Información del artículo
A pesar de que en varios ensayos clínicos con dosis altas de estatinas se alcanzan concentraciones óptimas de colesterol unido a lipoproteínas de baja densidad (cLDL), la incidencia de episodios cardiovasculares en éstos sigue siendo alta. La intervención sobre otros factores de riesgo, como el colesterol unido a lipoproteínas de alta densidad (cHDL), puede lograr minimizar los episodios en sujetos con cLDL normal. Los estudios con fármacos que incrementan el cHDL son escasos y con resultados menos consistentes que los que logran una reducción de cLDL, expresión del complejo metabolismo de las HDL, y nos indica que la modificación de la concentración de cHDL no es el objetivo, sino mejorar sus funciones antiaterogénicas que incluyen el transporte reverso de colesterol y su capacidad antioxidante y antiinflamatoria. Los nuevos fármacos con actividad PPAR alfa y/o gamma, inhibidores de la proteína transferidora de ésteres de colesterol (PTEC), inhibidores de los receptores cannabinoides, apolipoproteína A-I recombinante, agonistas LXR (liver X receptor) y FXR (farnesoid X receptor) son fármacos con alto potencial clínico al mejorar no sólo la concentración, sino las funciones deterioradas asociadas a un cHDL bajo.
Palabras clave:
HDL
Transporte reverso de colesterol
Tratamiento farmacológico
Apolipoproteína A
Key words:
HDL
Reverse cholesterol transport
Drug therapy
Apolipoprotein A
Several clinical trials with high-dose statins have reported optimal low-density lipoprotein cholesterol (LDL-C) concentrations. However the incidence of cardiovascular episodes in these clinical trials continues to be high. Interventions designed to act on other risk factors such as highdensity lipoprotein cholesterol (HDL-C) can minimize these episodes in subjects with normal LDL-C levels. Few studies have been performed with drugs that increase HDL-C and their results are less consistent than those that achieve a reduction of LDL-C, indicating the complex metabolism of HDL and that modification of HDL-C concentrations is not objective but rather improves its antiatherogenic functions, which include reverse cholesterol transport and its antioxidant and antiinflammatory capacity. New drugs with peroxisome proliferator activated receptors (PPAR) alpha and/or gamma activity, cholesteryl ester transfer protein (CETP) inhibitors, cannabinoid receptor inhibitors, recombinant apolipoprotein A-I, LXR and FXR agonists have strong clinical potential to improve not only the concentration but also the impaired functions associated with low HDL-C.
El Texto completo está disponible en PDF
Bibliografía
[1.]
S.M. Grundy, J.I. Cleeman, C.N. Merz, H.B. Brewer Jr, L.T. Clark, D.B. Hunninghake, National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association, et al.
Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.
Circulation, 110 (2004), pp. 227-239
[2.]
C. Baigent, A. Keech, P.M. Kearney, L. Blackwell, G. Buck, C. Pollicino, Cholesterol Treatment Trialists’ (CTT) Collaborators, et al.
Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
Lancet, 366 (2005), pp. 1267-1278
[3.]
J.C. LaRosa, S.M. Grundy, D.D. Waters, C. Shear, P. Barter, J.C. Fruchart, Treating to New Targets (TNT) Investigators, et al.
Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
N Engl J Med, 352 (2005), pp. 1425-1435
[4.]
C.P. Cannon, E. Braunwald, C.H. McCabe, D.J. Rader, J.L. Rouleau, R. Belder, Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators, et al.
Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
N Engl J Med, 350 (2004), pp. 1495-1504
[5.]
M.S. Brown, J.L. Goldstein.
Heart attacks: gone with the century?.
Science, 272 (1996), pp. 629
[6.]
P.P. Toth.
High-density lipoprotein as a therapeutic target: clinical evidence and treatment strategies.
Am J Cardiol, 96 (2005), pp. 50K-8K
[7.]
I. Shai, E.B. Rimm, S.E. Hankinson, G. Curhan, J.E. Manson, N. Rifai, et al.
Multivariate assessment of lipid parameters as predictors of coronary heart disease among postmenopausal women: potential implications for clinical guidelines.
Circulation, 110 (2004), pp. 2824-2830
[8.]
C.A. Aguilar-Salinas, H. Barrett, G. Schonfeld.
Metabolic modes of action of the statins in the hyperlipoproteinemias.
Atherosclerosis, 141 (1998), pp. 203-207
[9.]
J.R. Crouse 3rd, J. Frohlich, L. Ose, M. Mercuri, J.A. Tobert.
Effects of high doses of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I.
Am J Cardiol, 83 (1999), pp. 1476-1477
[10.]
M.D. Ashen, R.S. B.lumenthal.
