HDL-C as a new therapeutic target in the treatment of dyslipidemia

Clinical and epidemiological studies have suggested that low plasma levels of high-density lipoproteins cholesterol (HDL-C) are independently associated with an increased risk of cardio-vascular diseases (CVD). Accumulated data from epidemiologic, animal models and clinical studies support the view that raising HDL may be an effective new target to decrease cardio-vascular risks. New insights in the understanding of the physiology, mechanisms and pathways by which HDL may reduce atherosclerosis allow new promising agents for increasing plasma HDL-C. In this regards, apo-AI analogs, acute HDL-C infusions therapies and new cholesteryl ester transfer protein CETP inhibitors have opened new expectations in the treatment of CVD.

HDL-C as a new therapeutic target in the treatment of dyslipidemia

Clinical and epidemiological studies have suggested that low plasma levels of high-density lipoproteins cholesterol (HDL-C) are independently associated with an increased risk of cardio-vascular diseases (CVD). Accumulated data from epidemiologic, animal models and clinical studies support the view that raising HDL may be an effective new target to decrease cardio-vascular risks. New insights in the understanding of the physiology, mechanisms and pathways by which HDL may reduce atherosclerosis allow new promising agents for increasing plasma HDL-C. In this regards, apo-AI analogs, acute HDL-C infusions therapies and new cholesteryl ester transfer protein CETP inhibitors have opened new expectations in the treatment of CVD.

