Korean Circ J.  2007 Dec;37(12):599-608. 10.4070/kcj.2007.37.12.599.

Safety and Efficacy of Peroxisome Proliferator-Activated Receptor-alpha Agonist for Treating Cardiovascular Disease

• Kang YR
• Kwak CH
• Hwang JY

• KMID: 2227034
• DOI: http://doi.org/10.4070/kcj.2007.37.12.599

Abstract

Peroxisome proliferator-activated receptor (PPAR)-alpha belongs to the nuclear family of ligand-activated transcriptional factors. The main role of PPAR-alpha is to activate the expression of the genes that are involved in fatty acid oxidation to achieve energy homeostasis. Fibrates are a known class of PPAR-alpha agonists, and they been used clinically for their effects of lowering triglycerides and elevating high-density lipoprotein-cholesterol (HDL-C). Further, recent experimental studies have demonstrated the anti-inflammatory and anti-atherosclerotic actions of PPAR-alpha agonists directly on the vascular wall. PPAR agonists are currently emerging as a promising therapeutic option to control systemic and vascular atherogenic factors. Regardless of their strong anti-atherosclerotic properties, large clinical studies have demonstrated inconsistent results for the cardioprotective effect of PPAR-alpha agonists; moreover, it has been observed that they did not decrease the total mortality, which stands in contrast to the statin trials. This review summarizes the current knowledge regarding the PPAR biology and the mechanisms of the effects of PPAR-alpha on lipid metabolism, the vessel wall and the cardiac metabolism. We also describe the results and lessons learned from the important clinical trials of PPAR-alpha agonists and we discuss these drugs' efficacy and safety.

Keyword

PPAR-alpha; Fibrates; Safety

MeSH Terms

Biology
Cardiovascular Diseases*
Fibric Acids
Homeostasis
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Lipid Metabolism
Metabolism
Mortality
Nuclear Family
Peroxisome Proliferator-Activated Receptors
Peroxisomes*
Triglycerides
Fibric Acids
Peroxisome Proliferator-Activated Receptors
Triglycerides

Figure

• 

  Fig. 1 A: schematic structure of PPAR. B: PPAR mechanism of transcriptional regulation by ligand binding transactivation. In response to PPAR ligand, a conformational change in the AF2 domain induces the release of the corepressor and this recruits the coactivator. PPAR binds with the Retinoid X receptor (RXR) to form a heterodimeric complex to regulate transcription. This complex interacts with the specific PPAR response element (PPRE) in the promotor region, which activates target gene transcription. PPAR activation also can repress the expression of target genes via unknown mechanism. AF: activation function, PPAR: peroxisome proliferators-activated receptor.

Reference

1. Libby P. Inflammation in atherosclerosis. Nature. 2002. 420:868–874.

2. Plutzky J. Medicine: PPARs as therapeutic targets: reverse cardiology? Science. 2003. 302:406–407.

3. Kho JS, Park SJ, Im SI, Choi BR, Kwak CH, Hwang JY. Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist improves endothelial function in diabetic patients with mMetabolic syndrome: pivotal role of NOx and inflammation. Korean Circ J. 2007. 37:221–229.

4. Libby P, Plutzky J. Inflammation in diabetes mellitus: role of peroxisome proliferator-activated receptor-alpha and peroxisome proliferator-activated receptor-gamma agonists. Am J Cardiol. 2007. 99:27B–40B.

5. Brown JD, Plutzky J. Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets. Circulation. 2007. 115:518–533.

6. Frick MH, Elo O, Haapa K, 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. 1987. 317:1237–1245.

7. The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation. 2000. 102:21–27.

8. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999. 341:410–418.

9. Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT). Arch Intern Med. 2002. 162:2597–2604.

10. Robins SJ, Rubins HB, Faas FH, et al. Insulin resistance and cardiovascular events with low HDL cholesterol. Diabetes Care. 2003. 26:1513–1517.

11. Keech A, Simes RJ, Barter P, 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. 2005. 366:1849–1861.

12. Nissen SE, Nicholls SJ, Wolski K, et al. Effects of a potent and selective PPAR-alpha agonist in patients with atherogenic dyslipidemia or hypercholesterolemia: two randomized controlled trials. JAMA. 2007. 297:1362–1373.

13. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990. 347:645–650.

14. Glass CK, Ogawa S. Combinatorial roles of nuclear receptors in inflammation and immunity. Nat Rev Immunol. 2006. 6:44–55.

15. Shulman AI, Mangelsdorf DJ. Retinoid X receptor heterodimers in the metabolic syndrome. N Engl J Med. 2005. 353:604–615.

