaki M, ''et al'' |title=Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis |journal=Lancet |volume=369 |issue=9567 |pages=1090–8 |year=2007 |month=March |pmid=17398308 |doi=10.1016/S0140-6736(07)60527-3 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(07)60527-3 |issn=}}</ref> [[Ezetimibe]], a cholesterol-absorption inhibitor, was not clearly beneficial in a study of [[diabetes mellitus type 2]]<ref name="pmid18398080">{{cite journal |author=Howard BV, Roman MJ, Devereux RB, ''et al'' |title=Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: the SANDS randomized trial |journal=JAMA |volume=299 |issue=14 |pages=1678–89 |year=2008 |month=April |pmid=18398080 |doi=10.1001/jama.299.14.1678 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=18398080 |issn=}}</ref> and a study of mixed [[primary prevention]] and [[secondary prevention]]<ref name="pmid18376000">{{cite journal |author=Kastelein JJ, Akdim F, Stroes ES, ''et al'' |title=Simvastatin with or without ezetimibe in familial hypercholesterolemia |journal=N. Engl. J. Med. |volume=358 |issue=14 |pages=1431–43 |year=2008 |month=April |pmid=18376000 |doi=10.1056/NEJMoa0800742 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=18376000&promo=ONFLNS19 |issn=}}</ref>. [[Niacin]] has been studied with improvements in the LDL and HDL<ref name="pmid17239888">{{cite journal |author=McKenney JM, Jones PH, Bays HE, ''et al'' |title=Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study) |journal=Atherosclerosis |volume=192 |issue=2 |pages=432–7 |year=2007 |month=June |pmid=17239888 |doi=10.1016/j.atherosclerosis.2006.11.037 |url=http://linkinghub.elsevier.com/retrieve/pii/S0021-9150(06)00733-7 |issn=}}</ref> with uncertain<ref name="pmid15537681">{{cite journal |author=Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA |title=Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins |journal=Circulation |volume=110 |issue=23 |pages=3512–7 |year=2004 |month=December |pmid=15537681 |doi=10.1161/01.CIR.0000148955.19792.8D |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=15537681 |issn=}}</ref> effects on [[carotid intima-media thickness]].
If treatment with a [[hydroxymethylglutaryl-coenzyme A reductase inhibitor]] does not achieve a desirable cholesterol, other drugs that have been studied include [[eicosapentaenoic acid]] which is a metabolite of [[fish oil]].<ref name="pmid17398308">{{cite journal |author=Yokoyama M, Origasa H, Matsuzaki M, ''et al'' |title=Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis |journal=Lancet |volume=369 |issue=9567 |pages=1090–8 |year=2007 |month=March |pmid=17398308 |doi=10.1016/S0140-6736(07)60527-3 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(07)60527-3 |issn=}}</ref> [[Ezetimibe]], a cholesterol-absorption inhibitor, was not clearly beneficial in a study of [[diabetes mellitus type 2]]<ref name="pmid18398080"/> and a study of mixed [[primary prevention]] and [[secondary prevention]]<ref name="pmid18376000"/>. [[Niacin]] has been studied with improvements in the LDL and HDL<ref name="pmid17239888"/> with uncertain<ref name="pmid15537681"/> effects on [[carotid intima-media thickness]].


