Treating Atherogenic Dyslipidemia in Patients with Type 2 Diabetes—The Case for Using Fenofibrate

Average (ratings)
No ratings
Your rating
Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

The wide utilization of anti-cholesterol agents, such as the statins, has created confusion among patients and clinicians about what to do when the lipid problem is one of triglycerides and high-density lipoprotein (HDL), rather than one of low density lipoprotein (LDL). Although most patients with diabetes have a dyslipidemia characterized by high triglycerides and low HDL (atherogenic dyslipidemia), most doctors will prescribe an agent aimed at reducing LDL and will not pursue any further adjustment of the lipid profile. Statins have only modest effects on triglycerides and HDL, and patients with insulin resistance are therefore likely to achieve their LDL goals but continue expressing the atherogenic dyslipidemia for the long term. This article reviews the pharmacology, clinical trial data, and practice utilization of the fibrate drugs, a class of agents with a strong effect on atherogenic dyslipidemia.

The Problem

Lipid treatment was originally reserved for subjects with genetic abnormalities of lipid metabolism. It was only in 1994 that the importance of statin therapy was discovered in reducing cardiovascular risk in post-myocardial infarction (MI) patients with an LDL greater than 190mg/dl—a concept that seems so intuitive today. Since then, understanding of the role of lipids in atherogenesis has progressed in leaps and bounds, and the vast majority of patients currently on a statin do not have a genetic hypercholesterolemia, and both the National Cholesterol Education Program (NCEP) and the American Diabetes Association (ADA) are endorsing an LDL goal of around 70mg/dl in high-risk patients.

Dyslipidemia has multiple sub-diagnoses, and implementation of combination therapy is undertaken for two main reasons:

  • achieving a lower LDL goal (statin plus resin or ezetimibe); and
  • controlling LDL, triglycerides, and HDL in combined dyslipidemias (statin plus fibrate or niacin).

This means that the more aggressive the LDL targets become, the more likely it will be for doctors to find a combination statin and ezetimibe to achieve a lower LDL at the expense of the combination of statin and fibrate to adjust HDL and triglycerides. The problem with this approach is that the atherogenic dyslipidemia of insulin resistance is the most common form of lipid abnormality and does not respond well to statin therapy. Treatment of atherogenic dyslipidemia aims at controlling triglycerides and HDL. Of the two drugs that affect atherogenic dyslipidemia, niacin is used mostly to raise HDL, whereas fibrates are used mostly to reduce triglycerides. Because the challenge of atherogenic dyslipidemia is one of abnormal triglyceride removal, the rest of this article will focus on the role of fibrates in cardiovascular protection of insulin-resistant patients.


The fibrate molecule is similar to a long-chain fatty acid and acts by binding peroxisome proliferator receptor alpha (PPARα), a nuclear receptor that controls the expression of several genes, including several involved in lipoprotein regulation, inflammation, endothelial function, and smooth muscle regulation.1 The two drugs in this category are gemfibrozil and fenofibrate. Fibrates are excreted predominantly as glucuronide conjugates with 60% to 90% of an oral dose excreted in the urine, therefore, they should not be used in patients with renal failure. The most common side effects, upper gastrointestinal (GI) symptoms, occur in approximately 5% of patients, with fenofibrate significantly better tolerated than gemfibrozil.2 All of the fibrates cause increased biliary cholesterol concentrations and can cause gallstones. Minor elevations in liver transaminases have been reported.3 Fibrates displace warfarin from albumin-binding sites, and patients taking fibrates may need to reduce their dose of warfarin by 30%.

Fibrates and Plasma Lipids

Fibrates can lower triglycerides between 50% to 85%, depending on the patient's compliance to lifestyle measures. Fibrates also raise HDL levels between 10% and 25% through mechanisms related to both the PPAR action (upregulation of the HDL protein, apoAI) and improved clearance of triglycerides (upregulation of lipoprotein lipase). Fibrates are the drugs of choice for treatment of severe hypertriglyceridemia (TG>500mg/dl) or chylomicronemia syndrome (TG>1,000mg/dl), conditions associated with an increased risk of pancreatitis.4 Gemfibrozil has neutral LDL effects, whereas fenofibrate may produce LDL reductions ranging from 5% to 35%.5 An important aspect of LDL metabolism in patients with triglyceride and HDL problems is the accumulation of small dense LDL. Fenofibrate decreases small dense LDL particles in favor of larger, more buoyant LDL particles, which are less susceptible to oxidation and less 'atherogenic'.6,7

