Update on the clinical utility of fenofibrate in mixed dyslipidemias: Mechanisms of action and rational prescribing

Vascular Health and Risk Management

Volumn 4, Issue 5, 2008, Pages 991-1000

  Farnier, Michel ^a  

^a Point Medical   (France)

Author keywords

Fenofibrate; HDL cholesterol; LDL cholesterol; Mixed dyslipidemia; Triglycerides

Indexed keywords

BILE ACID SEQUESTRANT; CERIVASTATIN; COLESEVELAM; COUMARIN; CYCLOSPORIN; EZETIMIBE; FENOFIBRATE; GEMFIBROZIL; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PLACEBO; SIMVASTATIN;

ANTIINFLAMMATORY ACTIVITY; AREA UNDER THE CURVE; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CHOLESTEROL BLOOD LEVEL; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; CREATINE KINASE BLOOD LEVEL; CREATININE BLOOD LEVEL; DEEP VEIN THROMBOSIS; DIABETIC PATIENT; DOSE RESPONSE; DRUG CONTRAINDICATION; DRUG EFFICACY; DRUG INDICATION; DRUG MECHANISM; DRUG POTENCY; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSLIPIDEMIA; GASTROINTESTINAL SYMPTOM; HUMAN; INSULIN RESISTANCE; LIPID METABOLISM; LIVER FUNCTION TEST; LUNG EMBOLISM; MONOTHERAPY; MUSCULOSKELETAL DISEASE; MYOPATHY; PANCREATITIS; PLEIOTROPY; PRESCRIPTION; REVIEW; RHABDOMYOLYSIS; SECONDARY PREVENTION; SIDE EFFECT; SKIN MANIFESTATION;

ANTILIPEMIC AGENTS; CARDIOVASCULAR DISEASES; DRUG THERAPY, COMBINATION; DYSLIPIDEMIAS; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; PATIENT SELECTION; PRACTICE GUIDELINES AS TOPIC; PROCETOFEN; RISK ASSESSMENT; TREATMENT OUTCOME;

EID: 56849101891     PISSN: 11766344     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (96)

