Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Fibrates and future PPARα agonists in the treatment of cardiovascular disease

Abstract

Statins lower cardiovascular risk in patients with diabetes; however, as these patients are at higher risk than other cardiovascular patients, statins merely decrease coronary event rates to the level seen in untreated nondiabetic individuals at risk for cardiovascular disease, indicating the existence of substantial residual risk. One reasonable explanation resides in the fact that statins have only limited effectiveness on hypertriglyceridemia and low HDL cholesterol, and they do not normalize the LDL size–distribution pattern. Peroxisome proliferator-activated receptor (PPAR)α agonists, which include fibrates, normalize this atherogenic lipid profile, as well as several cardiovascular risk markers associated with the metabolic syndrome and type 2 diabetes. In particular, hypertriglyceridemia and the ratio of small dense:large buoyant LDL particles are significantly improved. Outcome trials of PPARα agonists have demonstrated reductions in cardiovascular morbidity in patients with diabetes and in those with the metabolic syndrome; plaque progression is diminished, diabetic nephropathy and retinopathy are counteracted and amputation-risk decreased. The combination of fibrates with statins improves overall lipoprotein profile further. PPARα agonists seem particularly indicated in patients with diabetes who have residual dyslipidemia (high triglyceride and/or low HDL) despite receiving statin therapy, and patients who are nondiabetic, overweight, insulin-resistant and who have hypertriglyceridemia and/or low HDL cholesterol and chronic inflammation.

Key Points

  • The metabolic syndrome and type 2 diabetes mellitus have dramatically increased in incidence and are associated with an atherogenic lipid profile (high triglycerides, low HDL cholesterol and elevated levels of small dense LDL particles)

  • Statins lower cardiovascular risk by approximately 25% in patients with diabetes, leaving these patients with a substantial residual risk for cardiovascular events

  • Peroxisome proliferator-activated receptor (PPAR)α agonists, such as fibrates, improve the atherogenic lipid profile and control several mechanisms implicated in the complications of type 2 diabetes

  • Fibrates slow the progression of atherosclerotic plaque as well as cardiovascular morbidity most efficiently in overweight patients with features of the metabolic syndrome, especially high triglycerides and/or low HDL cholesterol

  • Combinations of statins and PPARα agonists have a more powerful effect on the atherogenic lipid profile seen in type 2 diabetes and the metabolic syndrome than either agent alone

  • Future developments in this field should aim at identifying PPARα agonists with higher clinical efficacy

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Residual cardiovascular risk in statin outcome trials.
Figure 2: Risk reduction for major cardiovascular events in the Veterans Affairs–High density lipoprotein cholesterol Intervention Trial.60
Figure 3: Event rate reduction in patients with the metabolic syndrome in the Bezafibrate Infarction Prevention study, which compared bezafibrate with placebo.65
Figure 4: Data from the US on the number of cases of rhabdomyolysis per million prescriptions with fenofibrate or gemfibrozil in combination with statins.77

Similar content being viewed by others

References

  1. LaRosa JC (2005) At the heart of statin benefit. J Am Coll Cardiol 46: 1863

    Article  Google Scholar 

  2. Superko HR (1996) Beyond LDL cholesterol reduction. Circulation 94: 2351–2354

    Article  CAS  Google Scholar 

  3. Cannon CP et al. (2004) Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 350: 1495–1504

    Article  CAS  Google Scholar 

  4. Cordain L et al. (2002) The paradoxical nature of hunter-gatherer diets: meat based, yet non-atherogenic. Eur J Clin Nutr 56 (Suppl 1): S42–S52

    Article  Google Scholar 

  5. O'Keefe JH and Cordain L (2004) Cardiovascular disease resulting from a diet and lifestyle at odds with our Paleolithic genome: how to become a 21st century hunter-gatherer. Mayo Clin Proc 79: 101–108

    Article  Google Scholar 

  6. Libby P (2005) The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol 46: 1225–1228

    Article  Google Scholar 

  7. Bruckert E et al. (2005) Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther 19: 403–414

    Article  CAS  Google Scholar 

  8. Alsheikh-Ali AA et al. (2007) Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer. J Am Coll Cardiol 50: 409–418

    Article  CAS  Google Scholar 

  9. Violi F et al.; MRC/BHF Heart Protection Study (2002) MRC/BHF Heart Protection Study. Lancet 360: 7–22

    Article  Google Scholar 

  10. Colhoun HM et al.; CARDS Investigators (2004) 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: 685–696

    Article  CAS  Google Scholar 

  11. Sever PS et al. (2005) Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial—lipid-lowering arm (ASCOT-LLA). Diabetes Care 28: 1151–1157

