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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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| The antiatherogenic actions of HDL-C through reverse cholesterol transport and the cardioprotective effect through endothelial protection, anti-inflammatory activity, as well as antioxidant and antithrombotic effects has been the basis trials to increase HDL and to determine prognosis. [[High-density lipoprotein]] (HDL) cholesterol levels are inversely related to risk for [[coronary artery disease]] (CAD), but because HDL particles are heterogeneous in size and composition, they may be differentially associated with other cardiovascular risk factors and with cardiovascular risk.
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| ==Prognosis and Complications==
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| Epidemiological studies have shown an inverse relationship between HDL-C levels and CVD risk.<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> This strong negative association has lead to the development of the “HDL-C hypothesis” which proposes that pharmacological intervention to raise HDL-C 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 report that raising HDL-cholesterol in patients with a low baseline serum concentration may be effective for secondary prevention of coronary heart disease, other studies
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| ====VA-HIT Trial====
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| The [[VA-HIT Trial]] is a multicentered, randomized, double-blinded, placebo-controlled trial wherein 2531 patients with [[CAD]] along with [[LDL]] levels ≤140 mg/dL (mean 111 mg/dL) and HDL ≤40 mg/dL (mean 32 mg/dL) were randomly assigned to treatment with [[gemfibrozil]] (1200mg) or placebo. Results of the trial showed that the mean HDL-C level was higher by 6% in the group treated with gemfibrozil. Results of the trial showed that cardiac death and nonfatal [[myocardial infarction]] occurred less often in the [[gemfibrozil]] treated group. Acute coronary events were reduced by 11% with gemfibrozil for every 5 mg/dL rise in HDL-C; however, they did not correlate with any changes in LDL-cholesterol or [[triglycerides]] levels.<ref name="pmid11268266">{{cite journal| author=Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ et al.| title=Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. | journal=JAMA | year= 2001 | volume= 285 | issue= 12 | pages= 1585-91 | pmid=11268266 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11268266 }} </ref>
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| ====Trial of Simvastatin Plus Niacin====
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| In this study patients receiving simvastatin plus niacin were significantly less likely to sustain a cardiovascular event such as cardiac death, myocardial infarction or revascularization and experienced angiographic regression of the most significant coronary stenosis.<ref name="pmid11757504">{{cite journal| author=Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS et al.| title=Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. | journal=N Engl J Med | year= 2001 | volume= 345 | issue= 22 | pages= 1583-92 | pmid=11757504 | doi=10.1056/NEJMoa011090 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11757504 }} </ref>
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| ====AIM-HIGH Trial====
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| A randomized trial comparing-extended release niacin (target dose 2000 mg per day) with placebo (100 to 200 mg of immediate release niacin) in 3414 patients with cardiovascular disease though increased levels of HDL-C and lowered levels of triglycerides and LDL-C was stopped early for futility after a mean follow-up of three years.<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=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22085343 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22508748 Review in: Ann Intern Med. 2012 Apr 17;156(8):JC4-08] </ref>
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| ====ARBITER 2 Study====
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| A randomized trial that examined the effects of extended-release niacin 1000 mg daily in 167 patients with known CHD and an HDL-cholesterol concentration below 45 mg/dL who were already receiving a statin showed patients treated with niacin experienced a mean increase in HDL-cholesterol of 8 mg/dL (0.21 mmol/L) and had a trend toward decreased progression of carotid intima-media thickness.<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>
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| ====Infusion of Apo A-I Milano====
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| A pilot trial of intravenous therapy with recombinant apo A-1 Milano phospholipid complexes (ETC-216) was conducted in 57 patients who were within two weeks of onset of an acute coronary syndrome and showed a significant decrease in the mean percentage of coronary artery volume occupied by atheroma.<ref name="pmid7923682">{{cite journal| author=Ameli S, Hultgardh-Nilsson A, Cercek B, Shah PK, Forrester JS, Ageland H et al.| title=Recombinant apolipoprotein A-I Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits. | journal=Circulation | year= 1994 | volume= 90 | issue= 4 | pages= 1935-41 | pmid=7923682 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7923682 }} </ref>
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| ====Infusion of Reconstituted HDL====
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| The ERASE trial on 183 CHD patients with reconstituted human HDL estimating the coronary atheroma volume was associated with a high incidence of liver function test abnormalities, which led to early study discontinuation in this group.<ref name="pmid17387133">{{cite journal| author=Tardif JC, Grégoire J, L'Allier PL, Ibrahim R, Lespérance J, Heinonen TM et al.| title=Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. | journal=JAMA | year= 2007 | volume= 297 | issue= 15 | pages= 1675-82 | pmid=17387133 | doi=10.1001/jama.297.15.jpc70004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17387133 }} </ref>
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| ====Theobromine Study====
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| Theobromine, as found in cocoa, has been associated with an increase in HDL-C and has been associated with a decreased risk of cardiovascular disease in observational studies.<ref name="pmid17344491">{{cite journal| author=Baba S, Osakabe N, Kato Y, Natsume M, Yasuda A, Kido T et al.| title=Continuous intake of polyphenolic compounds containing cocoa powder reduces LDL oxidative susceptibility and has beneficial effects on plasma HDL-cholesterol concentrations in humans. | journal=Am J Clin Nutr | year= 2007 | volume= 85 | issue= 3 | pages= 709-17 | pmid=17344491 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17344491 }} </ref><ref name="pmid23595874">{{cite journal| author=Neufingerl N, Zebregs YE, Schuring EA, Trautwein EA| title=Effect of cocoa and theobromine consumption on serum HDL-cholesterol concentrations: a randomized controlled trial. | journal=Am J Clin Nutr | year= 2013 | volume= 97 | issue= 6 | pages= 1201-9 | pmid=23595874 | doi=10.3945/ajcn.112.047373 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23595874 }} </ref>
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| ====CETP Inhibition====
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| Torcetrapib, anacetrapib, evacetrapib, and dalcetrapib inhibit cholesteryl ester transfer protein (CETP) and raise HDL-cholesterol levels. Though investigation of torcetrapib and dalcetrapib has stopped due to the finding of an increased risk of cardiovascular events in the ILLUMINATE trial and dal-OUTCOMES, Anacetrapib in the DEFINE study has shown to increase HDL, but the overall safety in CHD is yet to be proved.<ref name="pmid21082868">{{cite journal| author=Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA, Gotto AM et al.| title=Safety of anacetrapib in patients with or at high risk for coronary heart disease. | journal=N Engl J Med | year= 2010 | volume= 363 | issue= 25 | pages= 2406-15 | pmid=21082868 | doi=10.1056/NEJMoa1009744 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21082868 }} </ref>
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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 significant decrease in atherosclerosis. <br> There was increase in blood pressure.
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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.
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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.
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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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