16. Pascual G, Fong AL, Ogawa S, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005. 437:759–763.

17. Mizukami J, Taniguchi T. The antidiabetic agent thiazolidinedione stimulates the interaction between PPAR gamma and CBP. Biochem Biophys Res Commun. 1997. 240:61–64.

18. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998. 92:829–839.

19. Zhu Y, Kan L, Qi C, et al. Isolation and characterization of peroxisome proliferator-activated receptor (PPAR) interacting protein (PRIP) as a coactivator for PPAR. J Biol Chem. 2000. 275:13510–13516.

20. Jia Y, Guo GL, Surapureddi S, et al. Transcription coactivator peroxisome proliferator-activated receptor-binding protein/mediator 1 deficiency abrogates acetaminophen hepatotoxicity. Proc Natl Acad Sci U S A. 2005. 102:12531–12536.

21. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005. 294:2581–2586.

22. Auboeuf D, Rieusset J, Fajas L, et al. Tissue distribution and quantification of the expression of PPARs and LXR in humans: no alterations in adipose tissue of obese and NIDDM patients. Diabetes. 1997. 46:1319–1327.

23. Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR -α,-β and -γ in the adult rat. Endocrinology. 1996. 137:354–366.

24. Chinetti G, Griglio S, Antonucci M, et al. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem. 1998. 273:25573–25580.

25. Inoue I, Shino K, Noji S, Awata T, Katayama S. Expression of peroxisome proliferator-activated receptor alpha (PPAR alpha) in primary cultures of human vascular endothelial cells. Biochem Biophys Res Commun. 1998. 246:370–374.

26. Staels B, Koenig W, Habib A, et al. Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPAR gamma activators. Nature. 1998. 393:790–793.

27. Vosper H, Khoudoli GA, Graham TL, Palmer CN. Peroxisome proliferator-activated receptor agonists, hyperlipidaemia, and atherosclerosis. Pharmacol Ther. 2002. 95:47–62.

28. Haubenwallner S, Essenburg AD, Barnett BC, et al. Hypolipidemic activity of select fibrates correlates to changes in hepatic apolipoprotein C-III expression: a potential physiologic basis for their mode of action. J Lipid Res. 1995. 36:2541–2551.

29. Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, et al. PPAR-α and PPAR-γ activators direct a tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J. 1996. 15:5336–5348.

30. Duez H, Lefebvre B, Poulain P, et al. Regulation of human apoA-I by gemfibrozil and fenofibrate through selective peroxisome proliferator-activated receptor alpha modulation. Arterioscler Thromb Vasc Biol. 2005. 25:585–591.

31. Schultze AE, Alborn WE, Newton RK, Konrad RJ. Administration of a PPARalpha agonist increases serum apolipoprotein A-V levels and the apolipoprotein A-VI apolipoprotein C-III ratio. J Lipid Res. 2005. 46:1591–1595.

32. Havel RJ, Kane JP. Structure and metabolism of plasma lipoproteins. The Metabolic and Molecular Bases of Inherited Disease. 1995. 7th ed. New York: McGraw Hill;1841–1852.

33. Chawla A, Boisvert WA, Lee CH, et al. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 2001. 7:161–171.

34. Feher MD, Caslake M, Foxton J, Cox A, Packard CJ. Atherogenic lipoprotein phenotype in type 2 diabetes: reversal with micronised fenofibrate. Diabetes Metab Res Rev. 1999. 15:395–399.

35. 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.

36. Lee H, Shi W, Tontonoz P, et al. Role for peroxisome proliferator-activated receptor alpha in oxidized phospholipid-induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells. Circ Res. 2000. 87:516–521.

37. Marx N, Sukhova GK, Collins T, Libby P, Plutzky J. PPAR-α activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation. 1999. 99:3125–3131.

38. Jackson SM, Parhami F, Xi XP, et al. Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leukocyte-endothelial cell interaction. Arterioscler Thromb Vasc Biol. 1999. 19:2094–2104.

39. Xu X, Otsuki M, Saito H, et al. PPARalpha and GR differentially down-regulate the expression of nuclear factor-kappaB-responsive genes in vascular endothelial cells. Endocrinology. 2001. 142:3332–3339.

40. Delerive P, Martin-Nizard F, Chinetti G, et al. Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circ Res. 1999. 85:394–402.

41. Satoh H, Tsukamoto K, Hashimoto Y, et al. Thiazolidinediones suppress endothelin-1 secretion from bovine vascular endothelial cells: a new possible role of PPARgamma on vascular endothelial function. Biochem Biophys Res Commun. 1999. 254:757–763.

42. Staels B, Koenig W, Habib A, et al. Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPAR gamma activators. Nature. 1998. 393:790–793.