Several non-traditional risk factors are also influenced by the fibrates. Fenofibrate decreases plasma levels of Lp(a) by 7% to 23%,5,8 reduces fibrinogen,9 and lowers levels of serum uric acid to the point where it might have therapeutic effects on gout.10

Fibrates and the Vessel Wall

The pleiotropic effects of fibrates may result in direct anti-atherogenic effects in the artery wall. PPARα is expressed by all of the major cell types in atherosclerotic lesions, including macrophages, endothelial cells, and vascular smooth muscle cells (SMC).11 Fibrate therapy reduces vascular inflammation12,13 and decreases the recruitment of blood cells to the vessel wall, a crucial step in the initiation of the arterial plaque.14 Furthermore, fenofibrate inhibits activation of vascular SMCs15 and lowers C-reactive protein (CRP) levels to a degree similar to that previously reported for statin therapy.16,17 These effects, not measurable as plasma lipid changes, are expected to contribute to cardiovascular protection.

Fibrates and Statins in the Treatment of Atherogenic Dyslipidemia

The new guidelines of the NCEP and ADA high-light the importance of LDL reduction in high-risk patients, while encouraging physicians to position all diabetic and insulin-resistant patients in the high-cardiovascular- risk category.18-20 Because these patients are commonly affected by a dyslipidemia characterized by hypertriglyceridemia with low HDL, it could be argued that the best lipid intervention in these cases would be the one directed at the primary metabolic abnormality. Triglyceride and HDL levels predict coronary event rates independently from LDL in European and US populations.21,22 This is reflected in the current NCEP guidelines, which suggest a secondary goal of non- HDL cholesterol less than 30mg/dL above the LDL goal for the risk level. As non-HDL cholesterol is determined largely by triglyceride levels, the current guidelines support aggressive treatment of triglycerides in the high-risk patient.

The importance of atherogenic dyslipidemia can also be indirectly inferred by the results of the major statin trials. For example, the most impressive statin effects on coronary heart disease (CHD) risk reduction in a high-risk population were seen in the 4S trial, where patients had high LDL but normal triglycerides and HDL.23 The equivalent pravastatin studies, Cholesterol and Recurrent Events Trial (CARE) and Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial, where subjects were enrolled with triglycerides as high as 350mg/dl, showed more modestly positive results, suggesting that, in a population with the atherogenic dyslipidemia, exclusive attention to LDL may be less effective than a more comprehensive lipid management approach.24,25

The Heart Protection Study (HPS) investigated the risk reduction potential afforded by simvastatin in a population of 20,000 subjects with high-risk (75% CHD, 25% diabetes or multiple risk factors) and normal lipid levels (51% of subjects had an LDL below 130mg/dl).26 Even though this study showed the preventive value of LDL control in subjects with modest dyslipidemia, it is important to note that the residual risk in patients with low HDL and high triglycerides was higher than average, suggesting that better risk reduction could be achieved by a more aggressive control of HDL and triglycerides in these patients.26 More recently, the Collaborative Atorvastatin Diabetes Study (CARDS) has shown that 10mg per day of atorvastatin protects patients with type 2 diabetes against atherosclerotic complications. Even in this case, however, a lower baseline HDL predicted higher residual risk in the treatment group, compatible with the possibility that an additional avenue for therapeutic control had remained untapped.27

Fibrates and Prevention of CHD

The Veterans' Administration HDL intervention trial (VA-HIT) evaluated the effect of gemfibrozil in CHD patients with type 2 diabetes or the metabolic syndrome and low HDL.28 The baseline lipids included LDL 111mg/dl, HDL 32mg/dl, and triglycerides 164mg/dl. Five years of therapy with gemfibrozil resulted in an average 7.5% increase in HDL, a 24% reduction in triglycerides, and no changes in LDL levels. This was accompanied with a very significant reduction in coronary and cerebrovascular events (22% and 31%, respectively).1 In addition, the effect of fibrate therapy on CHD rates among the nearly 700 diabetic subjects enrolled in this study was particularly large and apparently superior to the effects of statins in the same patient type (see Figure 1). Even more impressive is the recent report that among the non-diabetic subgroup of this study, the best predictor of CHD risk reduction afforded by fibrate therapy was fasting plasma insulin level, with subjects in the lowest quartile experiencing no benefits, and those in the highest quartile experiencing the most significant benefits.2 These data support the value of fibrate therapy in the metabolic syndrome patient.

