High Density Lipoprotein Cholesterol-The Next Battle Front in the Fight Against Heart Disease

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US Cardiology 2004;2004:1(1)

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Many patients on statin therapy understandably develop a false sense of security. They enjoy a lowered level of low-desity lipoprotein (LDL) and a risk reduction of some 35%. However, two out of three patients develop a myocardial infarction (MI) while on a statin therapy. Statins often do not increase HDL levels to any substantial degree (except for Rosuvastatin, which increases high-density lipoprotein (HDL) by 8% to 14%), nor do they alter the LDL particle size, from small dense LDL to a larger, less dangerous LDL particle size.3 These patients with low (or even normal) HDL levels do not avoid the attendant myocardial damage.4 Low HDL levels are linked to an increased risk of coronary heart disease (CHD)1 in the Framingham Study, and even in patients with relatively normal LDL and HDL levels, a small LDL particle size5 (pattern type B) can cause significant events in 50% of patients,2 as in the Quebec Cardiovascular Study6,7 (which also showed that HDL2 particles contributed to the cardioprotective effects of high HDL-C levels more than HDL3 particles). Thus, to provide more protection against unwarranted myocardial events - thrombosis and occlusion - more attention should be devoted to increasing HDL levels and to modification of LDL particle size. Although atherosclerosis occurs due to abnormal lipids, the entire damaging process has three components:

  • dyslipoproteinemia;
  • the inflammatory component, or endothelial inflammation caused by endothelial dysfunction; and
  • the thrombotic event.

It is as a result of the high triglycerides and low HDL, along with a large lipid load, that the inflammatory reaction occurs.

Atherosclerosis

It is well documented that reduced HDL-C levels are associated with an increased risk of coronary artery disease (CAD),8 while those patients whose HDL is increased after an event32 are afforded a partial protection against a second event. Intravenous infusion of HDL rapidly normalizes endothelium-dependent vasodilation by increasing nitric oxide (NO) bioavailability, and reduces the lipid load in the vascular wall. This may in part explain the protective effect of HDL9,10 from CHD and illustrates the potential therapeutic benefit of increasing HDL in patients at risk from atherosclerosis.12

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References
  1. Enzyme on HDL protective against CHD, may be modifiable target for preventing coronary events HeartWire News; May 19, 2003
  2. Mingpeng S and Zongli W, "The protective role of high-density lipoproteins in atherosclerosis", Exp. Gerontol. (1999), Jul; 34 (4): pp. 539-548.
    Crossref | PubMed
  3. Campos H, Genest J J Jr, Blijlevens E, McNamara J R, Jenner J L, Ordovas J M,Wilson P W F and Schaefer EJ,"Low density Lipoprotein particle size and coronary artery disease", Arterioscler.Thromb.Vasc. Biol. (1992), 12: pp. 187-195.
    Crossref
  4. Barter P, Kastelein J and Nunn A, "High density lipoproteins (HDLs) and atherosclerosis; the unanswered questions", Atherosclerosis (2003) Jun; 168 (2): pp. 195-211.
    Crossref | PubMed
  5. Coresh J, Kwiterovich P O Jr, Smith H H, Bachorik P S, "Association of plasma triglyceride concentration and LDL particle diameter,density and chemicalcomposition with premature coronary artery disease in men and women", J. Lipid. Res. (1993), 34: pp. 1,687-1,689.
    PubMed
  6. Lemieux I, Lamarche B, Couillard C, Pascot A, Cantin B, Bergeron J, Dagenais G R and Despres J P,"Total cholesterol/HDL cholesterol ratio vs LDL cholesterol/HDL cholesterol ratio as indices of ischemic heart disease risk in men: the Quebec Cardiovascular Study", Arch. Intern. Med. (2001), Dec 10-24; 161 (22): pp. 2,685-2,692.
    Crossref | PubMed
  7. Despres J P, Lemieux I, Dagenais GR, et al., "HDL-cholesterol as a marker of coronary heart disease risk: the Quebec cardiovascular study", Atherosclerosis (Ireland), Dec (2000), 153 (2) pp. 263-272.
    Crossref | PubMed
  8. Meyers C D and Kashyap M L,"Pharmacologic elevation of high-density lipoproteins: recent insights on mechanism of action and atherosclerosis protection",Curr. Opin. Cardiol. (2004) Jul;19 (4): pp. 366-373.