    Article  CAS  Google Scholar 

  12. Wanner C et al.; Deutsche Diabetes-Dialyse-Studie (4D) Study Group (2004) Randomized controlled trial on the efficacy and safety of atorvastatin in patients with type 2 diabetes on hemodialysis (4D study): demographic and baseline characteristics. Kidney Blood Press Res 27: 259–266

    Article  CAS  Google Scholar 

  13. Knopp RH et al. (2006) Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care 29: 1478–1485

    Article  CAS  Google Scholar 

  14. Costa J et al. (2006) Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials. BMJ 332: 1115–1124

    Article  CAS  Google Scholar 

  15. Stratton IM et al (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321: 405–412

    Article  CAS  Google Scholar 

  16. Hokanson JE and Austin MA (1996) Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 3: 213–219

    Article  CAS  Google Scholar 

  17. Bansal S et al. (2007) Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 298: 309–316

    Article  CAS  Google Scholar 

  18. McBride PE (2007) Triglycerides and risk for coronary heart disease. JAMA 298: 336–338

    Article  CAS  Google Scholar 

  19. Jacobson TA et al. (2007) Hypertriglyceridemia and cardiovascular risk reduction. Clin Ther 29: 763–777

    Article  CAS  Google Scholar 

  20. Miller M et al.; for the PROVE IT-TIMI 22 Investigators (2008) Impact of triglyceride levels beyond low density lipoprotein cholesterol after an acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 51: 724–730

    Article  CAS  Google Scholar 

  21. Ballantyne CM et al. (1999) Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy. Circulation 99: 736–743

    Article  CAS  Google Scholar 

  22. Mackness MI et al. (1993) The role of high-density lipoprotein and lipid-soluble antioxidant vitamins in inhibiting low-density lipoprotein oxidation. Biochem J 294: 829–834

    Article  CAS  Google Scholar 

  23. Cockerill GW et al. (1995) High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules. Arterioscler Thromb Vasc Biol 15: 1987–1994

    Article  CAS  Google Scholar 

  24. Kontush A and Chapman MJ (2006) Antiatherogenic small, dense HDL-guardian angel of the arterial wall? Nat Clin Pract Cardiovasc Med 3: 144–153

    CAS  Google Scholar 

  25. Lamarche B et al. (1999) HDL metabolism in hypertriglyceridemic states: an overview. Clin Chim Acta 286: 145–161

    Article  CAS  Google Scholar 

  26. Birjmohun RS et al. (2005) Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials. J Am Coll Cardiol 45: 185–197

    Article  CAS  Google Scholar 

  27. Robins SJ et al. (2001) Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA 285: 1585–1591

    Article  CAS  Google Scholar 

  28. Lefebvre et al. (2006) Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest 116: 571–580

    Article  CAS  Google Scholar 

  29. Grundy SM et al. (2005) Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol 95: 462–468

    Article  CAS  Google Scholar 

  30. Staels B et al. (1998) Mechanisms of action of fibrates on lipid and lipoprotein metabolism. Circulation 98: 2088–2093

    Article  CAS  Google Scholar 

  31. Seiler C et al. (1995) Exercise-induced vasomotion of angiographically normal and stenotic coronary arteries improves after cholesterol-lowering drug therapy with bezafibrate. J Am Coll Cardiol 26: 1615–1622

    Article  CAS  Google Scholar 

  32. Koh KK et al. (2005) Beneficial effects of fenofibrate to improve endothelial dysfunction and raise adiponectin levels in patients with primary hypertriglyceridemia. Diabetes Care 28: 1419–1424

    Article  CAS  Google Scholar 

  33. Playford DA et al. (2003) Combined effect of coenzyme Q10 and fenofibrate on forearm microcirculatory function in type 2 diabetes. Atherosclerosis 168: 169–179

    Article  CAS  Google Scholar 

  34. Evans M et al. (2000) Ciprofibrate therapy improves endothelial function and reduces postprandial lipemia and oxidative stress in type 2 diabetes mellitus. Circulation 101: 1773–1779

    Article  CAS  Google Scholar 

  35. Wilmink HW et al. (2001) Effect of statin versus fibrate on postprandial endothelial dysfunction: role of remnant-like particles. Cardiovasc Res 50: 577–582

    Article  CAS  Google Scholar 

  36. Andrews TC et al. (1997) Effect of gemfibrozil +/− niacin +/− cholestyramine on endothelial function in patients with serum low-density lipoprotein cholesterol levels <160 mg/dl and high-density lipoprotein cholesterol levels <40 mg/dl. Am J Cardiol 80: 831–835