43. Delerive P, Gervois P, Fruchart JC, Staels B. Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J Biol Chem. 2000. 275:36703–36707.

44. Marx N, Mackman N, SchOnbeck U, et al. PPARalpha activators inhibit tissue factor expression and activity in human monocytes. Circulation. 2001. 103:213–219.

45. Neve BP, Corseaux D, Chinetti G, et al. PPARalpha agonists inhibit tissue factor expression in human monocytes and macrophages. Circulation. 2001. 103:207–212.

46. Frost RJ, Otto C, Geiss HC, Schwandt P, Parhofer KG. Effects of atorvastatin versus fenofibrate on lipoprotein profiles, low-density lipoprotein subfraction distribution, and hemorheologic parameters in type 2 diabetes mellitus with mixed hyperlipoproteinemia. Am J Cardiol. 2001. 87:44–48.

47. Despres JP, Lemieux I, Pascot A, et al. Gemfibrozil reduces plasma C-reactive protein levels in abdominally obese men with the atherogenic dyslipidemia of the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2003. 23:702–703.

48. Gervois P, Kleemann R, Pilon A, et al. Global suppression of IL-6-induced acute phase response gene expression after chronic in vivo treatment with the peroxisome proliferator-activated receptor-alpha activator fenofibrate. J Biol Chem. 2004. 279:16154–16160.

49. Okopien B, Krysiak R, Kowalski J, et al. The effect of statins and fibrates on interferon-γ and interleukin-2 release in patients with primary type II dyslipidemia. Atherosclerosis. 2004. 176:327–335.

50. Sebestjen M, Keber I, Zegura B, et al. Statin and fibrate treatment of combined hyperlipidemia: the effects on some novel risk factors. Thromb haemost. 2004. 92:1129–1135.

51. Okopien B, Krysiak R, Kowalski J, et al. Monocyte release of tumor necrosis factor-α and interleukin-1β in primary type IIa and IIb dyslipidemic patients treated with statins or fibrates. J Cardiovasc Pharmacol. 2005. 46:377–386.

52. Sack MN, Rader TA, Park S, Bastin J, McCune SA, Kelly DP. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation. 1996. 94:2837–2842.

53. Barger PM, Brandt JM, Leone TC, Weinheimer CJ, Kelly DP. Deactivation of peroxisome proliferator-activated receptor-during cardiac hypertrophic growth. J Clin Invest. 2000. 105:1723–1730.

54. Young ME, Laws FA, Goodwin GW, Taegtmeyer H. Reactivation of peroxisome proliferator-activated receptor alpha is associated with contractile dysfunction in hypertrophied rat heart. J Biol Chem. 2001. 276:44390–44395.

55. Stanley WC, Lopaschuk GD, McCormack JG. Regulation of energy substrate metabolism in the diabetic heart. Cardiovasc Res. 1997. 34:25–33.

56. Aasum E, Belke DD, Severson DL, et al. Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-α activator. Am J Physiol Heart Circ Physiol. 2002. 283:H949–H957.

57. Lopaschuk GD. Optimizing cardiac energy metabolism: how can fatty acid and carbohydrate metabolism be manipulated? Coron Artery Dis. 2001. 12:Suppl 1. S8–S11.

58. Tabernero A, Schoonjans K, Jesel L, Carpusca I, Auwerx J, Andriantsitohaina R. Activation of the peroxisome proliferator-activated receptor alpha protects against myocardial ischaemic injury and improves endothelial vasodilatation. BMC Pharmacol. 2002. 2:10.

59. Wayman NS, Hattori Y, McDonald MC, et al. Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. FASEB J. 2002. 16:1027–1040.

60. Committee of Principal Investigators. A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Br Heart J. 1978. 40:1069–1118.

61. Committee of Principal Investigators. WHO cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Lancet. 1984. 2:600–604.

62. Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA. 1975. 231:360–381.

63. Meade T, Zuhrie R, Cook C, Cooper J. Bezafibrate in men with lower extremity arterial disease: randomised controlled trial. BMJ. 2002. 325:1139.

64. Tenkanen L, Manttari M, Manninen V. Some coronary risk factors related to the insulin resistance syndromes and treatment with gemfibrozil. Circulation. 1995. 92:1779–1785.

65. Frick MH, Heinonen OP, Huttunen JK, Koskinen P, Manttari M, Manninen V. Efficacy of gemfibrozil in dyslipidemic subjects with suspected heart disease. Ann Med. 1993. 25:41–45.

66. Frick MH, Syvanne M, Nieminen MS, et al. 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. Circulation. 1997. 96:2137–2143.

67. Diabetes Atherosclerosis Intervention 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.

68. 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.