    Crossref | PubMed
  9. Rubins H, Robins S J, Collins D, Fye C L, Anderson J W, Elam M B, Faas F H, Linares E, Schaefer E J, Schectman G,Wilt T J and Wittes J, "Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol",Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group, N. Engl. J. Med. (1999), 341: pp. 410-418.
    8. Miller N E and Miller G J, "High-density lipoprotein and atherosclerosis", Lancet (1975), 1: p. 1,033.
    9. Meyers C D and Kashyap M L,"Pharmacologic elevation of high-density lipoproteins:recent insights on mechanism of action and atherosclerosis protection", Curr. Opin. Cardiol. (2004) Jul;19 (4): pp. 366-373.
    Crossref | PubMed
  10. Price M J and Shah P K,"New strategies in managing and preventing atherosclerosis: focus on HDL", Rev. Cardiovasc. Med. (2002), Summer; 3 (3): pp. 129-137.
    PubMed
  11. Plump A S, Scott C J and Breslow J L, "Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse", Proc. Natl. Acad. Sci. USA (1994), 91: pp. 9,607-9,611.
    Crossref | PubMed
  12. Rader D J, "High-density lipoproteins and atherosclerosis", Am. J. Cardiol. (2002) Oct 17; 90 (8A): pp. 62i-70i.
    Crossref | PubMed
  13. Aikawa M, Rabkin E, Okada Y,Voglic S J, Clinton S K, Brinckerhoff C E, Sukhova G K and Libby P,"Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: a potential mechanism of lesion stabilization [see comments]", Circulation (1998), 97: pp. 2,433-2,444.
    Crossref | PubMed
  14. Ansell B J, Navab M, Hama S, et al.,"Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment", Circulation (2003), Nov 24; 108: pp. 2,751-2,756.
    Crossref | PubMed
  15. Ballantyne C M, Hoogeveen R C, Bang H, Coresh J, Folsom A R,Heiss G and Sharrett A R,"Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study" Circulation (2004), Feb 24;109 (7): pp. 837-842 (ISSN: 1524-4539).
    Crossref | PubMed
  16. Baker P W and Rye K A,"Effect of high-density lipoproteins on the expression of adhesion molecules in endothelial cells", Curr. Opin. Lipidol. (2002), Jun; 13 (3): pp. 285-288 (ISSN: 0957-9672).
    Crossref | PubMed
  17. Forrester J S,"Prevention of plaque rupture:Anew paradigm of therapy", Ann. Intern. Med. (2002), 1379 (10): pp. 823-833.
    Crossref | PubMed
  18. Laura Calabresi; Monica Gomaraschi; Barbara Villa; Laura Omoboni; Camille Dmitrieff; Guido Franceschini "Elevated Soluble Cellular Adhesion Molecules in Subjects With Low HDL-Cholesterol(In both hyperlipidemic and normolipidemic patients)".
  19. Libby P, "Molecular bases of the acute coronary syndromes", Circulation (1995), 91: pp. 2,844-2,850, Oxidation.
    Crossref | PubMed
  20. Libby P "Inflammation in atherosclerosis", Nature (2002), 420 (6917): pp. 86-74.
    Crossref | PubMed
  21. Calabresi L, Gomaraschi M,Villa B, Omoboni L, Dmitrieff C and Franceschini G,"Elevated soluble cellular adhesion molecules in subjects with low HDL-cholesterol", Arterioscler.Thromb.Vasc. Biol. (2002), Apr 1; 22 (4): pp. 656-661
    Crossref | PubMed
  22.  
  23. Spieker L E, Ruschitzka F, Luscher T F and Noll G, "HDL and inflammation in atherosclerosis", Curr. Drug Targets Immune Endocr.Metabol. Disord. (2004), Mar; 4 (1): pp. 51-57.
    Crossref | PubMed
  24. Sharma N, Desigan B, Ghosh S, Sanyal SN and Ganguly NK,"Majumdar Therole of oxidized HDL in monocyte/macrophage functions in the pathogenesis of atherosclerosis in Rhesus monkeys", Scand. J. Clin. Lab. Invest. (1999), May; 59 (3): pp. 215-225.
    Crossref | PubMed
  25. Naqvi T Z, Shah P K, Ivey PA, Molloy MD,Thomas AM, Panicker S,Ahmed A, Cercek B and Kaul S,"Evidence that highdensity lipoprotein cholesterol is an independent predictor of acute platelet-dependent thrombus formation", Am. J. Cardiol. (1999), Nov 1; 84 (9): pp. 1,011-1,017, (ISSN: 0002-9149).
