Antiatherogenic Properties of Fibrates
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动脉硬化血栓血管生物学 2005年第6期
From The Heart Research Institute, Sydney, Australia.
Correspondence to Prof Philip Barter, The Heart Research Institute, 145 Missenden Road, Camperdown, NSW 2050, Australia. Email p.barter@hri.org.au
Key Words: fibrates ? HDL ? ABCA1 ? LXR ? macrophages
In an era dominated by the use of statins as agents to reduce cardiovascular risk, fibrates have been largely forgotten. This is despite a remarkably robust evidence base certifying to the cardioprotective effects of these agents. In the Helsinki Heart Study (HHS), a 5-year, double-blind, placebo-controlled trial of the effects of gemfibrozil in 4081 men aged 40 to 55 years who were free of clinically manifest CHD at entry to the study, there was a statistically significant 34% reduction in the incidence of total coronary events from 41.4 per 1000 in the placebo group to 27.3 per 1000 in the gemfibrozil group.1 In the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), a 5-year, double-blind, placebo-controlled trial with gemfibrozil in 2531 men with clinical CHD and low levels of both high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, the primary end point (nonfatal myocardial infarction or death attributable to CHD) was reduced significantly by 22% from 21.7% in the placebo group to 17.3% in the gemfibrozil group.2 Positive results have also been obtained in angiographic studies with gemfibrozil in the Lopid Coronary Angiography Trial,3 with bezafibrate in the Bezafibrate Coronary Atherosclerosis Intervention Trial4 and with fenofibrate in the Diabetes Atherosclerosis Intervention Study.5
See page 1193
The cardiovascular benefits of treatment with fibrates appear to be greatest in people with insulin resistance and other features of the metabolic syndrome. In the HHS, a baseline level of serum triglyceride >200 mg/dL or a HDL cholesterol <40 mg/dL or a BMI >26 identified patients in whom treatment with gemfibrozil produced a reduction in CHD events that was substantially greater than in the study population as a whole.6 The presence of any one of these factors predicted a 40% to 50% reduction in CHD events. The presence of all three factors at baseline identified a group in which there was a massive 78% (statistically significant) reduction in CHD events during treatment with gemfibrozil. Comparable conclusions were drawn from subgroup analyses of the VA-HIT study in which an elevated plasma triglyceride at baseline or the presence of insulin resistance (with or without diabetes) were highly predictive of a greater CHD reduction in the group treated with gemfibrozil.7 Even in the reportedly negative Bezafibrate Infarction Prevention (BIP) study, a 5-year, double-blind, placebo-controlled trial with bezafibrate, in 3090 subjects with CHD, there was a significant 40% reduction in the combined incidence of nonfatal MI or death from CHD in the subgroup of subjects who entered the trial with elevated levels of plasma triglyceride.8 These subgroup analyses of the HHS, VA-HIT, and BIP suggest that features of the metabolic syndrome (elevated plasma triglyceride, low HDL cholesterol, increased BMI, insulin resistance) identify people in whom fibrates are especially effective in reducing CHD risk.
There are several potential mechanisms by which fibrates reduce cardiovascular risk. For example, fibrates increase the concentration of the protective HDL fraction. They also reduce the concentration of atherogenic chylomicron and very low density lipoprotein (VLDL) remnants. All of these changes have the potential to reduce CHD risk. However, it is of interest to note that the benefits in VA-HIT were substantially greater than predicted by the changes in plasma lipid levels,8 suggesting that fibrates have protective effects beyond those related to their ability to change the concentration of plasma lipids. One possible additional mechanism is a direct antiinflammatory effect in the artery wall. Another is an ability to enhance reverse cholesterol transport beyond that predicted by the observed increase in HDL concentration.
