Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endpoint studies have been performed with fibrates in coronary heart disease since 1971. The results have been confusing - starting with initial benefits in small studies, but contradicted by either minimal benefits in the Coronary Drug Project or adverse noncardiovascular (non-CV) effects in the World Health Organization Clofibrate Study. Fibrates returned for patients with low HDL-C and low LDL-C after a 25% event reduction were seen in the Veterans Affairs HDL Intervention Trial. The greater prominence ascribed to the lipid triad of the metabolic syndrome and the increasing prevalence of diabetes increased the topicality of fibrates given their main action of converting small dense to light buoyant LDL. The Fenofibrate Intervention in Event Lowering in Diabetes (FIELD) Study has carried on the tradition. Fenofibrate therapy in 9795 patients comprising a mixed low-risk primary and a medium-risk secondary prevention cohort resulted in an 11% reduction in coronary events (p = 0.16), a similar but significant reduction in CV events (p = 0.04; number needed to treat = 70). The benefits were concentrated in primary prevention and on nonfatal myocardial events, but the study was confounded by asymmetrical statin drop-in due to the LDL-C-lowering effect of fenofibrate. Safety was generally good, including in combination with statins, but old concerns about sudden death, pancreatitis and venous thrombosis returned. Unexpected benefits were seen with fenofibrate on microvascular endpoints including microalbuminuria and retinopathy. Fenofibrate is a reasonable second-line therapy for dyslipidaemia in diabetes and safe in combination therapy. Its benefits on microvascular disease and in combination therapy require further confirmation.
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PMID:FIELDS of dreams, fields of tears: a perspective on the fibrate trials. 1662 Mar 58

The prominent use of fibric acid derivatives has lessened over the years because of unimpressive results in major clinical trials, safety concerns, and the emergence of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Clofibrate was widely used in the 1970s, but after publication of results from two major trials demonstrating only modest reductions in the rate of coronary heart disease (CHD) and concerns regarding an increase in the frequency of gallstones and overall mortality, its use subsided dramatically. With the introduction of gemfibrozil in the 1980s came a renewed interest in the class, which was also supported by the published results of the Helsinki Heart Study; however, despite a significant reduction in CHD events and a sound safety profile, overall mortality was comparable to that with placebo. Again, in the 1990s, awareness of the fibrates was heightened with the availability of fenofibrate and the findings of another major trial using gemfibrozil, the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), which demonstrated impressive results in reducing cardiovascular events. To further strengthen the VA-HIT results, numerous post hoc analyses were performed on the data of major trials of fibrate therapy among patients with mixed dyslipidemia, with similar findings. Recently, however, data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were published, indicating mixed results. Nearly 40 years after the introduction of the fibrates, practitioners are still contemplating the role of these agents in the treatment of CHD.
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PMID:Fibrates: what have we learned in the past 40 years? 1731 52

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.
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PMID:Fibrates and microvascular complications in diabetes--insight from the FIELD study. 1919 80

Adiponectin receptors mediate the antidiabetic effects of adiponectin. Although suggested to be mainly expressed in muscle, liver, and adipocyte cells, the expression of adiponectin receptors in beta cells is unclear. Given the primary involvement of this cell type in diabetes mellitus, we presently examined the expression level of adiponectin receptor 2 (AdiR2) in beta cells. Expression was significantly increased under acute hyperlipidemic conditions but impaired under chronic conditions. The impaired AdiR2 expression may play a role in worsened beta cell function. Clofibrate, an agonist of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) delayed the palmitate-induced impairment of AdiR2 expression and PPAR-alpha; this delay was abolished by PPAR-alpha targeted small interfering RNA. The results suggest that AdiR2 expression is regulated by palmitate via PPAR-alpha.
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PMID:Regulation of adiponectin receptor 2 expression via PPAR-alpha in NIT-1 cells. 1933 49


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