The fibric acid derivatives, also known as fibrates, are well established as effective agents for managing dyslipidemia, in particular elevated concentrations of triglyceride-rich very-low-density lipoprotein (VLDL) and VLDL remnants and low levels of high-density lipoprotein cholesterol (HDLC) that are typically associated with the dyslipidemia characteristic of type 2 diabetes and the metabolic syndrome. Clofibrate has been discontinued in the United States since it has been associated with cholangiocarcinoma and other gastrointestinal cancers 1. Other fibrates that are available worldwide include bezafibrate and ciprofibrate.
Fibrates are indicated for the treatment of hypercholesterolemia, hypertriglyceridemia, and as adjunctive therapy to diet to reduce elevated total cholesterol, low-density lipoprotein cholesterol (LDLC), triglycerides, and apolipoprotein-B (apo-B), and to increase HDL-C in adult patients with primary hypercholesterolemia or mixed dyslipidemia. 2 The use of fibric acid derivatives has decreased over the years because of unimpressive results in major clinical trials, safety concerns, and the emergence of HMG-CoA reductase inhibitors, more commonly known as statins. While statins are considered firstline therapy for dyslipidemia based on their efficacy in reducing levels of LDL-C, they exhibit only modest effects by decreasing triglycerides about 15-35% and increasing HDL up to 15% 3. The safety and efficacy of fibrates have been reviewed in six major clinical trials during the past 30 years. The results have generated mixed findings when evaluating overall mortality, cardiovascular events, and adverse effects. The inconsistent outcomes may be a result of differences among individual fibrates and highly varied study populations. In this article, the pharmacology of the fibrates is discussed along with evaluating their role in the primary and secondary prevention of coronary heart disease (CHD).
Mechanism of Action
Fibrates have a complex mechanism of action, involving several steps in the metabolism of lipoproteins. Primarily, fibrates affect the peroxisome proliferator activated receptor (PPAR)-α (Table 1) 4. The PPARs are a group of nuclear receptors predominantly expressed in tissues, such as the liver, kidney, heart and muscle, that metabolize fatty acids 5. On activation by binding of the fibrate, PPAR-α binds as heterodimers with a retinoid X receptor (RXR), which then recognizes and binds to specific PPAR-α response elements leading to expression modulation of the target genes 5. In particular, the activity of lipoprotein lipase is increased and synthesis of apoC-III is decreased, which both enhance the clearance of circulating triglyceride-rich lipoproteins 6. PPAR-α activation regulates gene expression involved in metabolic pathways including lipid metabolism, thereby reducing triglyceride concentrations and increasing HDL concentrations.