Fibrates function as activators of PPAR-, a transcription factor that has the potential to raise HDL concentration and reduce that of plasma triglyceride by several mechanisms.9 PPAR- activists increase expression of the genes for apolipoprotein (apo) A-I and apoA-II, the 2 main apolipoproteins of HDL. They also increase expression of the LPL gene that leads to both a decrease in plasma triglyceride and an increase in the concentration of HDL. In addition, as demonstrated in the study reported by Arakawa et al in the current issue of this journal,10 PPAR- activists also induce expression of the gene encoding ABCA1, an ATP-binding cassette transporter that promotes the efflux of cholesterol from cells to apoA-I in the extracellular space.
An increased expression of ABCA1 in transgenic animals is accompanied by a small increase in the concentration of HDL cholesterol, an enhanced efflux of cholesterol from macrophages, and a marked reduction in atherosclerosis.11 Furthermore, selective inactivation of ABCA1 in macrophages is associated with markedly increased atherosclerosis and foam cell accumulation in apoE knock-out mice.12 Thus, an enhancement in the ABCA1-mediated efflux of cholesterol from macrophages within the artery wall may be regarded as an antiatherogenic process.
Arakawa et al10 report that ABCA1 expression is increased in several cell types (including macrophages) in response to treatment with fenofibric acid, the active form of fenofibrate, in a process dependent on activation of the LXR pathway. The experimental PPAR- activator, Wy14643, has previously been shown also to upregulate the ABCA1 gene in a process apparently related to activation of the LXR pathway.13 The study by Arakawa et al10 represents the first evidence that such upregulation of the ABCA1 gene is promoted by fibric acids derived from clinically used fibrates. The recent negative observation in mice that fibrates promote regression of atherosclerosis without enhancing ABCA1 expression14 may reflect no more than the fact that some effects of PPAR- activation in rodents are not replicated in other species.15
So, given the robust human clinical trial evidence that fibrates are atheroprotective, combined with a growing understanding of the mechanism by which these agents protect, the question arises: why are fibrates not more widely used to reduce cardiovascular risk in clinical practice? Perhaps the answer lies in a belief that the potential atheroprotective properties of fibrates and statins relate only to their effects on plasma lipids. Such a belief leads to the commonly posed question: should at-risk people be treated with a statin or a fibrate to correct their dyslipidemia and reduce their coronary risk?
However, on the basis of emerging evidence, this is almost certainly not the right question to ask. To ask whether someone should be given a statin or a fibrate to reduce cardiovascular risk has no more relevance than asking whether the patient should receive a statin or an ACE-inhibitor or aspirin. There is no argument that the mode of action of statins, ACE-inhibitors, and aspirin and their likely cardioprotective mechanisms are distinct and that, if indicated, all three agents should be used. The reality is that the mode of action and the cardioprotective properties of fibrates and statins appear also to be distinct and that it is not appropriate to ask which of the two agents should be used. Rather, if each class of drug is indicated, then both should be used: statins to reduce risk by lowering LDL cholesterol and inhibiting inflammation, and fibrates to reduce risk in people with diabetes or insulin resistance by increasing HDL cholesterol concentration, reducing levels of potentially atherogenic chylomicron and VLDL remnants and by increasing the expression of ABCA1 to enhance the efflux of cholesterol from macrophages in the artery wall. The circumstantial evidence is strong that treatment of people with diabetes or with insulin resistance with the combination of a statin and a fibrate has the potential to reduce risk much more than can be achieved by treatment with either class of drug when given as monotherapy. The results of a trial testing this hypothesis are awaited with great interest.
References
Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V. Helsinki Heart Study Primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med. 1987; 317: 1237–1245.
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: 410–418.
Frick MH, Syvanne M, Nieminen MS, Kauma H, Majahalme S, Virtanen V, Kesaniemi YA, Pasternack A, Taskinen MR. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Lopid Coronary Angiography Trial (LOCAT) Study Group. Circulation. 1997; 96: 2137–2143.
Ericsson CG, Hamsten A, Nilsson J, Grip L, Svane B, de Faire U. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet. 1996; 347: 849–853.
