Update on the use of fibrates: focus on bezafibrate

Abstract

Low-density lipoprotein-cholesterol (LDL-C) is a well established coronary heart disease (CHD) risk factor. However, the ability of this metabolic risk factor alone to identify individuals at rigk for future CHD events is limited. The raised triglycerides-low high-density lipoprotein-cholesterol (HDL-C) dyslipidaemia was shown to be an important cardiovascular risk factor independently of LDL-C levels. Fibric acid derivatives (fibrates) have been used in clinical practice for more than 2 decades as a class of agents known to decrease triglyceride levels while substantially increasing HDL-C levels. Through peroxisome proliferator-activated alpha-receptors, fibrates have a significant impact on the synthesis of several apolipoproteins and enzymes of lipoprotein metabolism as well as on the expression of several genes involved in fibrinolysis and inflammation. Data from recent primary and secondary prevention clinical trials demonstrate the efficacy of fibrate therapy in patients with the raised triglycerides-low HDL-C dyslipidaemia. This review summarizes current data regarding mechanism of action and the metbolic effects of fibrates, as well as results from major clinical trials on the efficacy of this mode of lipid lowering therapy. In addition, recent data from subgroup analyses of the Bezafibrate Infarction Prevention trial, demonstrating several important metabolic and long-term cardiovascular effects of bezafibrate therapy, are detailed.

Keywords: cardiac events; fibrates; high-density lipoprotein-cholsterol; metabolic syndrome; peroxisome proliferator-activated α-receptors.

Figure 1

Mechanism of action of fibrates. Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; PPAEα, peroxisome proliferator-activated receptor-α; PPRE, peroxisome proliferator response elements; RXR, retinoid X receptor; ↑ indicates increase; ↓ indicates decrease.

Figure 2

All-cause and cardiac mortality rates in tertiles of HDL-C change in the bezafibrate group compared to the placebo group. *p for trend < 0.05 Reprinted with permission from Goldenberg et al (2006).

Figure 3

Kaplan-Meier cumulative probability of outcome the combined endpoint of cardiac death or nonfatal myocardial infarction, and cardiac death separately, during an extended follow-up of the BIP trial. *p < 0.05.

Figure 4

Outcome of patients with the metabolic syndrome in BIP. *p < 0.05. Abbreviation: MI, myocardial infarction.

Figure 5

Two- and five-year Kaplan-Meier cumulative probability of diabetes incidence (in accordance with time of diagnosis after annual fasting blood glucose measurements) in the bezafibrate and placebo groups of the BIP trial.