===Secondary prevention===
====Secondary prevention====
[[Clinical practice guideline]]s by the [[National Institute for Health and Clinical Excellence]] recommend a treatment goal of <4 mmol/l (154 mg/dl) for total cholesterol ''or'' a low density lipoprotein cholesterol concentration of <2 mmol/l (77 mg/dl).<ref name="pmid">{{cite journal |author=Cooper A, O'Flynn N |title=Risk assessment and lipid modification for primary and secondary prevention of cardiovascular disease: summary of NICE guidance |journal=BMJ |volume= |issue= |pages= |year=2008 |pmid=18511800 |pmc=2405875 |doi= |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=18511800 |issn=}}</ref><ref name="urlNICE guidance by type">{{cite web |url=http://guidance.nice.org.uk/CG67 |title=Lipid modification |author=Anonymous |authorlink= |coauthors= |date=2008 |format= |work= |publisher=National Institute for Health and Clinical Excellence |pages= |language= |archiveurl= |archivedate= |quote= |accessdate=2008-08-26}}</ref> A [[systematic review]] summarized [[randomized controlled trial]]s in [[secondary prevention]].<ref name="pmid21067804">{{cite journal| author=Cholesterol Treatment Trialists’ (CTT) Collaboration. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C et al.| title=Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. | journal=Lancet | year= 2010 | volume= 376 | issue= 9753 | pages= 1670-81 | pmid=21067804 | doi=10.1016/S0140-6736(10)61350-5 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21067804  }} </ref>
[[Clinical practice guideline]]s by the [[National Institute for Health and Clinical Excellence]] recommend a treatment goal of <4 mmol/l (154 mg/dl) for total cholesterol ''or'' a low density lipoprotein cholesterol concentration of <2 mmol/l (77 mg/dl).<ref name="pmid">{{cite journal |author=Cooper A, O'Flynn N |title=Risk assessment and lipid modification for primary and secondary prevention of cardiovascular disease: summary of NICE guidance |journal=BMJ |volume= |issue= |pages= |year=2008 |pmid=18511800 |pmc=2405875 |doi= |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=18511800 |issn=}}</ref><ref name="urlNICE guidance by type"/> A [[systematic review]] summarized [[randomized controlled trial]]s in [[secondary prevention]].<ref name="pmid21067804">{{cite journal| author=Cholesterol Treatment Trialists’ (CTT) Collaboration. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C et al.| title=Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. | journal=Lancet | year= 2010 | volume= 376 | issue= 9753 | pages= 1670-81 | pmid=21067804 | doi=10.1016/S0140-6736(10)61350-5 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21067804  }} </ref>


;Combination treatment
;Combination treatment
If treatment with a [[hydroxymethylglutaryl-coenzyme A reductase inhibitor]] does not achieve a desirable cholesterol, other drugs that may be added for additional benefit include [[niacin]]<ref name="pmid19915217">{{cite journal| author=Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M et al.| title=Extended-release niacin or ezetimibe and carotid intima-media thickness. | journal=N Engl J Med | year= 2009 | volume= 361 | issue= 22 | pages= 2113-22 | pmid=19915217
If treatment with a [[hydroxymethylglutaryl-coenzyme A reductase inhibitor]] does not achieve a desirable cholesterol, other drugs that may be added for additional benefit include [[niacin]]<ref name="pmid19915217"/><ref name="pmid11757504"/><ref name="pmid15537681"/> and [[fish oil]]. [[Ezetimibe]], a cholesterol-absorption inhibitor, was not clearly beneficial in a study of [[diabetes mellitus type 2]]<ref name="pmid18398080"/> and a study of mixed [[primary prevention]] and [[secondary prevention]]<ref name="pmid18376000"/>.
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=19915217 | doi=10.1056/NEJMoa0907569 }}</ref><ref name="pmid11757504">{{cite journal |author=Brown BG, Zhao XQ, Chait A, ''et al.'' |title=Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease |journal=N. Engl. J. Med. |volume=345 |issue=22 |pages=1583–92 |year=2001 |month=November |pmid=11757504 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=11757504&promo=ONFLNS19 |issn=}}</ref><ref name="pmid15537681">{{cite journal |author=Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA |title=Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins |journal=Circulation |volume=110 |issue=23 |pages=3512–7 |year=2004 |month=December |pmid=15537681 |doi=10.1161/01.CIR.0000148955.19792.8D |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=15537681 |issn=}}</ref> and [[fish oil]]. [[Ezetimibe]], a cholesterol-absorption inhibitor, was not clearly beneficial in a study of [[diabetes mellitus type 2]]<ref name="pmid18398080">{{cite journal |author=Howard BV, Roman MJ, Devereux RB, ''et al'' |title=Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: the SANDS randomized trial |journal=JAMA |volume=299 |issue=14 |pages=1678–89 |year=2008 |month=April |pmid=18398080 |doi=10.1001/jama.299.14.1678 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=18398080 |issn=}}</ref> and a study of mixed [[primary prevention]] and [[secondary prevention]]<ref name="pmid18376000">{{cite journal |author=Kastelein JJ, Akdim F, Stroes ES, ''et al'' |title=Simvastatin with or without ezetimibe in familial hypercholesterolemia |journal=N. Engl. J. Med. |volume=358 |issue=14 |pages=1431–43 |year=2008 |month=April |pmid=18376000 |doi=10.1056/NEJMoa0800742 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=18376000&promo=ONFLNS19 |issn=}}</ref>.


