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| __NOTOC__
| | #Redirect [[High density lipoprotein natural history, complications and prognosis]] |
| {{High density lipoprotein}}
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| {{CMG}}; {{AE}} {{M.P}}
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| ==Overview==
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| Epidemiological studies have shown an inverse relationship between HDL-C levels and [[CVD]] risks.<ref name="pmid20425274">{{cite journal| author=Khera AV, Rader DJ| title=Future therapeutic directions in reverse cholesterol transport. | journal=Curr Atheroscler Rep | year= 2010 | volume= 12 | issue= 1 | pages= 73-81 | pmid=20425274 | doi=10.1007/s11883-009-0080-0 | pmc=PMC3315100 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20425274 }} </ref><ref name="pmid19903920">{{cite journal| author=Emerging Risk Factors Collaboration. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK et al.| title=Major lipids, apolipoproteins, and risk of vascular disease. | journal=JAMA | year= 2009 | volume= 302 | issue= 18 | pages= 1993-2000 | pmid=19903920 | doi=10.1001/jama.2009.1619 | pmc=PMC3284229 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19903920 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20157124 Review in: Ann Intern Med. 2010 Feb 16;152(4):JC-212] </ref><ref name="pmid2642759">{{cite journal| author=Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD et al.| title=High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. | journal=Circulation | year= 1989 | volume= 79 | issue= 1 | pages= 8-15 | pmid=2642759 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2642759 }} </ref> The protective role of HDL against CVD can be explained by the antiatherogenic and cardioprotective actions of HDL through reverse cholesterol transport, endothelial protection, anti-inflammatory activity, antioxidant and antithrombotic effects; however, it should be noted that HDL particles are heterogeneous in size and composition and they may be differentially associated with cardiovascular risks. The strong negative association between HDL level and CVD risks has lead to the development of the “HDL-C hypothesis” which suggests that raising HDL level with pharmacological intervention is likely to reduce cardiovascular risks. In fact, HDL based therapies are challenging and their efficacy in reducing cardiovascular risks has not been uniform among all studies. While some studies reported that raising HDL-cholesterol in patients with a low baseline serum concentration may be effective for secondary prevention of coronary heart disease, other studies failed to decrease cardiovascular risks by raising HDL.
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| ==Prognosis and Complications==
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| ===HDL Raising Therapies===
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| ====Niacin====
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| According to several studies, [[niacin]] therapy is associated with increasing levels of [[HDL]] and decreasing cardiovascular events. Increase in [[HDL]] level by niacin can be attributed to the direct effect of the drug itself as well as to niacin-induced decrease in triglyceride level. [[Niacin]] not only elevates HDL levels, but also improves the [[lipoprotein]] profile as a whole as it decreases LDL and triglycerides. The direct effect of increasing HDL and improving cardiovascular outcomes is difficult to interpret as niacin's effects are not only limited to HDL but also include [[LDL]] and [[triglyceride]].
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| Shown below is a table summarizing some studies that have investigated the role of niacin in increasing [[HDL]].
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| {| {| class="wikitable" border="1"
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| | '''Trial''' || '''Treatment'''|| '''Increase in HDL''' || '''Follow up'''
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| | [[ARBITER 2 Trial]]<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 | year= 2004 | volume= 110 | issue= 23 | pages= 3512-7 | pmid=15537681 | doi=10.1161/01.CIR.0000148955.19792.8D | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15537681 }} </ref>|| Extended release Niacin in patients on statin|| 21% || 12 months
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| | [[ARBITER 3 Trial]]<ref name="pmid17076985">{{cite journal| author=Taylor AJ, Lee HJ, Sullenberger LE| title=The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3. | journal=Curr Med Res Opin | year= 2006 | volume= 22 | issue= 11 | pages= 2243-50 | pmid=17076985 | doi=10.1185/030079906X148508 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17076985 }} </ref>|| Extended release Niacin in patients on statin||9.6 +/- 12.5 mg/dL ||24 months
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| | [[CLAS 1 Trial]]<ref name="pmid2243429">{{cite journal| author=Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH| title=Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up. | journal=JAMA | year= 1990 | volume= 264 | issue= 23 | pages= 3013-7 | pmid=2243429 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2243429 }} </ref>|| Niacin and colestipol||37% || 2 years
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| | [[CLAS 2 TRIAL]]<ref name="pmid2243429">{{cite journal| author=Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH| title=Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up. | journal=JAMA | year= 1990 | volume= 264 | issue= 23 | pages= 3013-7 | pmid=2243429 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2243429 }} </ref>|| Niacin and colestipol||37% || 4 years
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| | [[HATS Trial]]<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=[[The New England Journal of Medicine]] |volume=345 |issue=22 |pages=1583–92 |year=2001 |month=November |pmid=11757504 |doi=10.1056/NEJMoa011090 |url=}}</ref>|| Niacin and simvastatin +/- antioxidants||26%|| 3 years
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| | [[Coronary Drug Project]]<ref name="pmid1088963">{{cite journal| author=| title=Clofibrate and niacin in coronary heart disease. | journal=JAMA | year= 1975 | volume= 231 | issue= 4 | pages= 360-81 | pmid=1088963 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1088963 }} </ref>|| Niacin or clofibrate||-||6 years and 15 years
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| | [[Stockholm Ischemic Heart Disease Study]]<ref name="pmid3287837">{{cite journal| author=Carlson LA, Rosenhamer G| title=Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. | journal=Acta Med Scand | year= 1988 | volume= 223 | issue= 5 | pages= 405-18 | pmid=3287837 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3287837 }} </ref>|| Niacin + Clofibrate||-||5 years