Somewhat different results were obtained in the Bezafibrate Infarction Prevention (BIP) trial. In this study, 3,122 CHD subjects with LDL of 150mg/dl and HDL of 34mg/dl were treated with bezafibrate or placebo for five years and evaluated for lipid changes and CHD event rates. Despite significant changes in triglycerides and HDL, bezafibrate produced no effects on coronary events.29


However, bezafibrate was very beneficial for the subjects who had hypertriglyceridemia (triglycerides >200mg/dL) and LDL levels around 130mg/dl at baseline. In this group, risk reduction started during the first year of the study and reached an impressive 40% after five years.29 Given the diverging results of the VA-HIT and BIP trials, it is tempting to speculate that a threshold of LDL around 130mg/dl may determine whether the benefits of fibrate therapy can be collected. The Diabetes Atherosclerosis Intervention Study (DAIS) has tested the hypothesis that fibrate therapy can help diabetic patients with a baseline LDL around 130mg/dl. In this three-year study, fenofibrate treatment was accompanied by a 40% reduction in progression of focal CAD and a 23% reduction in the rate of CV events, including MIs, compared with placebo.30 These effects appeared to be explained by changes in HDL, triglyceride, and LDL levels, as well as by an increase in LDL particle size.31 It is, therefore, possible that high-risk subjects with an LDL below 130mg/dl may be best controlled by fibrate monotherapy, whereas higher LDL levels may render fibrates less effective even when triglycerides and HDL need adjustment. Figure 2 shows the effect of statins or gemfibrozil in diabetic patients in 4S, HPS, CARE, and VA-HIT. It is evident that an efficient risk reduction is not simply related to drug choice (simvastatin produced very different effects in 4S versus HPS), but is mostly the result of matching the right drug with the right patient type (i.e. a statin for the hypercholesterolemic patients of 4S, a fibrate for the hypertriglyceridemic, low HDL patients of VA-HIT).Whether the diabetic patients of CARE and HPS would have been better served by fibrate therapy remains a matter of speculation.

The question arises of whether combination therapy with statin and fibrate would produce synergistic effects and greater risk reductions compared with monotherapy with either drug in high-risk patients. Such a question is being investigated in the NIH-sponsored Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, designed to compare the effect of simvastatin monotherapy with the combination with fenofibrate in diabetic patients. The first results from this study are expected in 2010.

The Fenofibrate Intervention and Event Lowering in Diabetes Study

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study is a large trial of fenofibrate in patients with type 2 diabetes which has reached completion and for which results will be presented at the AHA Scientific Sessions in November 2005 in Dallas, Texas. Briefly, about 10,000 individuals with diabetes and with or without CHD were randomized to either placebo or full dose fenofibrate. The cohort includes a large sample of women (~39%) and a wide distribution of baseline cholesterol (from around 130mg/dl to around 250mg/dl). Subjects needed to have total cholesterol between 115 and 250mg/dL, and either triglycerides >88.6mg/dl or a total- to HDL-cholesterol ratio of >4 to qualify. The primary clinical outcome of the study is non-fatal MI and CHD death. This study will provide a strong insight of the utility of fenofibrate treatment in the primary and secondary prevention of vascular problems in diabetics.32 The most important aspect of this study is that, if positive, it will put a serious dent on the notion that statin therapy is mandatory first choice in diabetic patients without hypercholesterolemia.


Fibrates are safe, inexpensive, and effective drugs for the long-term management of combined dyslipidemia in a large number of patients with high CVD risk. Clinical trials appear to suggest:

  • a reduced efficacy of statin therapy in subjects with the features of the metabolic syndrome and atherogenic dyslipidemia without elevated LDL; and
  • a reduced efficacy of fibrate therapy in patients with high LDL (150mg/dl) even when triglyceride and HDL levels are abnormal.

These observations argue against the use of any one class of drugs in the management of high-risk dyslipidemia, and support a practice stance of matching a specific diagnosis of lipid abnormality with the therapeutic agent most likely to correct it.

