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.
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.