    Crossref | PubMed
  26. Anand S S,Yi Q, Gerstein H, Lonn E, Jacobs R,Vuksan V,Teo K, Davis B, Montague P and Yusuf S,"Relationship of metabolic syndrome and fibrinolytic dysfunction to cardiovascular disease", Circulation (2003), Jul 29; 108 (4): pp. 420-425 (ISSN: 1524-4539).
    Crossref | PubMed
  27. Cuchel M and Rader D J, "The role of high density lipoproteins in thrombosis", ScientificWorldJournal (2002), Jan 12; 2: pp. 89-95, (ISSN: 1537-744X).
    Crossref | PubMed
  28. Li D,Weng S,Yang B, Zander D S, Saldeen T, Nichols W W, Khan S and Mehta J L,"Inhibition of arterial thrombus formation by ApoA1Milano", Arterioscler.Thromb.Vasc. Biol. (1999), Feb;19 (2): pp. 378-383, (ISSN: 1079-5642).
    Crossref | PubMed
  29. Moss A J, Goldstein R E, Marder V J, Sparks C E, Oakes D, Greenberg H,Weiss H J, Zareba W, Brown M W, Liang C S, Lichstein E, Little W C, Gillespie J A,Van Voorhees L, Krone R J, Bodenheimer M M, Hochman J, Dwyer E M, Arora R, Marcus F I,Watelet L F and Case R B, "Thrombogenic factors and recurrent coronary events", Circulation (1999), May 18; 99 (19): pp. 2,517-2,522
    Crossref | PubMed
  30. Naqvi T Z, Shah P K, Ivey P A, Molloy M D,Thomas A M, Panicker S, Ahmed A, Cercek B and Kaul S, "Evidence that high-density lipoprotein cholesterol is an independent predictor of acute platelet-dependent thrombus formation", Am. J. Cardiol. (1999), Nov 1; 84 (9): pp. 1,011-1,017 (ISSN: 0002-9149).
    Crossref | PubMed
  31. Puccetti L, Bruni F, Pasqui A L, Pastorelli M, Bova G, Cercignani M, Palazzuoli A and Auteri A, "Dyslipidemias and fibrinolysis", Ital. Heart J. (2002), Oct; 3 (10): pp. 579-586.
    PubMed
  32. Moss A J, Goldstein R E, Marder V J, Sparks C E, Oakes D, Greenberg H,Weiss H J, Zareba W, Brown M W, Liang C S, Lichstein E, Little W C, Gillespie J A,Van Voorhees L, Krone R J, Bodenheimer M M, Hochman J, Dwyer E M, Arora R, Marcus F I,Watelet L F and Case R B, "Thrombogenic factors and recurrent coronary events", Circulation (1999), May 18; 99 (19): pp. 2,517-2,522
    Crossref | PubMed
  33. Cheung M C,Wolfbauer G, Brown B G and Albers J J "Relationship between plasma phospholipid transfer protein activity and HDL subclasses among patients with low HDL and cardiovascular disease", Atherosclerosis (1999), Jan; 142 (1): pp. 201-205.
    Crossref | PubMed
  34. Bortnick A E, Favari E,Tao J Q, Francone O L, Reilly M, Zhang Y, Rothblat G H and Bates S R, "Identification and characterization of rodent ABCA1 in isolated type II pneumocytes", Am. J. Physiol. Lung Cell. Mol. Physiol. (2003), Oct; 285 (4): pp. L869-L878
    Crossref | PubMed
  35. hambenoit O, Hamon Y, Marguet D, et al.,"Specific docking of apolipoprotein A-I at the cell surface requires a functional ABCA1 transporter", J. Biol. Chem. (United States), Mar 30 (2001), 276 (13) pp. 9,955-9,960
    Crossref | PubMed
  36. Haidar B, Denis M, Krimbou L, Marcil M and Genest J, "cAMP induces ABCA1 phosphorylation activity and promotes cholesterol efflux from fibroblasts", J. Lipid. Res. (2002) Dec; 43 (12): pp. 2,087-2,094 (ISSN: 0022-2275).