69. Westphal S, Dierkes J, Luley C. Effects of fenofibrate and gemfibrozil on plasma homocysteine. Lancet. 2001. 358:39–40.

70. Elisaf M. Effects of fibrates on serum metabolic parameters. Curr Med Res Opin. 2002. 18:269–276.

71. Barter PJ, Rye KA. Cardioprotective properties of fibrates: which fibrate, which patients, what mechanism? Circulation. 2006. 113:1553–1555.

72. Colhoun H. After FIELD: should fibrates be used to prevent cardiovascular disease in diabetes? Lancet. 2005. 366:1829–1831.

73. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate+statin versus gemfibrozil+any statin. Am J Cardiol. 2005. 95:120–122.

74. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007. 356:2457–2471.

75. Rubenstrunk A, Hanf R, Hum DW, Fruchart JC, Staels B. Safety issues and prospects for future generations of PPAR modulators. Biochim Biophys Acta. 2007. 1771:1065–1081.

76. Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with fibrate therapy. Am J Cardiol. 2007. 99:3C–18C.

77. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drug. JAMA. 2004. 292:2585–2590.

78. Levak-Frank S, Radner H, Walsh A, et al. Muscle-specific overexpression of lipoprotein lipase causes a severe myopathy characterized by proliferation of mitochondria and peroxisomes in transgenic mice. J Clin Invest. 1995. 96:976–986.

79. Motojima K. A metabolic switching hypothesis for the first step in the hypolipidemic effects of fibrates. Biol Pharm Bull. 2002. 25:1509–1511.

80. Motojima K, Seto K. Fibrates and statins rapidly and synergistically induce pyruvate dehydrogenase kinase 4 mRNA in the liver and muscles of mice. Biol Pharm Bull. 2003. 26:954–958.

81. Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with fibrates. Am J Cardiol. 2004. 94:935–938.

82. Decaudin B, Beraud G, Lannoy D, et al. Fibrate-induced increase in serum creatinine levels: two cases. Therapie. 2005. 60:601–602.

83. Lipkin GW, Tomson CR. Severe reversible renal failure with bezafibrate. Lancet. 1993. 341:371.

84. Broeders N, Knoop C, Antoine M, Tielemans C, Abramowicz D. Fibrate-induced increase in blood urea and creatinine: is gemfibrozil the only innocuous agent? Nephrol Dial Transplant. 2000. 15:1993–1999.

85. Ritter JL, Nabulsi S. Fenofibrate-induced elevation in serum creatinine. Pharmacotherapy. 2001. 21:1145–1149.

86. Ledwith BJ, Pauley CJ, Wagner LK, Rokos CL, Alberts DW, Manam S. Induction of cyclooxygenase-2 expression by peroxisome proliferators and non-tetradecanoylphorbol 12, 13-myristate-type tumor promoters in immortalized mouse liver cells. J Biol Chem. 1997. 272:3707–3714.

87. Devuyst O, Goffin E, Pirson Y, van Ypersele de Strihou C. Creatinine rise after fibrate therapy in renal graft recipients. Lancet. 1993. 341:840.

88. Goldstein BJ, Rosenstock J, Anzalone D, Tou C, Ohman KP. Effect of tesaglitazar, a dual PPAR alpha/gamma agonist, on glucose and lipid abnormalities in patients with type 2 diabetes: a 12-week dose-ranging trial. Curr Med Res Opin. 2006. 22:2575–2590.

89. Hottelart C, el Esper N, Achard JM, Pruna A, Fournier A. Fenofibrate increases blood creatinine, but does not change the glomerular filtration rate in patients with mild renal insufficiency. Nephrologie. 1999. 20:41–44.

90. Dierkes J, Westphal S, Luley C. Serum homocysteine increases after therapy with fenofibrate or bezafibrate. Lancet. 1999. 354:219–220.

91. Westphal S, Dierkes J, Luley C. Effects of fenofibrate and gemfibrozil on plasma homocystein. Lancet. 2001. 358:39–40.

92. de Lorgeril M, Salen P, Paillard F, Lacan P, Richard G. Lipid-lowering drugs and homocysteine. Lancet. 1999. 353:209–210.

93. Harats D, Yodfat O, Doolman R, et al. Homocysteine elevation with fibrates: is it a class effect? Isr Med Assoc J. 2001. 3:243–246.

94. Franken DG, Boers GH, Blom HJ, Trijbels FJ, Kloppenborg PW. Treatment of mild hyperhomocysteinemia in vascular disease patients. Arterioscler Thromb. 1994. 14:465–470.

95. Post SM, Duez H, Gervois PP, Staels B, Kuipers F, Princen HM. Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase expression. Arterioscler Thromb Vasc Biol. 2001. 21:1840–1845.