1. Adkins JC, Faulds D. 1997. Micronised fenofibrate. A review of its pharmacodynamic properties and clinical efficacy in the management of dyslipidaemia. Drugs, 54:615-33.
2. Alsheikh-Ali AA, Kuvin JT, Karas RH. 2004. Risk of adverse events with fibrates. Am J Cardiol, 94:935-8.
3. Ansquer JC, Foucher C, Rattier S, et al. 2005. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis, 45:485-93.
4. Athyros VG, Papageorgiou AA, Athyrou VV, et al. 2002. Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia. Diabetes Care, 25:1198-202.
5. Bansal S, Buring JE, Rifai N, et al. 2007. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA, 298:309-16.
6. Barter P, Gotto AM, La Rosa JC, et al. 2007. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med, 357:1301-10.
7. Barter PJ, Rye KA. 2008. Is there a role for fibrates in the management of dyslipidemia in the metabolic syndrome? Arterioscler Thromb Vasc Biol, 28:39-46.
8. Bergman AJ, Murphy G, Burke J, et al. 2004. Simvastatin does not have a clinically significant pharmacokinetic interaction with fenofibrate in humans. J Clin Pharmacol, 44:1054-62.
9. Best JD, O'Neal DN. 2000. Diabetic dyslipidemia. Current treatment recommendations. Drugs, 59:1101-11.
10. Birjmohun RS, Hutten BA, Kastelein JJP, et al. 2005. Efficacy and safety of high-density lipoprotein cholesterol-increasing coumpounds: a meta-analysis of randomized controlled trials. J Am Coll Cardiol, 45:185-97.
11. Burgess D, Hunt D, Li L, et al. 2007. on behalf of the FIELD Investigators. Effects of fenofibrate on silent myocardial infarction, hospitalization for acute coronary syndromes and amputation in type 2 diabetes: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Circulation, 116(Suppl II):838.
12. Buse JB, Ginsberg HN, Bakris GL, et al. 2007. for the American Heart Association and the American Diabetes Association. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation, 115:114-26.
13. Cannon CP, Steinberg BA, Murphy SA, et al. 2006. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol, 48:438-45.
14. Capell WH, De Souza CA, Poirier P, et al. 2003. Short-term triglyceride lowering with fenofibrate improves vasodilator function in subjects with hypertriglyceridemia. Arterioscler Thromb Vasc Biol, 23:307-13.
15. Chang JT, Staffa JA, Parks M, et al. 2004. Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy. Pharmacoepidemiol Drug Safety, 13:417-26.
16. Chapman MJ. 2006. Fibrates: therapeutic review. Br J Diabetes Vasc Dis, 6:11-8.
17. Chinetti G, Lestavel S, Bocher V, et al. 2001. PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med, 7:53-8.
18. Cholesterol Treatment Trialist's (CTT) Collaborators. 2005. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90056 participants in 14 randomised trials of statins. Lancet, 366:1267-78.
19. Corsini A, Bellosta S, Davidson MH. 2005. Pharmacokinetic interactions between statins and fibrates. Am J Cardiol, 96(Suppl):44K-49K.
20. Cui Y, Blumenthal RS, Flaws JA, et al. 2001. Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality. Arch Intern Med, 161:1413-9.
21. Davidson MH, Armani A, McKenney JM, et al. 2007. Safety considerations with fibrate therapy. Am J Cardiol, 99:3C-18C.
22. [DAIS] Diabetes Atherosclerosis Intervention Study Investigators. 2001. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study. Lancet, 357:905-10.
23. Dierkes J, Westphal S, Luley C. 2003. Fenofibrate-induced hyperhomocysteinaemia. Clinical implications and management. Drug Safety, 26:81-91.
24. Durrington, P. 2003. Dyslipidaemia. Lancet, 362:717-31.
25. Durrington PN, Tuomiletho J, Hamann A, et al. 2004. Rosuvastatin and fenofibrate alone and in combination in type 2 diabetes patients with combined hyperlipidaemia. Diab Res Clin Pract, 64:137-51.
26. Ellen RLB, McPherson R. 1998. Long-term efficacy and safety of fenofibrate and a statin in the treatment of combined hyperlipidemia. Am J Cardiol, 81(4A):60B-65B.
27. European guidelines on cardiovascular disease prevention in clinical practice: full text. 2007. Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice. Eur J Cardiovasc Prev Rehabil, 14(Suppl 2): S1-S113.
28. Farnier M. 2003. Combination therapy with an HMG-CoA reductase inhibitor and a fibric acid derivative. A critical review of potential benefits and drawbacks. Am J Cardiovasc Drugs, 3:169-78.
29. Farnier M. 2007. Ezetimibe plus fenofibrate: a new combination therapy for the management of mixed hyperlipidaemia? Expert Opin Pharmacother, 8:1345-52.
30. Farnier M, Dejager S; and the French Fluvastatin Study Group. 2000. Effect of combined fluvastatin-fenofibrate therapy compared with fenofibrate monotherapy in severe primary hypercholesterolemia. Am J Cardiol, 85:53-7.
31. Farnier M, Freeman MW, Macdonnel G, et al. 2005. Efficacy and safety of the coadministration of ezetimibe with fenofibrate in patients with mixed hyperlipidaemia. Eur Heart J, 26:897-905.
32. Farnier M, Roth E, Gil-Extremera B, et al; for the Ezetimibe/Simvastatin + Fenofibrate Study Group. 2007. Efficacy and safety of the coadministration of ezetimibe/simvastatin with fenofibrate in patients with mixed hyperlipidemia. Am Heart J, 153:335e1-335e8.
33. Fazio S, Linton McRF. 2004. The role of fibrates in managing hyperlipidemia: mechanisms of action and clinical efficacy. Curr Atheroscl Rep, 6:148-57.