    Article  CAS  Google Scholar 

  37. Ogata T et al. (2004) Myocardial fibrosis and diastolic dysfunction in deoxycorticosterone acetate-salt hypertensive rats is ameliorated by the peroxisome proliferator-activated receptor-alpha activator fenofibrate, partly by suppressing inflammatory responses associated with the nuclear factor-kappa-B pathway. J Am Coll Cardiol 43: 1481–1488

    Article  CAS  Google Scholar 

  38. Han SH et al. (2005) Beneficial vascular and metabolic effects of peroxisome proliferator-activated receptor-alpha activators. Hypertension 46: 1086–1092

    Article  CAS  Google Scholar 

  39. Zambon A 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: 977–986

    Article  CAS  Google Scholar 

  40. Koh et al. (2005) Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia. J Am Coll Cardiol 45: 1649–1653

    Article  CAS  Google Scholar 

  41. Aguilar-Salinas CA et al. (2001) Ciprofibrate versus gemfibrozil in the treatment of mixed hyperlipidemias: an open-label, multicenter study. Metabolism 50: 729–733

    Article  CAS  Google Scholar 

  42. Wilmer WA et al. (2002) PPAR-alpha ligands inhibit H2O2 mediated activation of transforming growth factor beta in human mesangial cells. Antiox Redox Signal 4: 877–884

    Article  CAS  Google Scholar 

  43. Park CW et al. (2006) PPARα agonist fenofibrate improves diabetic nephropathy in db/db mice. Kidney Int 69: 1511–1517

    Article  CAS  Google Scholar 

  44. Chen LL et al. (2006) Renoprotective effects of fenofibrate in diabetic rats are achieved by suppressing kidney plasminogen activator inhibitor-1. Vascul Pharmacol 44: 309–315

    Article  CAS  Google Scholar 

  45. Park CW et al. (2006) Accelerated diabetic nephropathy in mice lacking the peroxisome proliferator-activated receptor alpha. Diabetes 55: 885–893

    Article  CAS  Google Scholar 

  46. Kamijo Y et al. (2002) Identification of functions of peroxisome proliferator-activated receptor alpha in proximal tubules. J Am Soc Nephrol 13: 1691–1702

    Article  CAS  Google Scholar 

  47. Sato M (2005) Peroxisome proliferator activated receptor ligands and angiogenesis. Nippon Rinsho 63: 603–608

    PubMed  Google Scholar 

  48. Panigrahy D et al. (2008) PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition. Proc Natl Acad Sci USA 105: 985–990

    Article  CAS  Google Scholar 

  49. Ruotolo G et al. (2000) Serum insulin-like growth factor-I level is independently associated with coronary artery disease progression in young male survivors of myocardial infarction: beneficial effects of bezafibrate treatment. J Am Coll Cardiol 35: 647–654

    Article  CAS  Google Scholar 

  50. Wilkinson-Berka JL et al. (2006) The role of growth hormone, insulin-like growth factor and somatostatin in diabetic retinopathy. Curr Med Chem 13: 3307–3317

    Article  CAS  Google Scholar 

  51. Blann AD et al. (2001) Plasma vascular endothelial growth factor and its receptor Flt-1 in patients with hyperlipidemia and atherosclerosis and the effects of fluvastatin or fenofibrate. Am J Cardiol 15: 1160–1163

    Article  Google Scholar 

  52. Kim J et al. (2007) Fenofibrate regulates endothelial cell survival through the AMPK signal transduction pathway. Exp Eye Res 84: 886–893

    Article  CAS  Google Scholar 

  53. Harrold BP et al. (1969) A double-blind controlled trial of clofibrate in the treatment of diabetic retinopathy. Diabetes 18: 285–291

    Article  CAS  Google Scholar 

  54. Dorne PA (1977) Exudative diabetic retinopathy. The use of clofibrate in the treatment of hard exudates using a reduced but prolonged dosage over several years. Arch Ophtalmol 37: 393–400

    CAS  Google Scholar 

  55. Frick MH et al. (1997) 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 96: 2137–2143

    Article  CAS  Google Scholar 

  56. Ericsson CG et al. (1996) Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet 347: 849–853

    Article  CAS  Google Scholar 

  57. DAIS investigators (2001) Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 357: 905–910

  58. Rubins HB et al. (1999) Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 341: 410–418

    Article  CAS  Google Scholar 

  59. Robins SJ et al. (2001) Relation of gemfibrozil treatment and lipid levels with major coronary events. VA-HIT: a randomized controlled trial. JAMA 285: 1585–1591

