The effect of orlistat and fenofibrate, alone or in combination, on small dense LDL and lipoprotein-associated phospholipase A(2) in obese patients with metabolic syndrome
ABSTRACT Increased concentration of small dense LDL cholesterol (sdLDL-C) and activity of lipoprotein-associated phospholipase A2 (Lp-PLA(2)) are considered as emerging cardiovascular risk factors and are commonly encountered in subjects with metabolic syndrome (MetS).
The primary endpoint of this study was the effect of orlistat and fenofibrate, alone or in combination, on Lp-PLA(2) activity and LDL phenotype in overweight and obese patients (body mass index>28 kg/m(2)) with MetS.
Patients (n=89) were prescribed a low-fat low-calorie diet and were randomly allocated to receive orlistat 120 mg three times daily (O group), micronized fenofibrate 200mg/day (F group) or both (OF group) for 6 months.
Significant reductions of sdLDL-C levels were observed in all treatment groups. Groups F and OF experienced a greater reduction in sdLDL-C levels (p<0.05) together with a greater increase in LDL particle diameter (p<0.05) compared with group O. Total plasma Lp-PLA(2) activity significantly decreased in all treatment groups. The reduction of Lp-PLA(2) was more pronounced with OF administration compared with each monotherapy (p<0.05).
Orlistat and fenofibrate exhibited favorable effects on Lp-PLA(2) activity and LDL phenotype in overweight and obese patients with MetS. Importantly, combination treatment had a more favorable effect on these risk factors.
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ABSTRACT: Type 2 diabetes mellitus (T2DM) is associated with the development and progression of cardiovascular disease (CVD). Statins have an established efficacy in the management of dyslipidemia primarily by decreasing the levels of low-density lipoprotein cholesterol and thus decreasing CVD risk. They also have a favorable safety profile. Despite the statin-mediated benefit of CVD risk reduction a residual CVD risk remains, especially in T2DM patients with high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) values. Fibrates decrease TG levels, increase HDL-C concentrations, and improve many other atherosclerosis-related variables. Fibrate/statin co-administration improves the overall lipoprotein profile in patients with mixed dyslipidemia and may reduce the residual CVD risk during statin therapy. However, limited data exists regarding the effects of statin/fibrate combination on CVD outcomes in patients with T2DM. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study the statin/fibrate combination did not significantly reduce the rate of CVD events compared with simvastatin/placebo in patients with T2DM. However, it did show a possible benefit in a pre-specified analysis in the subgroup of patients with high TG and low HDL-C levels. Furthermore, in the ACCORD study the simvastatin/fenofibrate combination significantly reduced the rate of progression of retinopathy compared with statin/placebo administration in patients with T2DM. The present review presents the available data regarding the effects of statin/fibrate combination in patients with T2DM and atherogenic mixed dyslipidemia.The Review of Diabetic Studies 01/2013; 10(2-3):171-90. DOI:10.1900/RDS.2013.10.171
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ABSTRACT: Several lines of evidence suggest that the lipoprotein-associated phospholipase A 2 (Lp-PLA 2) plays an impor-tant role in the pathogenesis of atherosclerotic disease. From a pathophysiological point of view the enzyme bound to apolipoprotein-B-containing lipoproteins (which corresponds to more than 90% of plasma enzymatic activity) may play a proatherogenic role since it generates lysophosphatidylcholine and oxidized fatty acids, molecules that have been shown to promote atherogenesis. On the other hand, the enzyme associated with high-density lipoprotein (HDL) may play an antiatherogenic role since it protects low-density lipoprotein (LDL) from oxidation and diminishes the biological func-tions of oxidized LDL. Several large-scale, prospective studies have shown that both plasma Lp-PLA 2 mass and activity represent important predictors of future cardiovascular risk in primary and secondary prevention populations. In this re-view, we summarize the current knowledge on the effect of drugs used in the treatment of cardiovascular disease on the plasma levels of Lp-PLA 2 . This information may help clinicians to design safe and effective therapeutic strategies for the prevention and treatment of atherosclerotic disease.
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ABSTRACT: Evidence suggests that inflammation plays a central role in the pathogenesis of atherosclerosis (Libby, Nature 420:868-874, 2002). Inflammation is a physiologic process with highly regulated and often redundant mechanisms to balance pro-inflammatory and anti-inflammatory responses. The complexity of these networks has made it challenging to identify those specific pathways or key enzymes that contribute directly to atherogenesis and could act as a valuable therapeutic target. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a member of the phospholipase A2 family of enzymes and is believed to contribute to atherosclerotic plaque progression and instability by promoting inflammation. A large number of epidemiologic studies have demonstrated that elevated levels of Lp-PLA2 are associated with an increased risk of cardiovascular events across diverse patient populations, independent of established risk factors including low-density lipoprotein cholesterol. Further, a growing number of preclinical and genetic studies support a causal role for Lp-PLA2 in atherosclerosis. The development of a novel therapeutic agent that directly inhibits the Lp-PLA2 enzyme has provided a unique opportunity to directly test the hypothesis that inhibition of this inflammatory enzyme will translate into improved clinical outcomes. In this article, we will review the evidence to support the notion that Lp-PLA2 is causally implicated in the pathobiology of atherogenesis and discuss the potential utility of inhibiting this enzyme as a therapeutic target.12/2013; 2(2):125-34. DOI:10.1007/s40119-013-0022-3