DAIS Investigators. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet. 2001; 357: 905–910.
Tenkanen L, Manttari M, Manninen V. Some coronary risk factors related to the insulin resistance syndrome and treatment with gemfibrozil. Experience from the Helsinki Heart Study. Circulation. 1995; 92: 1779–1785.
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: 1585–1591.
Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation. 2000; 102: 21–27.
Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998; 98: 2088–2093.
Arakawa R, Tamehiro N, Nishimaki-Mogami T, Ueda K, Yokoyama S. Fenofibric acid, an active form of fenofibrate, increases apoAI–mediated HDL biogenesis by enhancing transcription of ABCA1 gene in an LXR-dependent manner. hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2005; 25: 1193–1197.
Singaraja RR, Fievet C, Castro G, James ER, Hennuyer N, Clee SM, Bissada N, Choy JC, Fruchart JC, McManus BM, Staels B, Hayden MR. ABCA1 activity protects against atherosclerosis. J Clin Invest. 2002; 110: 35–42.
Aiello RJ, Brees D, Bourassa PA, Royer L, Lindsey S, Coskran T, Haghpassand M, Francone OL. Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages. Arterioscler Thromb Vasc Biol. 2002; 22: 630–637.
Chinetti G, Lestavel S, Bocher V, Remaley AT, Neve B, Torra IP, Teissier E, Minnich A, Jaye M, Duverger N, Brewer BH, Fruchart JC, Clavey V, Staels B. PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med. 2001; 7: 53–58.
Li AC, Binder CJ, Gutierrez A, Brown KK, Plotkin CR, Pattison JW, Valledor AF, Davis RA, Willson TM, Witztum JL, Palinski W, Glass CK. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPAR-, ?/, and . J Clin Invest. 2004; 114: 1564–1576.
Berthou L, Duverger N, Emmanuel F, Langouet S, Auwerx J, Guillouzo A, Fruchart JC, Rubin E, Denefle P, Staels B, Branellec D. Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice. J Clin Invest. 1996; 97: 2408–2416.(P.J. Barter)
Correspondence to Prof Philip Barter, The Heart Research Institute, 145 Missenden Road, Camperdown, NSW 2050, Australia. Email p.barter@hri.org.au
Key Words: fibrates ? HDL ? ABCA1 ? LXR ? macrophages
In an era dominated by the use of statins as agents to reduce cardiovascular risk, fibrates have been largely forgotten. This is despite a remarkably robust evidence base certifying to the cardioprotective effects of these agents. In the Helsinki Heart Study (HHS), a 5-year, double-blind, placebo-controlled trial of the effects of gemfibrozil in 4081 men aged 40 to 55 years who were free of clinically manifest CHD at entry to the study, there was a statistically significant 34% reduction in the incidence of total coronary events from 41.4 per 1000 in the placebo group to 27.3 per 1000 in the gemfibrozil group.1 In the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), a 5-year, double-blind, placebo-controlled trial with gemfibrozil in 2531 men with clinical CHD and low levels of both high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, the primary end point (nonfatal myocardial infarction or death attributable to CHD) was reduced significantly by 22% from 21.7% in the placebo group to 17.3% in the gemfibrozil group.2 Positive results have also been obtained in angiographic studies with gemfibrozil in the Lopid Coronary Angiography Trial,3 with bezafibrate in the Bezafibrate Coronary Atherosclerosis Intervention Trial4 and with fenofibrate in the Diabetes Atherosclerosis Intervention Study.5
See page 1193
The cardiovascular benefits of treatment with fibrates appear to be greatest in people with insulin resistance and other features of the metabolic syndrome. In the HHS, a baseline level of serum triglyceride >200 mg/dL or a HDL cholesterol <40 mg/dL or a BMI >26 identified patients in whom treatment with gemfibrozil produced a reduction in CHD events that was substantially greater than in the study population as a whole.6 The presence of any one of these factors predicted a 40% to 50% reduction in CHD events. The presence of all three factors at baseline identified a group in which there was a massive 78% (statistically significant) reduction in CHD events during treatment with gemfibrozil. Comparable conclusions were drawn from subgroup analyses of the VA-HIT study in which an elevated plasma triglyceride at baseline or the presence of insulin resistance (with or without diabetes) were highly predictive of a greater CHD reduction in the group treated with gemfibrozil.7 Even in the reportedly negative Bezafibrate Infarction Prevention (BIP) study, a 5-year, double-blind, placebo-controlled trial with bezafibrate, in 3090 subjects with CHD, there was a significant 40% reduction in the combined incidence of nonfatal MI or death from CHD in the subgroup of subjects who entered the trial with elevated levels of plasma triglyceride.8 These subgroup analyses of the HHS, VA-HIT, and BIP suggest that features of the metabolic syndrome (elevated plasma triglyceride, low HDL cholesterol, increased BMI, insulin resistance) identify people in whom fibrates are especially effective in reducing CHD risk.
