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.
- SourceAvailable from: Michelle O'Donoghue
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- "Since growing evidence supports a pro-atherogenic role for Lp-PLA2, ongoing research is investigating its utility as a therapeutic target. Since Lp-PLA2 circulates primarily bound to LDL cholesterol, drugs that influence lipoprotein concentration have been shown to influence Lp-PLA2 levels, including statins [20, 21], niacin , fenofibrate , and gemfibrozil . The cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib (no longer in development) was shown in phase II testing to increase Lp-PLA2 mass by approximately 17% as compared with placebo . "
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
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- "Furthermore, ciprofibrate-induced TG reduction may effectively affect LDL-4 and LDL-5 . Fenofibrate was reported to reduce lipoproteinassociated phospholipase A2 (Lp-PLA 2 ) activity, a marker of sdLDL presence   and increase LDL buoyancy  ; Lp-PLA 2 reduction was more pronounced in patients treated with a combination of orlistat and fenofibrate compared with fenofibrate monotherapy . "
ABSTRACT: Dyslipidemia, and especially atherogenic dyslipidemia, a combination of small low-density lipoproteins cholesterol (LDL-C), decreased high-density lipoprotein cholesterol (HDL-C) and increased triglyceride (TG) concentrations, represents a major cardiovascular (CV) risk factor. Nuclear receptor peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of lipid metabolism; PPAR ligands are used to treat dyslipidemias. Fibrates have a major impact on TG metabolism as well as on modulating LDL size and subclasses. Fibrates target atherogenic dyslipidemia by increasing plasma HDL-C concentrations and decreasing small dense LDL (sdLDL) particles and TGs, thus contributing to dyslipidemia management, particularly in patients with diabetes (DM) or the metabolic syndrome (MetS). Furthermore, fibrates exert beneficial effects on adipokines, inflammation and oxidative stress as well as neuroprotective properties. However, further studies are needed to define the role of fibrates in the prevention of CV events. We review the effects of fibrates on atherogenic dyslipidemia and CV risk reduction.Current pharmaceutical design 01/2013; 19(17). DOI:10.2174/1381612811319170020 · 3.29 Impact Factor
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- "Fibrates, alone or combined with other drugs, have been demonstrated to reduce plasma levels of the small dense LDL particles and to induce a LDL phenotype modification [1, 3, 78–83]. Furthermore, evidence exists that fibrates improve inflammation-related parameters [10, 83–86]. There is also evidence that fibrates can alter HDL particle distribution, which may play a role in the residual CVD risk [87, 88]. "
ABSTRACT: Fibrates activate peroxisome proliferator activated receptor α and exert beneficial effects on triglycerides, high-density lipoprotein cholesterol, and low density lipoprotein subspecies. Fenofibric acid (FA) has been studied in a large number of patients with mixed dyslipidemia, combined with a low- or moderate-dose statin. The combination of FA with simvastatin, atorvastatin and rosuvastatin resulted in greater improvement of the overall lipid profile compared with the corresponding statin dose. The long-term efficacy of FA combined with low- or moderate- dose statin has been demonstrated in a wide range of patients, including patients with type 2 diabetes mellitus, metabolic syndrome, or elderly subjects. The FA and statin combination seems to be a reasonable option to further reduce cardiovascular risk in high-risk populations, although trials examining cardiovascular disease events are missing.Cardiovascular Drugs and Therapy 05/2012; 26(3):245-55. DOI:10.1007/s10557-012-6394-0 · 2.95 Impact Factor