34. Frick MH, Elo O, Haapa K, et al. 1987. 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, 317:1237-45.
35. Fruchart JC, Duriez P. 2006. Mode of action of fibrates in the regulation of triglycerides and HDL-cholesterol metabolism. Drugs Today, 42:39-64.
36. Fruchart JC, Staels B, Duriez P. 2001. The role of fibric acids in atherosclerosis. Curr Atheroscl Rep, 3:83-92.
37. Genest J, Frohlich J, Steiner G. 2004. Effect of fenofibrate-mediated increase in plasma homocysteine on the progression of coronary artery disease in type 2 diabetes mellitus. Am J Cardiol, 93:848-53.
38. Ginsberg HN, Bonds DE, Lovato LC, et al. 2007. Evolution of the lipid trial protocol of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol, 99(Suppl):56i-67i.
39. Gordon T, Castelli WP, Hjortland MC, et al. 1977. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med, 62:707-14.
40. Gordon DJ, Probstfield JL, Garrison RJ, et al. 1989. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation, 79:8-15.
41. Graham DJ, Staffa JA, Shatin D, et al. 2004. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA, 292:2585-90.
42. Grundy SM, Cleeman JI, Merz CNB, et al. 2004a. for the Coordinating Committee of the National Cholesterol Education Program. Implications or recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation, 110:227-39.
43. Grundy SM, Hansen B, Smith SC Jr et al. 2004b. for the American Heart Association, the National Heart, Lung, and Blood Institute, and The American Diabetes Association. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association Conference on scientific issues related to management. Circulation, 109:551-6.
44. Grundy SM, Vega GL, Yuan Z, et al. 2005. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol, 95:462-8.
45. Guerin M, Bruckert E, Dolphin PJ, et al. 1996. Fenofibrate reduces plasma cholesteryl ester transfer from HDL to VLDL and normalizes the atherogenic dense LDL profile in combined hyperlipidemia. Arterioscler Thromb Vasc Biol, 16:763-72.
46. Gustavson LE, Schweitzer SM, Koehne-Voss S, et al. 2005. The effects of multiple doses of fenofibrate on the pharmacokinetics of pravastatin and its 3alpha-hydroxy isomeric metabolite. J Clin Pharmacol, 45:947-53.
47. Hottelart C, El Esper N, Rose F, et al. 2002. Fenofibrate increases creatinemia by increasing metabolic production of creatinine. Nephron, 92:536-41.
48. Jones PH, Davidson MH. 2005. Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin. Am J Cardiol, 95:120-2.
49. Kaneko T, Fuji S, Matsumoto A, et al. 2002. Induction of plasminogen activator inhibitor-1 in endothelial cells by basic fibroblast growth factor and its modification by fibric acid. Arterioscler Thromb Vasc Biol, 22:855-60.
50. Kastelein JJP, van der Steeg WA, Holme I, et al. 2008. Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment. Circulation, 117:3002-9.
51. Keating GM, Croom KF. 2007. Fenofibrate. A review of its use in primary dyslipidaemia, the metabolic syndrome and type 2 diabetes mellitus. Drugs, 67:121-53.
52. Keating GM, Ormrod D. 2002. Micronised fenofibrate. An updated review of its clinical efficacy in the management of dyslipidaemia. Drugs, 62:1909-44.
53. Keech T. 2006. American Heart Association Annual Scientific Sessions, Chicago, 2006.
54. Koh KK, Han SH, Quon MJ, et al. 2005. Beneficial effects of fenofibrate to improve endothelial dysfunction and raise adinopectin levels in patients with primary hypertriglyceridemia. Diabetes Care, 28:1419-24.
55. Liamis G, Bairaktari ET, Elisaf MS. 1999. Effect of fenofibrate on serum uric acid levels. Am J Kidney Dis, 34:594.
56. McBride PE. 2007. Triglycerides and risk for coronary heart disease. JAMA, 298:336-8.
57. McKenney JM, Farnier M, Lo KW, et al. 2006. Safety and efficacy of long-term co-administration of fenofibrate and ezetimibe in patients with mixed hyperlipiderma. J Am Coll Cardiol, 47:1584-7.
58. McKenney J, Jones M, Abby S. 2005. Safety and efficacy of colesevelam hydrochloride in combination with fenofibrate for the treatment of mixed hyperlipidemia. Curr Med Res Opin, 21:1403-12.
59. Maison P, Mennen L, Sapinho D, et al. 2002. A pharmacoepidemiological assessment of the effect of statins and fibrates on fibrinogen concentration. Atherosclerosis, 160:155-60.
60. Mardones P, Pilon A, Bouly M, et al. 2003. Fibrates down-regulate hepatic scavenger receptor class B type 1 protein expression in mice. J Biol Chem, 278:7884-90.
61. Martin PD, Dane AL, Shneck DW, et al. 2003. An open-label, randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers. Clin Ther, 25:459-71.
62. May HT, Anderson JL, Pearson RR, et al. 2008. Comparison of effects of simvastatin alone versus fenofibrate alone versus simvastatin plus fenofibrate on lipoprotein subparticle profiles in diabetic patients with mixed dyslipidemia (from the Diabetes and Combined Lipid Therapy Regimen study). Am J Cardiol, 101:486-9.
63. Mikael LG, Genest J Jr, Rozen R. 2006. Elevated homocysteine reduces apolipoprotein A-I expression in hyperhomocysteinemic mice and in males with coronary artery disease. Circ Res, 98:564-71.
64. Miller M, Cannon CP, Murphy SA, et al. 2008. for the PROVE IT-TIMI 22 Investigators. Impact of triglycerides levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol, 51:724-30.