    Crossref | PubMed
  37. Haidar B, Denis M, Marcil M, Krimbou L and Genest J, "Apolipoprotein A-I activates cellular cAMP signaling through the ABCA1 transporter", J. Biol. Chem. (2004) Mar 12; 279 (11): pp. 9,963-9,969 (ISSN: 0021-9258).
    Crossref | PubMed
  38. Denis M, Haidar B, Marcil M, Bouvier M, Krimbou L and Genest J, "Molecular and cellular physiology of apolipoprotein A-I lipidation by the ATP-binding cassette transporter A1 (ABCA1)", J. Biol. Chem. (2004) Feb 27; 279 (9): pp. 7,384-7,394
    Crossref | PubMed
  39. Lin G and Bornfeldt K E, "Cyclic AMP-specific phosphodiesterase 4 inhibitors promote ABCA1 expression and cholesterol efflux", Biochem. Biophys. Res. Commun (2002) Jan 18; 290(2): pp. 663-669
    Crossref | PubMed
  40. Liu L, Bortnick A E, Nickel M, Dhanasekaran P, Subbaiah P V, Lund-Katz S, Rothblat G H and Phillips M C, "Effects of apolipoprotein A-I on ATP-binding cassette transporter A1-mediated efflux of macrophage phospholipid and cholesterol: formation of nascent high density lipoprotein particles", J. Biol. Chem. (2003) Oct 31; 278 (44): pp. 42,976-42,984.
    Crossref | PubMed
  41. Okuhira K,Tsujita M,Yamauchi Y, Abe-Dohmae S, Kato K, Handa T and Yokoyama S, "Potential involvement of dissociated apoA-I in the ABCA1-dependent cellular lipid release by HDL", J. Lipid. Res. (2004), Apr; 45 (4): pp. 645-652.
    Crossref | PubMed
  42. Oram J F and Lawn RM,"ABCA1.The gatekeeper for eliminating excess tissue cholesterol", J. Lipid. Res. (2001),Aug; 42 (8): pp. 1,173-1,179.
    PubMed
  43. Wang N and Tall A R,"Regulation and mechanisms of ATP-binding cassette transporter A1-mediated cellular cholesterol efflux", Arterioscler.Thromb.Vasc. Biol. (2003), Jul 1; 23 (7): pp. 1,178-1,184 (ISSN: 1524-4636).
    Crossref | PubMed
  44. Acton S L, Kozarsky K F and Rigotti A,"The HDL receptor SR-BI: a new therapeutic target for atherosclerosis?", Mol. Med. Today (1999), Dec; 5 (12): pp. 518-524.
    Crossref | PubMed
  45. Rigotti A,Trigatti B L, Penman M, Rayburn H, Herz J and Krieger M, "A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism", Proc. Natl. Acad. Sci. USA (1997), 94: pp. 12,610-12.615.
    Crossref | PubMed
  46. Spieker L E, Sudano I, Hurlimann D, Lerch P G, Lang M G, Binggeli C, Corti R, Ruschitzka F, Luscher T F and Noll G, "High-density lipoprotein restores endothelial function in hypercholesterolemic men", Circulation (2002), Mar 26; 105 (12): pp. 1,399-1,402.
    Crossref | PubMed
  47. Ramet M E, Ramet M, Lu Q, Nickerson M, Savolainen M J, Malzone A and Karas R H,"High-density lipoprotein increases the abundance of eNOS protein in human vascular endothelial cells by increasing its half-life", J. Am. Coll. Cardiol. (2003), Jun 18; 41 (12): pp. 2,288-2,297.
    Crossref | PubMed
  48. Calabresi L, Gomaraschi M and Franceschini G, "Endothelial protection by high-density lipoproteins: from bench to bedside", Arterioscler.Thromb.Vasc. Biol. (2003), Oct 1; 23 (10): pp. 1,724-1,731.
    Crossref | PubMed
  49. O'Connell B J and Genest J,"High-density lipoproteins and endothelial function", Circulation (2001), Oct 16; 104 (16): pp. 1,978-1,983.
    Crossref
  50.  
  51.  
  52.  
  53.  
  54.  
  55.  
  56.  
  57.  
  58.  
  59. CETP inhibitor markedly raises HDL: Benefit also seen in patients concomitantly receiving statins HeartWire Atherosclerosis; Apr 7, 2004.
  60. Brousseau M E, Schaefer E J,Wolfe M L, et al.,"Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol", N. Engl. J. Med. (2004), Apr 8; 350 (15): pp. 1,505-1,515.
