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<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>
<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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| [[BIP Trial]] ||Bezafibrate||18%|| There was no difference in fatal and non fatal [[MI]].<ref name="pmid10880410">{{cite journal| author=Bezafibrate Infarction Prevention (BIP) study| title=Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. | journal=Circulation | year= 2000 | volume= 102 | issue= 1 | pages= 21-7 | pmid=10880410 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10880410 }} </ref>
| '''[[BIP Trial]]''' ||Bezafibrate||18%|| There was no difference in fatal and non fatal [[MI]].<ref name="pmid10880410">{{cite journal| author=Bezafibrate Infarction Prevention (BIP) study| title=Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. | journal=Circulation | year= 2000 | volume= 102 | issue= 1 | pages= 21-7 | pmid=10880410 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10880410 }} </ref>
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| [[The FIELD study]]|| Fenofibrate||3%||There was no difference in mortality and cardiovascular disease events.<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=16646609 Review in: ACP J Club. 2006 May-Jun;144(3):65] [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] </ref>
| '''[[The FIELD study]]'''|| Fenofibrate||3%||There was no difference in mortality and cardiovascular disease events.<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=16646609 Review in: ACP J Club. 2006 May-Jun;144(3):65] [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] </ref>
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Revision as of 15:15, 9 October 2013

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mugilan Poongkunran M.B.B.S [2]

Overview

Epidemiological studies have shown an inverse relationship between HDL-C levels and CVD risks.[1][2][3] 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.

Prognosis and Complications

HDL Raising Therapies

Niacin

According to several studies, niacin therapy is associated with improved lipoprotein profile in general and increase in the level of HDL in particular, which has been associated with decrease in cardiovascular events, decrease in mortality and regression of atherosclerosis plaques. Increase in HDL level by niacin can be attributed to the direct effect of the drug itself as well as to the niacin-induced decrease in the triglycerides level. The link between increasing HDL and improving cardiovascular outcomes is difficult to interpret as niacin's effects are not only limited to HDL but also include decreasing LDL and triglyceride levels.[4]

Shown below is a table summarizing some studies that have investigated the role of niacin in increasing HDL.

Trial Name Drug HDL Increase Follow up
ARBITER 2 Trial[5] Extended release Niacin in patients on statin 21% 12 months
ARBITER 3 Trial[6] Extended release Niacin in patients on statin 9.6 +/- 12.5 mg/dL 24 months
CLAS 1 Trial[7] Niacin and colestipol 37% 2 years
CLAS 2 TRIAL[7] Niacin and colestipol 37% 4 years
HATS Trial[8] Niacin and simvastatin +/- antioxidants 26% 3 years
Coronary Drug Project[9] Niacin or clofibrate - 6 years and 15 years
Stockholm Ischemic Heart Disease Study[10] Niacin + Clofibrate - 5 years
FATS[11] Lovastatin + colestipol
Niacin + Colestipol		 15%
43%		 2.5 years
FATS Extended follow-up Niacin + lovastatin + colestipol - 10 years
UCSF-SCOR[12] Niacin + colestipol +/- Lovastatin and diet 28% 2 years

Fibrates

Trial Name Drug HDL Increase Follow up
VA-HIT Trial Gemfibrozil 6% 5 years
BECAIT Trial Bezafibrate 9% 5 years
Helsinki Heart Study Gemfibrozil 11% 5 years
Frick et al Gemfibrozil 3years
DAIS Fenofibrate 3 years

Challenging HDL-C Hypothesis

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.[4]

Trial Name Drug HDL Increase Endpoints
ILLUSTRATE Torcetrapib 61% There was no significant decrease in coronary atherosclerosis.
There was increase in blood pressure.[13]
RADIANCE 1 Torcetrapib 24.5±0.4 mg/dL There was no significant relationship between HDL levels and carotid intima-media thickness.
There was increase in blood pressure.[14]
RADIANCE 2 Torcetrapib 63.4% There was no significant relationship between HDL levels and carotid intima-media thickness.
There was increase in blood pressure.[15]
ILLUMINATE Trial Torcetrapib 72.1% Hazard ratio for death was 1.58 in torcetrapib group at the end of the study (p=0.006).
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).
Significant increase in adverse events in torcetrapib group was reported: Hypertension, peripheral edema, angina pectoris, dyspnea, and headache (p<0.001).[16]
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.[17]
AIM-HIGH Trial Niacin + Statin 25% There was no reduction in the rate of primary endpoint or all-cause mortality with niacin.
Moreover, there was a trend towards more ischemic strokes in the niacin group.