Low HDL Cholesterol Levels.
N Engl J Med, 353 (2005), pp. 1252-1260
[11.]
M. Bevilacqua, B. Guazzini, V. Righini, M. Barrella, R. Toscano, E. Chebat.
Metabolic Effects of Fluvastatin Extended Release 80 mg and Atorvastatin 20mg in Patients with Type ¿ Diabetes Mellitus and Low FERUM High-Density Lipoprotein Cholesterol Levels: A 4-Month, Prospective, Open-Label, Randomized, Blinded-End Point (Probe) Trial.
Current Therapeutic Research, 65 (2004), pp. 330-344
[12.]
P.H. Jones, M.H. Davidson, E.A. Stein, H.E. Bays, J.M. McKenney, E. Miller, STELLAR Study Group, et al.
Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial).
Am J Cardiol, 15 (2003), pp. 152-160
[13.]
G. Martin, H. Duez, C. Blanquart, V. Berezowski, P. Poulain, J.C. Fruchart, et al.
Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apo A-I.
J Clin Invest, 107 (2001), pp. 1423-1432
[14.]
J.G. Robinson, B. Smith, N. Maheshwari, H. Schrott.
Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis.
J Am Coll Cardiol, 46 (2005), pp. 1855-1862
[15.]
Heart Protection Study Collaborative Group.
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
Lancet, 360 (2002), pp. 7-22
[16.]
H.M. Colhoun, D.J. Betteridge, P.N. Durrington, G.A. Hitman, H.A. Neil, S.J. Livingstone, CARDS investigators, et al.
Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.
Lancet, 364 (2004), pp. 685-696
[17.]
R.H. Knopp, H. Gitter, T. Truitt, H. Bays, C.V. Manion, L.J. Lipka.
Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia.
Eur Heart J, 8 (2003), pp. 729-741
[18.]
M.H. Davidson, T. McGarry, R. Bettis, L. Melani, L.J. Lipka, A.P. LeBeaut, et al.
Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia.
J Am Coll Cardiol, 40 (2002), pp. 2125-2134
[19.]
M. Farnier, M.W. Freeman, G. Macdonell, I. Perevozskaya, M.J. Davies, Y.B. Mitchel, the Ezetimibe Study Group, et al.
Efficacy and safety of the coadministration of ezetimibe with fenofibrate in patients with mixed hyperlipidaemia.
Eur Heart J, 26 (2005), pp. 897-905
[20.]
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, 106 (2002), pp. 3143-3421
[21.]
M.H. Davidson, P.P. Toth.
Comparative effects of lipid-lowering therapies.
Prog Cardiovasc Dis, 47 (2004), pp. 73-104
[22.]
H.B. Rubins, S.J. Robins, D. Collins, C.L. Fye, J.W. Anderson, M.B. Elam, et al.
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, 341 (1999), pp. 410-418
[23.]
M.H. Frick, O. Elo, K. Haapa, O.P. Heinonen, P. Heinsalmi, P. Helo, et al.
Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease.
N Engl J Med, 317 (1987), pp. 1237-1245
[24.]
BIP Study group.
Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study.
Circulation, 102 (2000), pp. 21-27
[25.]
A. Keech, R.J. Simes, P. Barter, J. Best, R. Scott, M.R. Taskinen, FIELD study investigators, et al.
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 (2005), pp. 1849-1861
[26.]
J. McKenney.
New perspectives on the use of niacin in the treatment of lipid disorders.
Arch Intern Med, 164 (2004), pp. 697-705
[27.]
T. Sakai, V.S. Kamanna, Kashyap.
Niacin, but not gemfibrozil, selectively increases LP-AI, a cardioprotective subfraction of HDL, in patients with low HDL cholesterol.
Arterioscler Thromb Vasc Biol, 21 (2001), pp. 1783-1789
[28.]
The Coronary Drug Project Research Group.
Clofibrate and niacin in coronary heart disease.
JAMA, 231 (1975), pp. 360-381
[29.]
L.A. Carlson, G. Rosenhamer.
Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid.
Acta Med Scand, 223 (1988), pp. 405-418
[30.]
L. Cashin-Hemphill, W.J. Mack, J.M. Pogada, M.E. Sanmarco, S.P. Azen, D.H. Blankenhorn.
Beneficial effects of colestipol-niacin on coronary atherosclerosis: A 4-year follow-up.
JAMA, 264 (1990), pp. 3013-3037
[31.]
G. Brown, J.J. Albers, L.D. Fisher, S.M. Schaefer, J.T. Lin, C. Kaplan, et al.
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 (1990), pp. 1289-1298
[32.]
B.G. Brown, X.Q. Zhao, A. Chait, L.D. Fisher, M.C. Cheung, J.S. Morse, et al.
Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.
N Engl J Med, 345 (2001), pp. 1583-1592
[33.]
H. Yki-Jarvinen.
Thiazolidinediones.
N Engl J Med, 351 (2004), pp. 1106-1118
[34.]
J. Sakamoto, H. Kimura, S. Moriyama, H. Odaka, Y. Momose, Y. Sugiyama, et al.
Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone.
Biochem Biophys Res Commun, 278 (2000), pp. 704-711
[35.]
J.A. Dormandy, B. Charbonnel, D.J. Eckland, E. Erdmann, M. Massi-Benedetti, I.K. Moules, et al.
Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.
Lancet, 366 (2005), pp. 1279-1289
[36.]
H. Yki-Jarvinen.
The PROactive study: some answers, many questions.
Lancet, 366 (2005), pp. 1241-1242
[37.]
D. Cota, G. Marsicano, M. Tschop, Y. Grubler, C. Flachskamm, M. Schubert, et al.
The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis.
J Clin Invest, 112 (2003), pp. 423-431
[38.]
L.F. Van Gaal, A.M. Rissanen, A.J. Scheen, O. Ziegler, S. Rossner, RIOEurope Study Group.
Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study.
Lancet, 365 (2005), pp. 1389-1397
[39.]
J.P. Despres, A. Golay, L. Sjostrom, Rimonabant in Obesity-Lipids Study Group.
Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia.
N Engl J Med, 353 (2005), pp. 2121-2134
[40.]
M.A. Carai, G. Colombo, G.L. Gessa.
Rimonabant: the first therapeutically relevant cannabinoid antagonist.
Life Sci, 77 (2005), pp. 2339-2350
[41.]
O. Stein, Y. Stein.
Lipid transfer proteins (LTP) and atherosclerosis.
Atherosclerosis, 178 (2005), pp. 217-230
[42.]
J.D. Curb, R.D. Abbott, B.L. Rodríguez, K. Masaki, R. Chen, D.S. Sharp, et al.
A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly.
J Lipid Res, 45 (2004), pp. 948-953
[43.]
H.B. Brewer Jr.
Increasing HDL cholesterol levels.
N Engl J Med, 350 (2004), pp. 1491-1494
[44.]
P.J. Barter, H.B. Brewer Jr, M.J. Chapman, C.H. Hennekens, D.J. Rader, A.R. Tall.
Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis.
Arterioscler Thromb Vasc Biol, 23 (2003), pp. 160-167
[45.]
M.E. Brousseau, E.J. Schaefer, M.L. Wolfe, L.T. Bloedon, A.G. Digenio, R.W. Clark, et al.
Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol.
N Engl J Med, 350 (2004), pp. 1505-1515
[46.]
C.R. Sirtori, L. Calabresi, G. Franceschini, D. Baldassarre, M. Amato, J. Johansson, et al.
Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study.
Circulation, 103 (2001), pp. 1949-1954
[47.]
P.K. Shah, J. Yano, O. Reyes, K.Y. Chyu, S. Kaul, C.L. Bisgaier, et al.
High-dose recombinant apolipoprotein A-I(milano) mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein e-deficient mice. Potential implications for acute plaque stabilization.
Circulation, 103 (2001), pp. 3047-3050
[48.]
G. Chiesa, E. Monteggia, M. Marchesi, P. Lorenzon, M. Laucello, V. Lorusso, et al.
Recombinant apolipoprotein A-I (Milano) infusion into rabbit carotid artery rapidly removes lipid from fatty streaks.
Circ Res, 90 (2002), pp. 974-980
[49.]
S.E. Nissen, T. Tsunoda, E.M. Tuzcu, P. Schoenhagen, C.J. Cooper, M. Yasin, et al.
Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial.
JAMA, 290 (2003), pp. 2292-2300
[50.]
M. Navab, G.M. Anantharamaiah, S. Hama, D.W. Garber, M. Chaddha, G. Hough, et al.
Oral administration of an Apo A-I mimetic Peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol.
Circulation, 105 (2002), pp. 290-292
[51.]
P. Linsel-Nitschke, A.R. Tall.
HDL as a target in the treatment of atherosclerotic cardiovascular disease.
Nat Rev Drug Discov, 4 (2005), pp. 193-205
[52.]
S.B. Joseph, E. McKilligin, L. Pei, M.A. Watson, A.R. Collins, B.A. Laffitte, et al.
Synthetic LXR ligand inhibits the development of atherosclerosis in mice.
Proc Natl Acad Sci USA, 99 (2002), pp. 7604-7609
Copyright © 2006. Sociedad Española de Arteriosclerosis y Elsevier España S.L.