    Article  CAS  Google Scholar 

  60. Bloomfield-Rubins H 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: 2597–2604

    Article  Google Scholar 

  61. Frick MH 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: 1237–1245

    Article  CAS  Google Scholar 

  62. Tenkanen L et al. (1995) Some coronary risk factors related to the insulin resistance syndrome and treatment with gemfibrozil: experience from the Helsinki Heart Study. Circulation 92: 1779–1785

    Article  CAS  Google Scholar 

  63. The Bezafibrate Infarction Prevention study Group (2000) Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: The Bezafibrate Infarction Prevention (BIP) study. Circulation 102: 21–27

  64. Goldenberg I et al. (2008) Secondary prevention with bezafibrate therapy for the treatment of dyslipidemia: an extended follow-up of the BIP trial. J Am Coll Cardiol 51: 459–465

    Article  CAS  Google Scholar 

  65. Tenenbaum A et al. (2005) Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome. Arch Intern Med 165: 1154–1160

    Article  CAS  Google Scholar 

  66. Keech A et al.; FIELD study investigators (2005) Effects of long-term fenofibrate therapy on cardiovascular events in 9,795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366: 1849–1861

    Article  CAS  Google Scholar 

  67. Scott R et al.; on behalf of the FIELD Investigators (2007) Features of metabolic syndrome identify individuals with type 2 diabetes mellitus at high risk for cardiovascular events and greater absolute benefits of fenofibrate [abstract]. Circulation 116: II_838

    Google Scholar 

  68. Keech A et al.; FIELD study investigators (2007) Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 370: 1687–1697

    Article  CAS  Google Scholar 

  69. Hiukka A et al. (2007) Long-term effects of fenofibrate on VLDL and HDL subspecies in participants with type 2 diabetes mellitus. Diabetologia 50: 2067–2075

    Article  CAS  Google Scholar 

  70. Grundy SM et al. (2004) Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 110: 227–239

    Article  Google Scholar 

  71. Athyros VG et al. (2002) Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia. Diabetes Care 25: 1198–1202

    Article  CAS  Google Scholar 

  72. Watts GF (2003) Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome. Diabetes 52: 803–811

    Article  CAS  Google Scholar 

  73. Farnier M et al. (2007) Efficacy and safety of the coadministration of ezetimibe/simvastatin with fenofibrate in patients with mixed hyperlipidemia. Am Heart J 153: 335–338

    Article  Google Scholar 

  74. Hottelart C et al. (1999) Fenofibrate increases blood creatinine, but does not change the glomerular filtration rate in patients with mild renal insufficiency. Nephrologie 20: 41–44

    CAS  PubMed  Google Scholar 

  75. Luc G et al. (2004) Fenofibrate increases homocysteinemia through a PPARα-mediated mechanism. J Cardiovasc Pharmacol 43: 452–453

    Article  CAS  Google Scholar 

  76. Genest J et al. (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: 848–853

    Article  CAS  Google Scholar 

  77. Davidson MH et al. (2006) Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions. Expert Opin Drug Saf 5: 145–156

    Article  CAS  Google Scholar 

  78. Davidson MH et al. (2007) Safety considerations with fibrate therapy. Am J Cardiol 99 (Suppl): 3C–18C

    Article  CAS  Google Scholar 

  79. Prueksaritanont T et al. (2002) Effect of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos 30: 1280–1287

    Article  CAS  Google Scholar 

  80. Pourcet B et al. (2006) Selective PPAR modulators, dual and pan PPAR agonists: multimodal drugs for the treatment of type 2 diabetes and atherosclerosis. Expert Opin Emerg Drugs 11: 379–401

    Article  CAS  Google Scholar 

  81. Duez H et al. (2005) Regulation of human apo A-I by gemfibrozil and fenofibrate through selective PPAR-α modulation. Arterioscler Thromb Vasc Biol 25: 585–591

    Article  CAS  Google Scholar 

  82. ACCORD Study Group; Buse JB et al. (2007) Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol 99 (Suppl): 21i–33i

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bart Staels.

Ethics declarations

Competing interests

B Staels, M Maes and A Zambon have all received honoraria (speakers bureau) from Solvay.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Staels, B., Maes, M. & Zambon, A. Fibrates and future PPARα agonists in the treatment of cardiovascular disease. Nat Rev Cardiol 5, 542–553 (2008). https://doi.org/10.1038/ncpcardio1278

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpcardio1278

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing