Fibrates and Microvascular Complications in Diabetes - Insight from the FIELD Study

Abstract

Fibrates are widely prescribed lipid-lowering drug in the treatment of dyslipidemia. Their main clinical effects, mediated by peroxisome proliferative activated receptor (PPAR) alpha activation, are a moderate reduction in total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels, a marked reduction in triglycerides (TG) and an increase in high-density lipoprotein cholesterol (HDL-C), usually dependent of their baseline levels and dyslipidemia type. A beneficial effect on cardiovascular outcomes but also on inflammatory and thrombogenesis pathways as well as antioxidant properties have been evidenced conferring other pleiotropic effects to fibrates. Diabetic retinopathy, nephropathy and neuropathy are the major microvascular complications of Type 2 diabetes mellitus (T2DM) and their presence can accentuate the risk of cardiovascular disease. Hyperglycemia, hypertension, genetic susceptibility among other risk factors play a significant role in the development and progression of these complications. Plasma lipid abnormalities are also involved in the pathogenesis of microvascular diseases suggesting a potential benefit of lipid lowering drugs in their prevention. Clofibrate was the first fibrate in the 60's to show an improvement in the retinal hard exudation in subjects with diabetic retinopathy. Recently, in the Fenofibrate Intervention in Event Lowering in Diabetes (FIELD) study fenofibrate treatment demonstrated a significant 30% reduction in the need for laser therapy in patients with and without known diabetic retinopathy, and more particularly in the first course of laser treatment for both macular edema and proliferative retinopathy. In addition, fenofibrate treatment was associated with less albuminuria progression and reduced risk of non traumatic distal amputations. These results, along with previous evidence of positive effects on microvascular complications, suggest that fibrates, and particularly fenofibrate, offer good opportunity to prevent the most serious complications of diabetes.

Effects of taurine and housing density on renal function in laying hens

“…PPAR-α regulates both lipid metabolism and inflammation (Guan and Breyer, 2001). The activation of PPAR-α significantly decreases triglycerides and appropriately reduces total cholesterol and lowdensity lipoprotein (LDL) levels, and elevates highdensity lipoprotein (HDL) levels (Ansquer et al, 2009). In the current study, PPAR-α mRNA expression in the free range group was higher than that in the high-density group.…”

Long-Chain Acyl Coenzyme A Synthetase 1 Overexpression in Primary Cultured Schwann Cells Prevents Long Chain Fatty Acid-Induced Oxidative Stress and Mitochondrial Dysfunction

“…High circulating triglycerides and LCFAs are implicated in the development and progression of DN (1,7,34,40). Microarray studies have allowed us to explore the role of hyperlipidemia-driven gene changes in the diabetic peripheral nerve (13,21).…”

“…These data suggest that the LCFA-induced increase in oxidative stress in control Schwann cells is injurious and can be blocked by antioxidant pretreatment. Basal OCR (E), coupling efficiency (F), respiratory control ratio (G), and spare respiratory capacity (H) were calculated after subtracting nonmitochondrial respiration as described in (1). Data are mean -SEM of 3 replicate cultures, with 10 replicate measures (10 wells) per condition per experiment; *p < 0.05, **p < 0.01 versus Ctrl; x p < 0.05 versus Ctrl + FA; { p < 0.05, {{ p < 0.01, {{{ p < 0.001 versus Acsl1.…”

“…The consequences of DN, including chronic pain or loss of sensation, recurrent foot ulcerations, and amputation, are responsible for significant morbidity and high economic impact (10). Dyslipidemia is a recognized risk factor for the development of DN (1,30,40). Lipid profiles are commonly abnormal early in the course of type 2 diabetes and correlate with the onset of early DN (7).…”

Natural Aldose Reductase Inhibitors Act as Potent Agonists of PPARγ

“…Chlorofibrate was the first fibrate drug to be used in 1960's for the treatment of Diabetic Retinopathy that caused 30 % reduction in the need for laser therapy with patients with diabetic retinopathy. 8 10 TZDs have satisfactory effects on patients in pre-diabetic stage.…”