===Diabetic patients===
===Diabetic patients===
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==References==
==References==
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Hypercholesterolemia is "a condition with abnormally high levels of cholesterol in the blood. It is defined as a cholesterol value exceeding the 95th percentile for the population."[1] It should be differentiated from dyslipidemia, where the total cholesterol may not be abnormally high, but the ratios of lipid components are in an unhealthy range.

Prognostication

Non-HDL cholesterol and apolipoprotein B levels may better predict subsequent vascular disease thatn LDL-C levels.[2]According to the Friedewald formula, non-HDL cholesterol is LDL-cholesterol LDL-C and VLDL-C.[3] If LDL-C levels are used as goals of therapy:[4]

"A 'normal' VLDL cholesterol can be defined as that present when triglycerides are <150 mg/dL; this value typically is ≤30 mg/dL. Conversely, when triglyceride levels are >150 mg/dL, VLDL cholesterol usually is >30 mg/dL. Thus, a reasonable goal for non-HDL cholesterol is one that is 30 mg/dL higher than the LDL-cholesterol goal."

Accordingly, the U.S. Preventive Services Task Force states:[5].

  • "The preferred screening tests for dyslipidemia are total cholesterol and HDL-C on non-fasting or fasting samples. There is currently insufficient evidence of the benefit of including TG as a part of the initial tests used to screen routinely for dyslipidemia. Abnormal screening test results should be confirmed by a repeated sample on a separate occasion, and the average of both results should be used for risk assessment."
  • "Measuring total cholesterol alone is acceptable for screening if available laboratory services cannot provide reliable measurements of HDL-C; measuring both total cholesterol and HDL-C is more sensitive and specific for assessing coronary heart disease risk than measuring total cholesterol alone. In conjunction with HDL-C, the addition of either LDL-C or total cholesterol would provide comparable information, but measuring LDL-C requires a fasting sample and is more expensive. Direct LDL-C testing, which does not require a fasting sample measurement, is now available; however, calculated LDL (total cholesterol minus HDL minus TG/5) is the validated measurement used in trials for risk assessment and treatment decisions. In patients with dyslipidemia identified by screening, complete lipoprotein analysis is useful."

A more recent study confirms that non-fasting samples may be accurate.[6]

Regarding when to repeat evaluation of risk, "Repeat risk estimation before 8-10 years is not warranted for most people initially not requiring treatment. However, remeasurement within a year seems warranted in those with an initial 15-<20% risk [of cardiovascular disease within ten years]".[7]

Treatment

Antilipemic agents such include:

Studies of drugs other than statins show other drugs can lower the cholesterol, but without definite benefit on clinical events.[8] Examples include randomized controlled trials of:

It is not clear whether to treat to LDL targets. Studies are currently evaluating this.[25][26]

Clinical practice guidelines

Various clinical practice guidelines have addressed the treatment of hypercholesterolemia.

U.S. Preventive Services Task Force published in 2012 guidelines about screening. [5].

Clinical practice guidelines by the National Institute for Health and Clinical Excellence in 2008 recommend treatment if the estimated 10 year risk of cardiovascular disease is at least 20%.[27][28]

The American College of Physicians in 2004 addressed hypercholesterolemia in patients with diabetes [29]. Their recommendations are:

  • Recommendation 1: Lipid-lowering therapy should be used for secondary prevention of cardiovascular mortality and morbidity for all patients (both men and women) with known coronary artery disease and type 2 diabetes.
  • Recommendation 2: Statins should be used for primary prevention against macrovascular complications in patients (both men and women) with type 2 diabetes and other cardiovascular risk factors.
  • Recommendation 3: Once lipid-lowering therapy is initiated, patients with type 2 diabetes mellitus should be taking at least moderate doses of a statin (the accompanying evidence report states "simvastatin, 40 mg/d; pravastatin, 40 mg/d; lovastatin, 40 mg/d; atorvastatin, 20 mg/d; or an equivalent dose of another statin")[30].
  • Recommendation 4: For those patients with type 2 diabetes who are taking statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in specific circumstances.

