Fibrates - The Other Life-saving Lipid Drugs

Fibrates - The Other Life-saving Lipid Drugs

Fazio Sergio
This article was published in US Cardiology 2004
Published: August 2004
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Introduction
The main controversy in the area of lipid management today is related to the usefulness of ‘non-statin’ agents to maximize cardiovascular risk reduction in particular patient types, such as those with diabetes and metabolic syndrome. Fibrate drugs, such as gemfibrozil (Lopid) and fenofibrate (TriCor), are undoubtedly the best tools to address the condition characterized by high triglycerides, low high-density lipoprotein, and small dense low-density lipoprotein (atherogenic dyslipidemia), but the most recent guidelines from both the American Diabetes Association (ADA) and the National Cholesterol Education Panel continue to focus on low-density lipoprotein control as the target of therapy. However, statinbased interventions are unlikely to correct problems of triglycerides and high-density lipoprotein, whereas the use of fibrates has a stronger effect on the atherogenic dyslipidemia and might even produce significant low-density lipoprotein reduction in some patients. Thus, physicians dealing with the common phenotype of insulin resistance are presented with a practical problem – the use of statins primarily to control low-density lipoprotein, or the use of fibrates primarily to control triglycerides and high-density lipoprotein.Welldesigned outcome studies published in the last few years have shown the value of fibrate therapy in patients with obesity, the metabolic syndrome, and diabetes, particularly when low-density lipoprotein levels are below 130mg/dl and when triglycerides and levels are only modestly abnormal.

Mechanism of Action of Fibrates

Gemfibrozil and fenofibrate are the fibrates currently approved for use in the US and, in addition to these, bezafibrate and ciprofibrate are also available in Europe. The fibrates have been in use since the late 1960s, and for about 25 years their mode of action was not known.The relatively recent understanding of the molecular mechanisms of fibrate action1 represents one of the biggest breakthroughs in cardiovascular pharmacology. Fibrates are now known to alter the transcription of several genes involved in lipoprotein metabolism and other pathways.2 Fibrates are able to activate gene transcription because they are synthetic ligands for peroxisome proliferator-activated receptor (PPARa), a ligand-activated transcription factor and member of the nuclear hormone receptor superfamily. PPARa transmits signals from lipid-soluble factors, such as fatty acids, eicosanoids, hormones and vitamins, to genes in the nucleus by binding to DNA within specific response elements (PPRE).1

Effects of Fibrates on Plasma Lipids
A number of factors influence the response of plasma lipid levels to treatment with fibrates, including the baseline lipoprotein profile, the genetic and environmental factors underlying the hyperlipidemia, and the drug used. Fibrates are clearly the drug 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.3 Patients with severe hypertriglyceridemia frequently have low levels of low-density lipoprotein cholesterol, and treatment with fibrates may raise their low-density lipoprotein cholesterol levels by increasing intravascular lypolysis of very lowdensity lipoproteins (VLDL) through lipoprotein lipase, with resultant accumulation of newly formed low-density lipoprotein (‘beta-shift’ phenomenon). However, in the setting of more moderate hypertriglyceridemia (TG<500mg/dl), fibrates produce 30% to 50% reductions in serum triglycerides, 15% to 25% increases in high-density lipoprotein cholesterol, and have variable effects on low-density lipoprotein depending on the molecule used. Gemfibrozil has neutral low-density lipoprotein effects, whereas fenofibrate may produce low-density lipoprotein reductions ranging from 5% to 35%.4 An important aspect of low-density lipoprotein metabolism in patients with triglyceride and high-density lipoprotein problems is the accumulation of small, dense low-density lipoprotein. Fenofibrate decreases small, dense low-density lipoprotein particles, which are more susceptible to oxidation and more ‘atherogenic’ than larger, more buoyant low-density lipoprotein particles.5,6 Several nontraditional risk factors are also influenced by fibrates. Fenofibrate decreases plasma levels of Lp(a) by 7% to 23%,4,7 reduces fibrinogen,8 and lowers levels of serum uric acid to the point that it may have therapeutic effects on gout.9

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