There are several potential mechanisms by which fibrates reduce cardiovascular risk. For example, fibrates increase the concentration of the protective HDL fraction. They also reduce the concentration of atherogenic chylomicron and very low density lipoprotein (VLDL) remnants. All of these changes have the potential to reduce CHD risk. However, it is of interest to note that the benefits in VA-HIT were substantially greater than predicted by the changes in plasma lipid levels,8 suggesting that fibrates have protective effects beyond those related to their ability to change the concentration of plasma lipids. One possible additional mechanism is a direct antiinflammatory effect in the artery wall. Another is an ability to enhance reverse cholesterol transport beyond that predicted by the observed increase in HDL concentration.
Fibrates function as activators of PPAR-, a transcription factor that has the potential to raise HDL concentration and reduce that of plasma triglyceride by several mechanisms.9 PPAR- activists increase expression of the genes for apolipoprotein (apo) A-I and apoA-II, the 2 main apolipoproteins of HDL. They also increase expression of the LPL gene that leads to both a decrease in plasma triglyceride and an increase in the concentration of HDL. In addition, as demonstrated in the study reported by Arakawa et al in the current issue of this journal,10 PPAR- activists also induce expression of the gene encoding ABCA1, an ATP-binding cassette transporter that promotes the efflux of cholesterol from cells to apoA-I in the extracellular space.
An increased expression of ABCA1 in transgenic animals is accompanied by a small increase in the concentration of HDL cholesterol, an enhanced efflux of cholesterol from macrophages, and a marked reduction in atherosclerosis.11 Furthermore, selective inactivation of ABCA1 in macrophages is associated with markedly increased atherosclerosis and foam cell accumulation in apoE knock-out mice.12 Thus, an enhancement in the ABCA1-mediated efflux of cholesterol from macrophages within the artery wall may be regarded as an antiatherogenic process.
Arakawa et al10 report that ABCA1 expression is increased in several cell types (including macrophages) in response to treatment with fenofibric acid, the active form of fenofibrate, in a process dependent on activation of the LXR pathway. The experimental PPAR- activator, Wy14643, has previously been shown also to upregulate the ABCA1 gene in a process apparently related to activation of the LXR pathway.13 The study by Arakawa et al10 represents the first evidence that such upregulation of the ABCA1 gene is promoted by fibric acids derived from clinically used fibrates. The recent negative observation in mice that fibrates promote regression of atherosclerosis without enhancing ABCA1 expression14 may reflect no more than the fact that some effects of PPAR- activation in rodents are not replicated in other species.15
So, given the robust human clinical trial evidence that fibrates are atheroprotective, combined with a growing understanding of the mechanism by which these agents protect, the question arises: why are fibrates not more widely used to reduce cardiovascular risk in clinical practice? Perhaps the answer lies in a belief that the potential atheroprotective properties of fibrates and statins relate only to their effects on plasma lipids. Such a belief leads to the commonly posed question: should at-risk people be treated with a statin or a fibrate to correct their dyslipidemia and reduce their coronary risk?