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| | [[FATS]]<ref name="pmid2215615">{{cite journal| author=Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C et al.| title=Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. | journal=N Engl J Med | year= 1990 | volume= 323 | issue= 19 | pages= 1289-98 | pmid=2215615 | doi=10.1056/NEJM199011083231901 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2215615 }} </ref>||Lovastatin + colestipol<br> Niacin + Colestipol||15% <br> 43%|| 2.5 years
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| | [[FATS Extended follow-up]]|| Niacin + lovastatin + colestipol||-||10 years
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| | [[UCSF-SCOR]]<ref name="pmid2243428">{{cite journal| author=Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ| title=Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. | journal=JAMA | year= 1990 | volume= 264 | issue= 23 | pages= 3007-12 | pmid=2243428 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2243428 }} </ref>|| Niacin + colestipol +/- Lovastatin and diet||28%||2 years
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| |}
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| ===Challenging HDL-C Hypothesis===
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| Studies have proven the inverse relationship between HDL levels and cardiovascular risks. Several therapies were designed to increase HDL levels aiming for secondary prevention of coronary heart diseases. While some trials succeeded to improve the cardiovascular outcomes by increasing HDL quantity, other trials failed to achieve this goal. The failure of these trials have raised questions regarding the efficacy of HDL-targeted therapies and the concept of improving HDL quality rather than quantity. The main trials that failed to improve cardiovascular outcomes by raising HDL levels are [[ILLUSTRATE]], [[RADIANCE 1]], [[RADIANCE 2]], [[ILLUMINATE Trial]] and [[Dal-OUTCOMES Trial]] which investigated CETP inhibitors as well as [[AIM-HIGH Trial]] which investigated the combination of niacin and statin. The failure of the CETP inhibitors studies can be attributed to the associated increase in [[blood pressure]] or direct impairment of the HDL quality by the CETP inhibitor.<ref name="pmid18239670">{{cite journal| author=Joy T, Hegele RA| title=Is raising HDL a futile strategy for atheroprotection? | journal=Nat Rev Drug Discov | year= 2008 | volume= 7 | issue= 2 | pages= 143-55 | pmid=18239670 | doi=10.1038/nrd2489 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18239670 }} </ref>
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| {| class="wikitable" border="1"
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| | '''Trial Name''' || '''Drug''' || '''HDL Increase'''||'''Endpoints'''
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| | '''[[ILLUSTRATE]]''' || Torcetrapib || 61% || There was no significant decrease in coronary atherosclerosis. <br> There was increase in blood pressure.<ref name="pmid17387129">{{cite journal| author=Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT et al.| title=Effect of torcetrapib on the progression of coronary atherosclerosis. | journal=N Engl J Med | year= 2007 | volume= 356 | issue= 13 | pages= 1304-16 | pmid=17387129 | doi=10.1056/NEJMoa070635 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17387129 }} </ref>
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| | '''[[RADIANCE 1]]''' || Torcetrapib ||24.5±0.4 mg/dL|| There was no significant relationship between HDL levels and carotid intima-media thickness. <br> There was increase in blood pressure.<ref name="pmid19029469">{{cite journal| author=Vergeer M, Bots ML, van Leuven SI, Basart DC, Sijbrands EJ, Evans GW et al.| title=Cholesteryl ester transfer protein inhibitor torcetrapib and off-target toxicity: a pooled analysis of the rating atherosclerotic disease change by imaging with a new CETP inhibitor (RADIANCE) trials. | journal=Circulation | year= 2008 | volume= 118 | issue= 24 | pages= 2515-22 | pmid=19029469 | doi=10.1161/CIRCULATIONAHA.108.772665 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19029469 }} </ref>
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| | '''[[RADIANCE 2]]''' || Torcetrapib || 63.4% ||There was no significant relationship between HDL levels and carotid intima-media thickness. <br> There was increase in blood pressure.<ref name="pmid17630038">{{cite journal| author=Bots ML, Visseren FL, Evans GW, Riley WA, Revkin JH, Tegeler CH et al.| title=Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. | journal=Lancet | year= 2007 | volume= 370 | issue= 9582 | pages= 153-60 | pmid=17630038 | doi=10.1016/S0140-6736(07)61088-5 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17630038 }} </ref>
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| | '''[[ILLUMINATE Trial]]''' || Torcetrapib || 72.1% || Hazard ratio for death was 1.58 in torcetrapib group at the end of the study (p=0.006).<br>Torcetrapib group had a 1.25 hazard ratio for primary outcomes (p=0.001), mostly significant for unstable angina (p=0.001) and least important for stroke (0.74).<br>Significant increase in adverse events in torcetrapib group was reported: Hypertension, peripheral edema, angina pectoris, dyspnea, and headache (p<0.001).<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>
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| | '''[[Dal-OUTCOMES Trial]]''' || Dalcetrapib || 31-40% || Dalcetrapib had no significant effect on primary end point or the frequency of any primary end point component with a hazard ratio of 1.04 only.<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= 367 | issue= 22 | pages= 2089-99 | 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>
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| | '''[[AIM-HIGH Trial]]'''|| Niacin + Statin || 25% || There was no reduction in the rate of primary endpoint or all-cause mortality with niacin. <br> Moreover, there was a trend towards more ischemic strokes in the niacin group.
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| ==References==
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| {{Reflist|2}}
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| {{Lipopedia}}
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| [[Category:Lipopedia]]
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| [[Category:Lipid disorders]]
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| [[Category:Cardiology]]
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| [[Category:Lipoproteins]]
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