There are obvious scenarios where the drug choice is limited. For example, a diabetic patient with an LDL of 160mg/dl or higher will need statin therapy irrespective of triglyceride or HDL levels. Likewise, a diabetic subject with triglycerides higher than 500mg/dl will need fibrate treatment irrespective of LDL levels. However, a large number of these patients fall in the gray zone of moderate combined dyslipidemia, with triglycerides below 500mg/dl, HDL in the 30s, and LDL ranging between 100mg/dl and 150mg/dl. In these subjects, combination therapy with a statin and a fibrate should be planned from the onset. At a time when new trials and new guidelines are moving toward the endorsement of ever-lower LDL goals, the danger.


  1. Staels B, Dallongeville J,Auwerx J, Schoonjans K, Leitersdorf E, Fruchart J C, "Mechanism of action of fibrates on lipid and lipoprotein metabolism", Circulation (1998);98: pp. 2,088-2,093.
    Crossref | PubMed
  2. Knopp R H,"Drug treatment of lipid disorders", New England Journal of Medicine (1999);341: pp. 498-511.
    Crossref | PubMed
  3. Witztum J L, "Drugs used in the treatment of hyperlipoproteinemias", In: Hardman J G Limbird L E (eds), Goodman & Gilman's The Pharmacological Basis of Therapeutics McGraw-Hill, New York, (1996), pp. 875-897.
  4. Brunzell J D,"Familial lipoprotein lipase deficiency and other causes of the chylomicronemia syndrome", In: Scriver C R, Beaudet A L, Sly W S,Valle D (eds), The metabolic and molecular bases of inherited disease McGraw Hill, Inc, New York, (1995);Vol II, pp. 1,913-1,932.
  5. Adkins J C, Faulds D,"Micronised fenofibrate: a review of its pharmacodynamic properties and clinical efficacy in the management of dyslipidaemia", Drugs (1997);54: pp. 615-633.
    Crossref | PubMed
  6. Caslake M J, Packard C J, Gaw A, Murray E, Griffin B A, Vallance B D Shepherd J, "Fenofibrate and LDL metabolic heterogeneity in hypercholesterolemia", Arteriosclerosis & Thrombosis (1993);13: pp. 702-711.
    Crossref | PubMed
  7. Guerin M, Bruckert E, Dolphin P J,Turpin G, Chapman M J, "Fenofibrate reduces plasma cholesteryl ester transfer from HDL to VLDL and normalizes the atherogenic, dense LDL profile in combined hyperlipidemia", Arteriosclerosis, Thrombosis & Vascular Biology (1996);16: pp. 763-772.
    Crossref | PubMed
  8. Farnier M, Bonnefous F, Debbas N, Irvine A, "Comparative efficacy and safety of micronized fenofibrate and simvastatin in patients with primary type IIa or IIb hyperlipidemia", Archives of Internal Medicine (1994);154: pp. 441-449.
    Crossref | PubMed
  9. Steinmetz A, Schwartz T, Hehnke U, Kaffarnik H,"Multicenter comparison of micronized fenofibrate and simvastatin in patients with primary type IIA or IIB hyperlipoproteinemia", Journal of Cardiovascular Pharmacology (1996);27: pp. 563-570.
    Crossref | PubMed
  10. Feher M D, Hepburn A L, Hogarth M B, Ball S G, Kaye S A, "Fenofibrate enhances urate reduction in men treated with allopurinol for hyperuricaemia and gout", Rheumatology (2003);42: pp. 321-325.
    Crossref | PubMed
  11. Pineda Torra I, Gervois P, Staels B, "Peroxisome proliferator-activated receptor alpha in metabolic disease, inflammation, atherosclerosis and aging", Current Opinion In Lipidology (1999);10: pp. 151-159.
    Crossref | PubMed
  12. Poynter M E, Daynes R A, "Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging", Journal of Biological Chemistry (1998);273: pp. 32,833-32,841.
    Crossref | PubMed
  13. Delerive P, De Bosscher K, Besnard S,Vanden Berghe W, Peters J M,Gonzalez F J, Fruchart J-C,Tedgui A, Haegeman G, Staels B,"Peroxisome Proliferator-activated Receptor alpha Negatively Regulates the Vascular Inflammatory Gene Response by Negative Cross-talk with Transcription Factors NF-kappa B and AP-1", J. Biol. Chem. (1999);274: pp. 32,048-32,054.
    Crossref | PubMed
  14. Marx N, Sukhova G K, Collins T, Libby P, Plutzky J, "PPARalpha activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells", Circulation (1999);99: pp. 3,125-3,131.