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  • ) National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 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 2002; 106:3143-21.
  • ) Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007; 357:1301-10.
  • ) Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;
344: 1383–89.
  • ) Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on 
coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001–09.
  • ) Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease: the Framingham Study. Am J Med 1977;62:707-14.
  • ) The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362:1563–1574.
  • ) Rosenson RS. Low HDL-C: a secondary target of dyslipidemia therapy. Am J Med 2005; 118:1067-77.
  • ) Castelli WP. Cardiovascular disease and multifactorial risk: challenge of the 1980s. Am Heart J 1983; 106:1191-200.
  • ) Rubins HB, Robins SJ, Collins D, Iranmanesh A, Wilt TJ, Mann D, Mayo-Smith M, Faas FH, Elam MB, Rutan GH. Distribution of lipids in 8500 men with coronary artery disease. Department of Veterans Affairs HDL Intervention Trial Study Group. Am J Cardiol 1995; 75:1196 –1201.
  • ) Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study. JAMA. 1986;256(20):2835-2838.
  • ) Sharrett AR, Ballantyne CM, Coady SA, Heiss G, Sorlie PD, Catellier D, Patsch W. Coronary heart disease prediction from lipoprotein cho- lesterol levels, triglycerides, lipoprotein(a), apolipo roteins A-I and B, and HDL density subfractions: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2001;104(10):1108- 1113.
  • ) Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, Jacobs DR Jr, Bangdiwala S, Tyroler HA. High-density lipoprotein choles- terol and cardiovascular disease:four prospective American studies. Circulation 1989;79:8-15.
  • ) Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004; 350(15):1495-1504.
  • ) Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, AFCAPS/ TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA. 1998;279(20):1615-1622.
  • ) Asmann G, Nofer JR. Atheroprotective effects of high-density lipoproteins. Annu Rev Med 2003; 54:321-341.
  • ) Okura H, Yamashita S, Ohama T, Saga A, Yamamoto-Kakuta A, Hamada Y, Sougawa N, Ohyama R, Sawa Y, Matsuyama A. HDL/apolipoprotein A-I binds to macrophage- derived progranulin and suppresses its conversion into proinflammatory granulins. J Atheroscler Thromb 2010;17:568-577.
  • ) Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL. Circ Res 2004; 95:764-772.
  • ) Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, 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; 341:410-18.
  • ) Bloomfield Rubins H, Davenport J, Babikian V, Brass LM, Collins D, Wexler L, Wagner S, Papademetriou V, Rutan G, Robins SJ. VA-HIT Study Group. Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT). Circulation 2001; 103:2828-33.
  • ) Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ, McNamara JR, Kashyap ML, Hershman JM, Wexler LF, Rubins HB; VA-HIT Study Group. Veterans Affairs High-Density Lipoprotein Intervention Trial. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA 2001; 285:1585-91.
  • ) Brown BG, Zhao XQ, Chait A. Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ.Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001; 345:1583-92.
  • ) Cohen JC, Kiss RS, Pertsemlidis A, Marcel YL, McPherson R, Hobbs HH. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 2004; 305:869-72.
  • ) Vergani C, Bettale G. Familial hypo-alpha-lipoproteinemia. Clin Chim Acta 1981; 114:45-52.
  • ) Glueck CJ, Daniels SR, Bates S, Benton C, Tracy T, Third JL. Pediatric victims of unexplained stroke and their families: familial lipid and lipoprotein abnormalities. Pediatrics 1982; 69:308-16.
  • ) Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C, Garimella KV, Fisher S, Abreu J, Barry AJ, Fennell T, Banks E, Ambrogio L, Cibulskis K, Kernytsky A, Gonzalez E, Rudzicz N, Engert JC, DePristo MA, Daly MJ, Cohen JC, Hobbs HH, Altshuler D, Schonfeld G, Gabriel SB, Yue P, Kathiresan S. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med 2010; 363:2220-7.
  • ) Nordestgaard BG, Abildgaard S, Wittrup HH, Steffensen R, Jensen G, Tybjaerg-Hansen A. Heterozygous lipoprotein lipase deficiency: frequency in the general population, effect on plasma lipid levels, and risk of ischemic heart disease. Circulation 1997; 96:1737-44.
  • ) Wittrup HH, Tybjaerg-Hansen A, Nordestgaard BG. Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis. Circulation 1999; 99:2901-7.
  • ) Blades B, Vega GL, Grundy SM. Activities of lipoprotein lipase and hepatic triglyceride lipase in postheparin plasma of patients with low concentrations of HDL cholesterol. Arterioscler Thromb 1993; 13:1227-35.
  • ) Funke H, von Eckardstein A, Pritchard PH, Albers JJ, Kastelein JJ, Droste C, Assmann G. A molecular defect causing fish eye disease: an amino acid exchange in lecithin- cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity. Proc Natl Acad Sci U S A 1991; 88:4855-9.
  • ) Klein HG, Lohse P, Pritchard PH, Bojanovski D, Schmidt H, Brewer HB Jr. Two different allelic mutations in the lecithin-cholesterol acyltransferase gene associated with the fish eye syndrome. Lecithin-cholesterol acyltransferase (Thr123----Ile) and lecithin- cholesterol acyltransferase (Thr347----Met). J Clin Invest 1992; 89:499-506.
  • ) Abate N, Vega GL, Garg A, Grundy SM. Abnormal cholesterol distribution among lipoprotein fractions in normolipidemic patients with mild NIDDM. Atherosclerosis 1995; 118:111-22.
  • ) Barter P. HDL-C: Role as a risk modifier Atherosclerosis Supplements 2011;12(3) :267–270.
  • ) Kasiske BL, Ma JZ, Kalil RS, Louis TA. Effects of antihypertensive therapy on serum lipids. Ann Intern Med 1995; 122:133-41.
  • ) Bagatell CJ, Heiman JR, Matsumoto AM, Rivier JE, Bremner WJ. Metabolic and behavioral effects of high-dose, exogenous testosterone in healthy men. J Clin Endocrinol Metab 1994; 79:561-7.
  • ) Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 2004; 350:1505-15.
  • ) Forrester JS, Makkar R, Shah PK. Increasing high-density lipoprotein cholesterol in dyslipidemia by cholesteryl ester transfer protein inhibition: an update for clinicians. Circulation 2005; 111:1847-54.
  • ) Brewer HB Jr. Increasing HDL Cholesterol Levels. N Engl J Med 2004; 350:1491-4.
  • ) Niesor EJ, Magg C, Ogawa N, Okamoto H, von der Mark E, Matile H, Schmid G, Clerc RG, Chaput E, Blum-Kaelin D, Huber W, Thoma R, Pflieger P, Kakutani M, Takahashi D, Dernick G, Maugeais C. Modulating cholesteryl ester transfer protein activity maintains efficient pre-β-HDL formation and increases reverse cholesterol transport. J Lipid Res 2010; 51:3443-54.
  • ) Ghosh RK, Ghosh SM. Current Status of CETP Inhibitors in the Treatment of Hyperlipidemia: An update Curr Clin Pharmacol. 2012;7(2):102-10.
  • ) Johns DG, Duffy J, Fisher T, Hubbard BK, Forrest MJ. On- and Off-Target Pharmacology of Torcetrapib: Current Understanding and Implications for the Structure Activity Relationships (SAR), Discovery and Development of Cholesteryl Ester- Transfer Protein (CETP) Inhibitors. Drugs. 2012;72(4):491-507
  • ) Ameli S, Hultgardh-Nilsson A, Cercek B, Shah PK, Forrester JS, Ageland H, Nilsson J. Recombinant apolipoprotein A-I Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits. Circulation 1994; 90:1935-41.
  • ) Tardif JC, Grégoire J, L'Allier PL, Ibrahim R, Lespérance J, Heinonen TM, Kouz S, Berry C, Basser R, Lavoie MA, Guertin MC, Rodés-Cabau J. Effect of rHDL on Atherosclerosis-Safety and Efficacy (ERASE) Investigators. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 2007; 297:1675-82.
  • ) Rosenson RS. Beyond low-density lipoprotein cholesterol. A perspective on low high- density lipoprotein disorders and Lp(a) lipoprotein excess. Arch Intern Med 1996; 156:1278-84.
  • ) Frost PH, Davis BR, Burlando AJ, Curb JD, Guthrie GP Jr, Isaacsohn JL, Wassertheil- Smoller S, Wilson AC, Stamler J. Serum lipids and incidence
of coronary heart disease. Findings from the Systolic Hypertension
in the Elderly Program (SHEP). Circulation 1996; 94: 2381–88.