    Crossref | PubMed
  61. Clark R W, Sutfin T A, Ruggeri R B, et al., "Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib", Arterioscler.Thromb.Vasc. Biol. (2004), Mar; 24 (3): pp. 490-497.
    Crossref | PubMed
  62. de Vries R, Borggreve S E and Dullaart R P, "Role of lipases, lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein in abnormal high density lipoprotein metabolism in insulin resistance and type 2 diabetes mellitus", Clin. Lab. (2003); 49 (11-12): pp. 601-613.
    PubMed
  63. Yamamoto M and Katoh N, "Decreased apolipoprotein C-III concentration in the high-density lipoprotein fraction from calves inoculated with Pasteurella haemolytica and bovine herpes virus-1", J.Vet. Med. Sci. (2000) Jan; 62 (1): pp. 49-52.
    Crossref | PubMed
  64. Fredenrich A, "Role of Apolipoprotein CIII in triglyceride-rich lipoprotein metabolism", Diabetes Care (1998), 24: pp. 490-495.
    PubMed
  65. Westphal S, Gekeler G H, Dierkes J,Wieland H and Luley C, "A free fatty acid tolerance test identifies patients with coronary artery disease among individuals with a low conventional coronary risk profile", Heart Vessels (2002), Mar; 16 (3): pp. 79-85.
    Crossref | PubMed
  66. Pirro M, Mauriege P,Tchernof A, et al., "Plasma free fatty acid levels and the risk of ischemic heart disease in men: prospective results from the Quebec Cardiovascular Study", Atherosclerosis (Ireland), Feb 2002, 160 (2) pp. 377-384.
    Crossref | PubMed
  67. Andersen R V,Wittrup H H,Tybjaerg-J. Lipid Res. (1999), Jun; 40 (6): pp. 1,064-1,070, Hansen A, Steffensen R, Schnohr P and Nordestgaard B G, "Hepatic lipase mutations,elevated high-density lipoprotein cholesterol, and increased risk of ischemic heart disease: the Copenhagen City Heart Study", J.Am. Coll. Cardiol. (2003), Jun 4; 41 (11): pp. 1,972-1,982
    Crossref | PubMed
  68. Ramsamy T A, Boucher J, Brown R J,Yao Z and Sparks D L,"HDL regulates the displacement of hepatic lipase from cell surface proteoglycans and the hydrolysis of VLDL triacylglycerol", J. Lipid Res. (2003), Apr; 44 (4): pp. 733-741.
    Crossref | PubMed
  69. Jin W, Marchadier D and Rader D J,"Lipases and HDL metabolism", Trends Endocrinol. Metab. (2002), May-Jun; 13 (4): pp. 174-178, (ISSN: 1043-2760).
    Crossref | PubMed
  70. Sakai N,Vaisman B L, Koch C A, Hoyt R F Jr, Meyn S M,Talley G D, Paiz J A, Brewer H B Jr and Santamarina-Fojo S, "Targeted disruption of the mouse lecithin:cholesterol acyltransferase (LCAT) gene: generation of a new animal model for human LCAT deficiency", J. Biol. Chem. (1997), 272: pp. 7,506-7,510.
    Crossref | PubMed
  71. McCoy M G, Sun G S, Marchadier D, Maugeais C, Glick J M and Rader D J, "Characterization of the lipolytic activity of endothelial lipase", J. Lipid Res. (2002), Jun; 43 (6): pp. 921-929.
    PubMed
  72. McNamara J R, Jenner J L, Li Z,Wilson P W F and Schaefer E J,"Change in LDL particle size is associated with change in plasma triglyceride concentration", Arterioscler.Thromb.Vasc. Biol. (1992), 12: pp. 1,284-1,290.
    Crossref | PubMed
  73. Grundy S M,Vega G L, Otvos J D, Rainwater D L and Cohen J C,"Hepatic lipase activity influences high density lipoprotein subclass distribution in normotriglyceridemic men, Genetic and pharmacological evidence", J. Lipid Res. (1999), Feb; 40 (2): pp. 229-234.
    PubMed
  74. McNamara J R, Jenner J L, Li Z,Wilson P W F and Schaefer E J,"Change in LDL particle size is associated with change in plasma triglyceride concentration", Arterioscler.Thromb.Vasc. Biol. (1992), 12: pp. 1,284-1,290.
