Fibrates, dyslipoproteinaemia and cardiovascular disease

Recent epidemiological data have reaffirmed that elevated plasma triglyceri de and low HDL-cholesterol levels are important risk factors for atheroscle rotic vascular disease. The rationale for the clinical use of fibric acid d erivatives, which are designed to correct this metabolic nexus, is now on f irmer ground. The mechanism of action of fibrates on lipoprotein metabolism has recently been elucidated at the molecular level and involves the activ ation of peroxisome proliferator-activated recepior-alpha 1 in the liver, w ith the net effect of improving the plasma transport rates of several lipop roteins. Other potential anti-atherothrombotic effects include the inhibiti on of coagulation and enhancement of fibrinolysis, as well as the inhibitio n of inflammatory mediators involved in atherogenesis. These consequences p robably underpin the favourable effects of fibrates seen in recent angiogra phic and clinical trials. Two important clinical trials on the effect of ge mfibrozil (Veterans Administration-HDL-Cholesterol Intervention Trial) and bezafibrate (Bezafibrate Infarction Prevention Study) have recently been co mpleted in subjects with elevated triglyceride, low HDL and normal or near- normal LDL-cholesterol levels, The results testify to the efficacy of these agents in decreasing the incidence of cardiovascular events, particularly in patients with multiple risk factors and plasma triglyceride levels of ov er 2.2 mmol/l, The findings of these trials are compared with the statin-ba sed Air Force/Texas Coronary Atherosclerosis Prevention Study, with a recom mendation that future studies in appropriately selected patients should exa mine the synergistic effect of the fibrate/statin combination. The absolute risk reduction in the incidence of coronary events in the Veterans Adminis tration-HDL-Cholesterol Intervention Trial compares favourably with the sta tin trials. The therapeutic aspects of the efficacy and safety of fibrates are reviewed. Besides primary mixed hyperlipidaemias, particular indication s for the clinical use of fibrates include type 2 diabetes, the metabolic s yndrome and renal insufficiency. The St Mary's, Ealing, Northwick Park Diab etes Cardiovascular Disease Prevention Study has suggested that fibrates ma y decrease the incidence of coronary events in type 2 diabetes, but this hy pothesis will be more extensively tested in the Diabetes Atherosclerosis In tervention Study, Fenofibrate in Event Lowering in Diabetes Study and Lipid s in Diabetes Study projects. Although significant new knowledge has accrue d over the past few years concerning the fundamental and clinical aspects o f fibrates, the success of these agents in clinical practice depends on the availability of methods for assessing cardiovascular risk as well as on tr eatment guidelines, which as presently designed and recommended may be inac curate and suboptimal. Curr Opin Lipidol 10:561-574. (C) 1999 Lippincott Wi lliams & Wilkins.