[18]

BIP Trial Bezafibrate 18% There was no difference in fatal and non fatal MI.[19]
The FIELD study Fenofibrate 3% There was no difference in mortality and cardiovascular disease events.[20]

References

  1. ↑ Khera AV, Rader DJ (2010). "Future therapeutic directions in reverse cholesterol transport". Curr Atheroscler Rep. 12 (1): 73–81. doi:10.1007/s11883-009-0080-0. PMC 3315100. PMID 20425274.
  2. ↑ Emerging Risk Factors Collaboration. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK; et al. (2009). "Major lipids, apolipoproteins, and risk of vascular disease". JAMA. 302 (18): 1993–2000. doi:10.1001/jama.2009.1619. PMC 3284229. PMID 19903920. Review in: Ann Intern Med. 2010 Feb 16;152(4):JC-212
  3. ↑ Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD; et al. (1989). "High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies". Circulation. 79 (1): 8–15. PMID 2642759.
  4. ↑ 4.0 4.1 Joy T, Hegele RA (2008). "Is raising HDL a futile strategy for atheroprotection?". Nat Rev Drug Discov. 7 (2): 143–55. doi:10.1038/nrd2489. PMID 18239670.
  5. ↑ Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA (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.
  6. ↑ Taylor AJ, Lee HJ, Sullenberger LE (2006). "The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3". Curr Med Res Opin. 22 (11): 2243–50. doi:10.1185/030079906X148508. PMID 17076985.
  7. ↑ 7.0 7.1 Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH (1990). "Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up". JAMA. 264 (23): 3013–7. PMID 2243429.
  8. ↑ Brown BG, Zhao XQ, Chait A; et al. (2001). "Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease". The New England Journal of Medicine. 345 (22): 1583–92. doi:10.1056/NEJMoa011090. PMID 11757504. Unknown parameter |month= ignored (help)
  9. ↑ "Clofibrate and niacin in coronary heart disease". JAMA. 231 (4): 360–81. 1975. PMID 1088963.
  10. ↑ Carlson LA, Rosenhamer G (1988). "Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid". Acta Med Scand. 223 (5): 405–18. PMID 3287837.
  11. ↑ Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C; et al. (1990). "Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B." N Engl J Med. 323 (19): 1289–98. doi:10.1056/NEJM199011083231901. PMID 2215615.
  12. ↑ Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ (1990). "Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens". JAMA. 264 (23): 3007–12. PMID 2243428.
  13. ↑ Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT; et al. (2007). "Effect of torcetrapib on the progression of coronary atherosclerosis". N Engl J Med. 356 (13): 1304–16. doi:10.1056/NEJMoa070635. PMID 17387129.
  14. ↑ Vergeer M, Bots ML, van Leuven SI, Basart DC, Sijbrands EJ, Evans GW; et al. (2008). "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". Circulation. 118 (24): 2515–22. doi:10.1161/CIRCULATIONAHA.108.772665. PMID 19029469.
  15. ↑ Bots ML, Visseren FL, Evans GW, Riley WA, Revkin JH, Tegeler CH; et al. (2007). "Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial". Lancet. 370 (9582): 153–60. doi:10.1016/S0140-6736(07)61088-5. PMID 17630038.
  16. ↑ 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.
  17. ↑ 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. 367 (22): 2089–99. doi:10.1056/NEJMoa1206797. PMID 23126252.
  18. ↑ 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. Review in: Ann Intern Med. 2012 Apr 17;156(8):JC4-08
  19. ↑ Bezafibrate Infarction Prevention (BIP) study (2000). "Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease". Circulation. 102 (1): 21–7. PMID 10880410.
  20. ↑ 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. Review in: ACP J Club. 2006 May-Jun;144(3):65 Review in: Evid Based Med. 2006 Jun;11(3):86


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