The National Cholesterol Education Program revised their 2001 guidelines[31] in 2004 to include goal LDL values.[32]; however, their 2004 revisions have been criticized for use of nonrandomized, observational data.[33] A decision analysis found that treating to targets is not efficient.[34] However, in this analysis, an older version of the Framingham was used which incorporated EKG findings and included diabetics.[35]

Meta-analyses and trials

In 2012, a meta-analysis of 27 randomized controlled trials of patients, including some at low risk of vascular disease and some with prior vascular disease, reported reduced vascular events, "statins reduced the risks of vascular (RR per 1.0 mmol/L LDL cholesterol reduction 0.85, 95% CI 0.77—0.95) and all-cause mortality (RR 0.91, 95% CI 0.85—0.97)".[36]

Primary prevention

Several meta-analyses, summarizing the randomized controlled trials, have been published.

Older meta-analyses report similar results:

  • In 2001, a meta-analysis estimated that after 5 to 7 years of treatment with statins, the relative risk reduction of coronary heart disease events is decreased by approximately 30%[42]
  • In 2000, a meta-analysis concluded "treatment with lipid lowering drugs lasting five to seven years reduces coronary heart disease events but not all cause mortality in people with no known cardiovascular disease."[43]

Treating based on risk factors is probably better than treating to a specific target LDL cholesterol.[34] Using a calculator such as the NIH calculator:

Important randomized controlled trials included in the meta-analyses are:

  • AFCAPS/TexCAPS.[44] The 10 year risk of coronary heart disease among an average patient in this study ((age 57, male, non-smoker, total and HDL cholesterol values of 221 mg/dL and 36 mg/dL, respectively, SBP 138 mm/Hg with medications for hypertension) was 12%.
  • JUPITER which found that yreating patients with normal cholesterol level may benefit patients if their high sensitivity c-reactive protein is elevated according to the Jupiter randomized controlled trial.[45] However, the Jupiter trial was stopped early, the subjects had a projected 6.3% risk of coronary events over 5 years and only 17% of patients were taking aspirin.[45]
  • Excel studied low risk patients.[46]
  • Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study). These subjects had a 3% risk of coronary events in 5 years.[47]
Combination treatment

It is not clear that combination therapy is better than high dose hydroxymethylglutaryl-coenzyme A reductase inhibitors.[48]

If treatment with a hydroxymethylglutaryl-coenzyme A reductase inhibitor does not achieve a desirable cholesterol, other drugs that have been studied include eicosapentaenoic acid which is a metabolite of fish oil.[24] Ezetimibe, a cholesterol-absorption inhibitor, was not clearly beneficial in a study of diabetes mellitus type 2[12] and a study of mixed primary prevention and secondary prevention[14]. Niacin has been studied with improvements in the LDL and HDL[17] with uncertain[19] effects on carotid intima-media thickness.

Secondary prevention

Clinical practice guidelines by the National Institute for Health and Clinical Excellence recommend a treatment goal of <4 mmol/l (154 mg/dl) for total cholesterol or a low density lipoprotein cholesterol concentration of <2 mmol/l (77 mg/dl).[27][28] A systematic review summarized randomized controlled trials in secondary prevention.[49]

Combination treatment

If treatment with a hydroxymethylglutaryl-coenzyme A reductase inhibitor does not achieve a desirable cholesterol, other drugs that may be added for additional benefit include niacin[13][18][19] and fish oil. Ezetimibe, a cholesterol-absorption inhibitor, was not clearly beneficial in a study of diabetes mellitus type 2[12] and a study of mixed primary prevention and secondary prevention[14].

Diabetic patients

For more information, see: Diabetes_mellitus_type_2#Hypercholesterolemia.


Whether diabetes is an equivalent risk factor to having an existing myocardial infarction is debated.[50]

Statin therapy prevents major vascular events in about 1 of every 24 patients with diabetes who use the treatment for 5 years if they are similar to the patients in the meta-analysis by Kearney et al (Number needed to treat is 24).[51]

Treating to a goal of LDL-C < 70 mg/dl and systolic blood pressure to < 115 mm Hg may cause regression of carotid intima-media thickness in a randomized controlled trial.[52]

Complementary and alternative medicine

Preliminary research suggests possible benefit from artichoke leaf.[53]