However, on the basis of emerging evidence, this is almost certainly not the right question to ask. To ask whether someone should be given a statin or a fibrate to reduce cardiovascular risk has no more relevance than asking whether the patient should receive a statin or an ACE-inhibitor or aspirin. There is no argument that the mode of action of statins, ACE-inhibitors, and aspirin and their likely cardioprotective mechanisms are distinct and that, if indicated, all three agents should be used. The reality is that the mode of action and the cardioprotective properties of fibrates and statins appear also to be distinct and that it is not appropriate to ask which of the two agents should be used. Rather, if each class of drug is indicated, then both should be used: statins to reduce risk by lowering LDL cholesterol and inhibiting inflammation, and fibrates to reduce risk in people with diabetes or insulin resistance by increasing HDL cholesterol concentration, reducing levels of potentially atherogenic chylomicron and VLDL remnants and by increasing the expression of ABCA1 to enhance the efflux of cholesterol from macrophages in the artery wall. The circumstantial evidence is strong that treatment of people with diabetes or with insulin resistance with the combination of a statin and a fibrate has the potential to reduce risk much more than can be achieved by treatment with either class of drug when given as monotherapy. The results of a trial testing this hypothesis are awaited with great interest.
References
Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V. Helsinki Heart Study Primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med. 1987; 317: 1237–1245.
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: 410–418.
Frick MH, Syvanne M, Nieminen MS, Kauma H, Majahalme S, Virtanen V, Kesaniemi YA, Pasternack A, Taskinen MR. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Lopid Coronary Angiography Trial (LOCAT) Study Group. Circulation. 1997; 96: 2137–2143.
Ericsson CG, Hamsten A, Nilsson J, Grip L, Svane B, de Faire U. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet. 1996; 347: 849–853.
DAIS Investigators. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet. 2001; 357: 905–910.
Tenkanen L, Manttari M, Manninen V. Some coronary risk factors related to the insulin resistance syndrome and treatment with gemfibrozil. Experience from the Helsinki Heart Study. Circulation. 1995; 92: 1779–1785.
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: 1585–1591.
Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation. 2000; 102: 21–27.
Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998; 98: 2088–2093.
Arakawa R, Tamehiro N, Nishimaki-Mogami T, Ueda K, Yokoyama S. Fenofibric acid, an active form of fenofibrate, increases apoAI–mediated HDL biogenesis by enhancing transcription of ABCA1 gene in an LXR-dependent manner. hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2005; 25: 1193–1197.
Singaraja RR, Fievet C, Castro G, James ER, Hennuyer N, Clee SM, Bissada N, Choy JC, Fruchart JC, McManus BM, Staels B, Hayden MR. ABCA1 activity protects against atherosclerosis. J Clin Invest. 2002; 110: 35–42.
Aiello RJ, Brees D, Bourassa PA, Royer L, Lindsey S, Coskran T, Haghpassand M, Francone OL. Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages. Arterioscler Thromb Vasc Biol. 2002; 22: 630–637.
Chinetti G, Lestavel S, Bocher V, Remaley AT, Neve B, Torra IP, Teissier E, Minnich A, Jaye M, Duverger N, Brewer BH, Fruchart JC, Clavey V, Staels B. PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med. 2001; 7: 53–58.
Li AC, Binder CJ, Gutierrez A, Brown KK, Plotkin CR, Pattison JW, Valledor AF, Davis RA, Willson TM, Witztum JL, Palinski W, Glass CK. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPAR-, ?/, and . J Clin Invest. 2004; 114: 1564–1576.
Berthou L, Duverger N, Emmanuel F, Langouet S, Auwerx J, Guillouzo A, Fruchart JC, Rubin E, Denefle P, Staels B, Branellec D. Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice. J Clin Invest. 1996; 97: 2408–2416.(P.J. Barter)