Fenofibrate: Metabolic and Pleiotropic Effects

Abstract

Disturbances of lipoprotein metabolism represent one of the most important risk factors for vascular events. However, dyslipidaemic patients often have a number of additional abnormalities (such as endothelial dysfunction, hypertension, low-grade inflammation, haemostatic abnormalities and hyperuricaemia) that may accelerate the atherosclerotic process. Thus, the ideal lipid-modifying drug, along with exerting beneficial effects on lipoprotein metabolism, should also improve these coexisting disturbances. Fibric acid derivatives (fibrates) are a class of lipid-modifying drugs mainly used in patients with elevated triglyceride levels. These drugs mainly exert their actions via the activation of specific nuclear receptors called peroxisome proliferator-activated receptors alpha (PPARalpha). In this review, we summarize the current evidence suggesting that fenofibrate, one of the most widely used fibric acid derivatives, along with its well established actions on lipids also exerts several other antiatherogenic actions. Based on recently published studies, fenofibrate is a useful option for patients with primary combined dyslipidaemias or secondary dyslipidaemias, such as those associated with diabetes mellitus, metabolic syndrome or HIV infection. Additionally, in cases of refractory dyslipidaemia, the combination of fenofibrate with statins is a therapeutic option.

High Doses of Rosuvastatin are Superior to Low Doses of Rosuvastatin Plus Fenofibrate or n‐3 Fatty Acids in Mixed Dyslipidemia

“…However, controversy exists as to whether this phenomenon represents a true deterioration in renal function or an increase in the rate of metabolic production of creatinine. On the other hand, the well-known uricosuric properties of fenofibrate possibly underlie the greater reduction in serum uric acid levels observed in the RF patient group [26]. In agreement with previous studies we found that the high doses of rosuvastatin (40 mg) may adversely affect glucose homeostasis leading to a worsening of insulin resistance indices [6,27].…”

Obesity, Metabolic Syndrome, and Diabetes: Cardiovascular Implications and Therapy

“…They might therefore appear to be an ideal treatment for atherogenic dyslipidemia in diabetes mellitus. 42 However, the FIELD study showed that fenofibrate, one of the most widely used fibrates, did not significantly reduce the risk of coronary events. 43 This has led to its usefulness as a preventive treatment being questioned.…”

The genetic architecture of fasting plasma triglyceride response to fenofibrate treatment

“…8 Fenofibrate reduces fasting TG level and induces a shift to a less atherogenic TG-rich lipoprotein profile. 10 The effects of fenofibrate on the levels of total plasma TG and circulating very low-density lipoprotein (VLDL) particles, the primary carrier of TG during fasting, 11 are mediated through its binding to PPAR-a. 8 The resulting up-and downregulation of a number of genes involved in lipoprotein metabolism lowers TG by several mechanisms: (1) reducing the availability of free fatty acids for TG formation, (2) increasing the catabolism of VLDL, and (3) reducing neutral lipid (cholesterol ester and TG) exchange between VLDL and HDL.…”

“…8 The resulting up-and downregulation of a number of genes involved in lipoprotein metabolism lowers TG by several mechanisms: (1) reducing the availability of free fatty acids for TG formation, (2) increasing the catabolism of VLDL, and (3) reducing neutral lipid (cholesterol ester and TG) exchange between VLDL and HDL. 10,12 Genes that are upregulated in response to PPAR-a include LPL, which is involved in TG lipolysis, 8 APOA5, which enhances LPL action and may restrict VLDL secretion from the liver, 8,13 and several genes related to HDL-C metabolism including APOA1, APOA2, and FABP. PPAR-a also downregulates APOC3, an apolipoprotein that inhibits VLDL clearance.…”