References

  1. ↑ Anonymous. Hypercholesterolemia. National Library of Medicine. Retrieved on 2008-01-18.
  2. ↑ Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC, Nestel PJ et al. (2012). "Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.". JAMA 307 (12): 1302-9. DOI:10.1001/jama.2012.366. PMID 22453571. Research Blogging.
  3. ↑ Friedewald WT, Levy RI, Fredrickson DS (1972). "Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.". Clin Chem 18 (6): 499-502. PMID 4337382. [e]
  4. ↑ National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (2002). "Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.". Circulation 106 (25): 3143-421. PMID 12485966. [e]
  5. ↑ 5.0 5.1 Screening for Lipid Disorders: Recommendations and Rationale. Retrieved on 2012-01-05.
  6. ↑ Sidhu D, Naugler C (2012). "Fasting Time and Lipid Levels in a Community-Based Population: A Cross-sectional Study.". Arch Intern Med: 1-4. DOI:10.1001/archinternmed.2012.3708. PMID 23147400. Research Blogging.
  7. ↑ Bell KJ, Hayen A, Irwig L, Takahashi O, Ohde S, Glasziou P (2013). "When to remeasure cardiovascular risk in untreated people at low and intermediate risk: observational study.". BMJ 346: f1895. DOI:10.1136/bmj.f1895. PMID 23553971. Research Blogging.
  8. ↑ Keene D, Price C, Shun-Shin MJ, Francis DP (2014). "Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117 411 patients.". BMJ 349: g4379. DOI:10.1136/bmj.g4379. PMID 25038074. Research Blogging.
  9. ↑ Abourbih S, Filion KB, Joseph L, Schiffrin EL, Rinfret S, Poirier P et al. (2009). "Effect of fibrates on lipid profiles and cardiovascular outcomes: a systematic review.". Am J Med 122 (10): 962.e1-8. DOI:10.1016/j.amjmed.2009.03.030. PMID 19698935. Research Blogging.
  10. ↑ 10.0 10.1 ACCORD Study Group. Ginsberg HN, Elam MB, Lovato LC, Crouse JR, Leiter LA et al. (2010). "Effects of combination lipid therapy in type 2 diabetes mellitus.". N Engl J Med 362 (17): 1563-74. DOI:10.1056/NEJMoa1001282. PMID 20228404. PMC PMC2879499. Research Blogging. Review in: J Fam Pract. 2010 Oct;59(10):582-4 Review in: Ann Intern Med. 2010 Jul 20;153(2):JC1-5
  11. ↑ Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR et al. (2005). "Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.". Lancet 366 (9500): 1849-61. DOI:10.1016/S0140-6736(05)67667-2. PMID 16310551. Research Blogging. Review in: Evid Based Med. 2006 Jun;11(3):86 Review in: ACP J Club. 2006 May-Jun;144(3):65
  12. ↑ 12.0 12.1 12.2 Howard BV, Roman MJ, Devereux RB, et al (April 2008). "Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: the SANDS randomized trial". JAMA 299 (14): 1678–89. DOI:10.1001/jama.299.14.1678. PMID 18398080. Research Blogging.
  13. ↑ 13.0 13.1 13.2 Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M et al. (2009). "Extended-release niacin or ezetimibe and carotid intima-media thickness.". N Engl J Med 361 (22): 2113-22. DOI:10.1056/NEJMoa0907569. PMID 19915217. Research Blogging.
  14. ↑ 14.0 14.1 14.2 Kastelein JJ, Akdim F, Stroes ES, et al (April 2008). "Simvastatin with or without ezetimibe in familial hypercholesterolemia". N. Engl. J. Med. 358 (14): 1431–43. DOI:10.1056/NEJMoa0800742. PMID 18376000. Research Blogging.
  15. ↑ Rossebø AB, Pedersen TR, Boman K, Brudi P, Chambers JB, Egstrup K et al. (2008). "Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.". N Engl J Med 359 (13): 1343-56. DOI:10.1056/NEJMoa0804602. PMID 18765433. Research Blogging.
  16. ↑ AIM-HIGH Investigators. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P et al. (2011). "Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.". N Engl J Med 365 (24): 2255-67. DOI:10.1056/NEJMoa1107579. PMID 22085343. Research Blogging.
  17. ↑ 17.0 17.1 McKenney JM, Jones PH, Bays HE, et al (June 2007). "Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study)". Atherosclerosis 192 (2): 432–7. DOI:10.1016/j.atherosclerosis.2006.11.037. PMID 17239888. Research Blogging.
  18. ↑ 18.0 18.1 Brown BG, Zhao XQ, Chait A, et al. (November 2001). "Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease". N. Engl. J. Med. 345 (22): 1583–92. PMID 11757504. [e]
  19. ↑ 19.0 19.1 19.2 Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA (December 2004). "Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins". Circulation 110 (23): 3512–7. DOI:10.1161/01.CIR.0000148955.19792.8D. PMID 15537681. Research Blogging.