    Crossref | PubMed
  75. Horio T, Miyazato J, Kamide K,Takiuchi S and Kawano Y,"Influence of low high-density lipoprotein cholesterol on left ventricular hypertrophy and diastolic function in essential hypertension", Am. J. Hypertens. (2003), Nov; 16 (11 Pt 1): pp. 938-944.
    Crossref | PubMed
  76. Calabresi L, Rossoni G, Gomaraschi M, Sisto F, Berti F and Franceschini G,"High-density lipoproteins protect isolated rat hearts from ischemia-reperfusion injury by reducing cardiac tumor necrosis factor-alpha content and enhancing prostaglandin release", Circ. Res. (2003), Feb 21; 92 (3): pp. 330-337
    Crossref | PubMed
  77. Oram J F and Lawn R M,"ABCA1.The gatekeeper for eliminating excess tissue cholesterol", J. Lipid Res. (2001),Aug; 42 (8): pp. 1,173-1,179.
    PubMed
  78. Ikeda T, Saito H,Tanno K, Shimizu H,Watanabe J, Ohnishi Y, Kasamaki Y and Ozawa Y,"T-Wave alternans as a predictor for sudden cardiac death after myocardial infarction", Am. J. Cardiol. (2002), 89: pp. 79-82.
    Crossref | PubMed
  79. Koeller J and Talbert R L, "Modification of high-density lipoprotein cholesterol in the management of cardiovascular risk", Pharmacotherapy (2002), Oct; 22 (10): pp. 1,266-1,277, Meyers C D and Kashyap M L,"Pharmacologic elevation of highdensity lipoproteins: recent insights on mechanism of action and atherosclerosis protection", Curr. Opin. Cardiol. (2004), Jul; 19 (4): pp. 366-374.
    Crossref | PubMed
  80. Rosenson R S, "Antiatherothrombotic effects of nicotinic acid", Atherosclerosis (2003), Nov; 171 (1): pp. 87-96.
    Crossref | PubMed
  81. Kamanna V S and Kashyap M L,"Mechanism of action of niacin on lipoprotein metabolism", Curr.Atheroscler. Rep. (2000), 2: pp. 36-46.
    Crossref | PubMed
  82. Saareks V, Mucha I, Sievi E and Riutta A,"Nicotinic acid and pyridoxine modulate arachidonic acid metabolism in vitro and ex vivo in man", Pharmacol.Toxicol. (1999), Jun; 84 (6): pp. 274-280.
    Crossref | PubMed
  83. Sheperd J,"Mechanism of action of fibrates", Postgraduate Med. J. (1993), 69 (Suppl. 1) : pp. 534-541.
    Crossref
  84. Elisaf M, "Effects of fibrates on serum metabolic parameters", Curr. Med. Res. Opin. (2002), 18 (5): pp. 269-276 (ISSN: 0300-7995).
    Crossref | PubMed
  85. Davidson M H, "Combination therapy for dyslipidemia: Safety and regulatory considerations", Am. J. Cardiol. (2002), 90 (Suppl 10B): pp. 50K-60K.
    Crossref | PubMed
  86. Winkler K, Konrad T, Fullert S, Friedrich I, Destani R, Baumstark M W, Krebs K,Wieland H and Marz W, "Pioglitazone reduces atherogenic dense LDL particles in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study", Diabetes Care (2003), Sep; 26 (9): pp. 2,588-2,594.
    Crossref | PubMed
  87. Athyros V G, Papgergiou A A, Athyrou V V, Dimitriadis D S and Kontopoulos A G, "Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia", Diabetes Care (2002), 25: pp. 1,198-1,202.
    Crossref | PubMed
  88. Duvall W L, Blazing M A, Saxena S and Guyton J R,"Targeting cardiovascular risk associated with both low density and high density lipoproteins using statin-niacin combination therapy", J. Cardiovasc. Risk (2002), Dec; 9 (6): pp. 339-347.
    Crossref | PubMed
  89. Tawakol R and King A B, "Marked HDL Cholesterol Benefit in Patients with Low HDL-C and Type 2 Diabetes or Impaired Glucose Tolerance with Combined Treatment of Pioglitazone and Low Dose Nicotinic Acid", Diabetes Care (Suppl 2004) In publication.
  90. Tawakol R, "Clinical trials for Nicotinic acid aspirin combination, with fenofibrate and Pioglitizone", (Letter to Gate Pharmaceutical and Teva USA,Trial).