65. Muhlestein JB, May HT, Jensen FR, et al. 2006. The reduction of inflammatory biomarkers by statin, fibrate, and combination therapy among diabetic patients with mixed dyslipidemia. The DIACOR (Diabetes and Combined Lipid Therapy Regimen) study. J Am Coll Cardiol, 48:396-401.
66. [NCEP] Executive summary of the 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). 2001. JAMA, 285:2486-97.
67. Nissen SE, Tuzcu EM, Schoenhagen P, et al. 2004. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis. A randomized controlled trial. JAMA, 291:1071-80.
68. Nordestgaard BG, Benn M, Schnohr P, et al. 2007. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA, 298:299-308.
69. Pan WJ, Gustavson LE, Achari R, et al. 2000. Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers. J Clin Pharmacol, 40:316-23.
70. Paumelle R, Staels B. 2008. Cross-talk between statins and PPARα in cardiovascular diseases: clinical evidence and basic mechanisms. Trends Cardiovasc Med, 18:73-8.
71. Playford DA, Watts GF, Best JD, et al. 2002. Effect of fenofibrate on brachial artery flow-mediated dilatation in type 2 diabetes mellitus. Am J Cardiol, 90:1254-7.
72. Prueksaritanont T, Subramanian R, Fang X, et al. 2002b. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos, 30:505-12.
73. Prueksaritanont T, Tang C, Qiu Y, et al. 2002a. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos, 30:1280-7.
74. Ridker PM, Rifai N, Cook NR, et al. 2005. Non-HDL-cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA, 294:326-33.
75. Robins SJ, Collins D, Wittes JT, et al. 2001. for the VA-HIT Study Group. Relation of gemfibrozil treatment and lipid levels with major coronary events - VA-HIT: a randomized controlled trial. JAMA, 285:1585-91.
76. Rosenson RS, Kuskin AL, Wolff DA, et al. 2008. Fenofibrate reduces fasting and postprandial inflammatory responses among hypertriglyceridemia patients with the metabolic syndrome. Atherosclerosis, 198:381-8.
77. Rubins HB, Robins SJ, Collins D, et al. 2002. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Arch Intern Med, 162:2597-604.
78. Sarwar N, Danesh J, Eiriksdottir G, et al. 2007. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation, 115:450-8.
79. Scott R, d'Emden M, Best J, et al. 2007. on behalf of the FIELD Investigators. Features of metabolic syndrome indentify individuals with type 2 diabetes mellitus at high risk for cardiovascular events and greater absolute benefits of fenofibrate. Circulation, 116(Suppl II):838.
80. Shek A, Ferrill MJ. 2001. Statin-fibrate combination therapy. Ann Pharmacother, 35:908-17.
81. Staels B, Dallongeville J, Auwerx J, et al. 1998. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation, 98:2088-93.
82. Stefanutti C, Bucci A, Di Giacomo S, et al. 2004. Efficacy, safety and tolerability of combined low-dose simvastatin-fenofibrate treatment in primary mixed hyperlipidaemia. Clin Drug Invest, 24:465-77.
83. Stone NJ, Bilek S, Rosenbaum S. 2005. Recent National Cholesterol Education Program Adult Treatment Panel III update: adjustments and options. Am J Cardiol, 96:53E-59E.
84. Syvanne M, Whittall RA, Turpeinen U, et al. 2004. Serum homocysteine concentrations, gemfibrozil treatment, and progression of coronary atherosclerosis. Atherosclerosis, 172:267-72.
85. Szapary PO, Rader DJ. 2004. The triglyceride-high density lipoprotein axis: an important target of therapy? Am Heart J, 148:211-21.
86. The ACCORD Study Group. 2007. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol, 99 (Suppl):21i-33i.
87. The FIELD study investigators. 2005. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD Study):randomised controlled trial. Lancet, 366:1849-61.
88. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD). 2007. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. Eur Heart J, 28:88-136.
89. Tribble DL, Farnier M, Macdonell G, et al. 2008. Effects of fenofibrate and ezetunibe, both as monotherapy and in coadministration, on cholesterol mass within lipoprotein subfractions and low-density lipoprotein peak particle size in patients with mixed hyperlipidemia. Metab Clin Experim, 57:796-801.
90. Tsimichodimos V, Bairaktari E, Elisaf M. 2002. Fibrate-induced increase in serum urea and creatinine levels. Nephrol Dial Transplant, 17:682.
91. Undas A, Brozek J, Szczeklik A. 2005. Homocysteine and thrombosis: from basic science to clinical evidence. Thromb Haemost, 94:907-15.
92. Vakkilainen J, Steiner G, Ansquer JC, et al. 2003. Relationships between low-density lipoprotein particle size, plasma lipoproteins, and progression of coronary artery disease: the Diabetes Atherosclerosis Intervention Study (DAIS). Circulation, 107:1733-7.
93. Vega GL, Ma PTS, Cater NB, et al. 2003. Effects of adding fenofibrate (200 mg/day) to simvastatin (10 mg/day) in patients with combined hyperlipidemia and metabolic syndrome. Am J Cardiol, 91:956-60.
94. Wierzbicki AS, Mikhailidis DP, Wray R, et al. 2003. Statin-fibrate combination therapy for hyperlipidaemia: a review. Curr Med Res Opin, 19:1-14.
95. World Health Statistics. 2008. www.who.int/whosis
96. Zambon A, Gervois P, Pauletto P, et al. 2006. Modulation of hepatic inflammatory risk markers of cardiovascular diseases by PPAR-alpha activators: clinical and experimental evidence. Arterioscler Thromb Vasc Biol, 26:977-86.