  20. ↑ Phan BA, Muñoz L, Shadzi P, Isquith D, Triller M, Brown BG et al. (2012). "Effects of Niacin on Glucose Levels, Coronary Stenosis Progression, and Clinical Events in Subjects With Normal Baseline Glucose Levels (<100 mg/dl): A Combined Analysis of the Familial Atherosclerosis Treatment Study (FATS), HDL-Atherosclerosis Treatment Study (HATS), Armed Forces Regression Study (AFREGS), and Carotid Plaque Composition by MRI During Lipid-lowering (CPC) Study.". Am J Cardiol. DOI:10.1016/j.amjcard.2012.09.034. PMID 23168285. Research Blogging.
  21. ↑ Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M et al. (2007). "Effects of torcetrapib in patients at high risk for coronary events.". N Engl J Med 357 (21): 2109-22. DOI:10.1056/NEJMoa0706628. PMID 17984165. Research Blogging.
  22. ↑ Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J et al. (2012). "Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome.". N Engl J Med. DOI:10.1056/NEJMoa1206797. PMID 23126252. Research Blogging.
  23. ↑ Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R et al. (2015). "Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial.". Eur Heart J. DOI:10.1093/eurheartj/ehv028. PMID 25687353. Research Blogging.
  24. ↑ 24.0 24.1 Yokoyama M, Origasa H, Matsuzaki M, et al (March 2007). "Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis". Lancet 369 (9567): 1090–8. DOI:10.1016/S0140-6736(07)60527-3. PMID 17398308. Research Blogging.
  25. ↑ IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs Simvastatin (Study P04103AM3) Clinical Trials.gov
  26. ↑ Treat Stroke to Target (TST) ClinicalTrials.gov
  27. ↑ 27.0 27.1 Cooper A, O'Flynn N (2008). "Risk assessment and lipid modification for primary and secondary prevention of cardiovascular disease: summary of NICE guidance". BMJ. PMID 18511800. PMC 2405875. [e]
  28. ↑ 28.0 28.1 Anonymous (2008). Lipid modification. National Institute for Health and Clinical Excellence. Retrieved on 2008-08-26.
  29. ↑ Snow V, Aronson M, Hornbake E, Mottur-Pilson C, Weiss K (2004). "Lipid control in the management of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians". Ann Intern Med 140 (8): 644-9. PMID 15096336.
  30. ↑ Vijan S, Hayward RA (2004). "Pharmacologic lipid-lowering therapy in type 2 diabetes mellitus: background paper for the American College of Physicians". Ann. Intern. Med. 140 (8): 650-8. PMID 15096337. [e]
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  41. ↑ Baigent C, Keech A, Kearney PM, et al (2005). "Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins". Lancet 366 (9493): 1267-78. DOI:10.1016/S0140-6736(05)67394-1. PMID 16214597. Research Blogging.
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  44. ↑ Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA et al. (1998). "Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.". JAMA 279 (20): 1615-22. DOI:10.1001/jama.279.20.1615. PMID 9613910. Research Blogging.
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  46. ↑ Bradford RH, Shear CL, Chremos AN, Dujovne C, Downton M, Franklin FA et al. (1991). "Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia.". Arch Intern Med 151 (1): 43-9. PMID 1985608. [e]
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  49. ↑ Cholesterol Treatment Trialists’ (CTT) Collaboration. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C et al. (2010). "Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.". Lancet 376 (9753): 1670-81. DOI:10.1016/S0140-6736(10)61350-5. PMID 21067804. Research Blogging.
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  52. ↑ Howard, B. V., Roman, M. J., Devereux, R. B., Fleg, J. L., Galloway, J. M., Henderson, J. A., et al. (2008). Effect of Lower Targets for Blood Pressure and LDL Cholesterol on Atherosclerosis in Diabetes: The SANDS Randomized Trial. JAMA, 299(14), 1678-1689. DOI:10.1001/jama.299.14.1678.
  53. ↑ Wider B, Pittler MH, Thompson-Coon J, Ernst E (2009). "Artichoke leaf extract for treating hypercholesterolaemia.". Cochrane Database Syst Rev (4): CD003335. DOI:10.1002/14651858.CD003335.pub2. PMID 19821306. Research Blogging.

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