    Crossref | PubMed
  15. Staels B, Koenig W, Habib A, Merval R, Lebret M,Torra I P, Delerive P, Fadel A, Chinetti G, Fruchart J C, Najib J, Maclouf J,Tedgui A, "Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators", Nature (1998);393: pp. 790-793.
    Crossref | PubMed
  16. Jonkers I J, Mohrschladt M F,Westendorp R G, van der Laarse A, Smelt A H,"Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: reversal with bezafibrate therapy in a randomized controlled trial", Am. J. Med. (2002);112: pp. 275-280.
    Crossref | PubMed
  17. Despres J P, Lemieux I, Pascot A,Almeras N, Dumont M, Nadeau A, Bergeron J, Prud'homme D,"Gemfibrozil reduces plasma C-reactive protein levels in abdominally obese men with the atherogenic dyslipidemia of the metabolic syndrome", Arteriosclerosis,Thrombosis & Vascular Biology (2003);23: pp. 702-703.
    Crossref | PubMed
  18. National Cholesterol Education Program Expert Panel on Detection, E, and A,"Treatment of High Blood Cholesterol in 2002. 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.[comment]", Circulation 106: pp. 3,143-3,421.
  19. American Diabetes,A, "Management of dyslipidemia in adults with diabetes", Diabetes Care (2000);23: pp. S57-60.
  20. Haffner S M, "Management of dyslipidemia in adults with diabetes", Diabetes Care (2003); p. 26.
  21. Gordon T, Castelli W P, Hjortland M C, Kannel W B, Dawber R T, "High density lipoprotein as a protective factor against coronary heart disease",The Framingham study, Am. J. Med. (1997);62: pp. 707-714.
    Crossref | PubMed
  22. Levy D, Kannel W B,"Cardiovascular risks: new insights from Framingham", Am. Heart J. (1998);166: pp. 266-272.
    Crossref | PubMed
  23. Scandinavian, Simvastatin, Survival, Study, and Group."Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the scandinavian simvastatin survival study (4S)", Lancet (1994);344: pp. 1,383-1,389.
  24. Sacks F M, Pfeffer M A, Moye L A, Rouleau J L, Rutherford J D, Cole T G, Brown L,Warnica J W,Arnold J M,Wun C C, Davis B R, Braunwald E, "The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.[comment]", N. Eng. J. Med. (1996);335: pp. 1,001-1,009.
    Crossref | PubMed
  25. Group,T.L.-T.I.w.P.i.I.D.L.S, "Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.[comment]", N. Eng. J. Med. (1998);339: pp. 1,349-1,357.
    Crossref | PubMed
  26. Heart Protection Study Collaborative, G, "MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.[comment][summary for patients in Curr Cardiol Rep. 2002 Nov;4(6):486-7; PMID: 12379169]", Lancet (2002);360: pp. 7-22.
  27. Colhoun H M, Betteridge J D, Durrington P N, Hitman G A,Andrew H, Neil W, Livingstone S J,Thomason M J, Mackness M I, Charlton-Menys V, Fuller J H,"Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial", Lancet (2004);364: pp. 685-696.
    Crossref | PubMed
  28. Rubins H B, Robins S J, Collins D, Fye C L, Anderson J W, Elam M B, Faas F H, Linares E, Schaefer E J, Schectman G, Wilt T J, 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. Eng. J. Med. (1999);341: pp. 410-418.
    Crossref | PubMed
  29. The BIP Study Group, "Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study.[comment]", Circulation (2000);102: pp. 21-27.
    Crossref | PubMed
  30. DAIS Study Investigators, "Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study",[erratum appears in Lancet 2001 Jun 9;357(9271): p. 1,890], Lancet (2001);357: pp. 905-910.
    Crossref | PubMed
  31. Vakkilainen J, Steiner G, Ansquer J C,Aubin F, Rattier S, Foucher C, Hamsten A,Taskinen M R, Group D, "Relationships between low-density lipoprotein particle size, plasma lipoproteins, and progression of coronary artery disease: the Diabetes Atherosclerosis Intervention Study (DAIS)", Circulation (2003);107: pp. 1,733-1,737.
    Crossref | PubMed
  32. The FIELD Study Investigators, "The need for a large-scale trial of fibrate therapy in diabetes: the rationale and design of Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study", Cardiovascular Diabetology (2004);3: p. 9.
    Crossref | PubMed