Effects of bezafibrate on lipoprotein subclasses and inflammatory markers in patients with hypertriglyceridemia—a nuclear magnetic resonance study
Introduction
There is a growing body of evidence that, in addition to LDL-cholesterol (C), increased TG-rich lipoproteins (increased remnants), decreased HDL-C and small dense LDL comprise a new cluster of atherogenic dyslipidemia. This type of dyslipidemia represents metabolic perturbations as a consequence of abdominal obesity and involves metabolic abnormalities over entire lipoprotein spectrums and more importantly associates with the increased risk for coronary artery disease (CAD) [1].
Bezafibrate, one of fibrate derivatives, has been considered to be highly effective in treating hypertriglyceridemia and provided a benefit in CAD patients with high TG and low HDL-C levels [2]. Previous studies also revealed that bezafibrate increased HDL-C and altered LDL particles size in favor of decreasing small dense LDL [3], [4]. While these studies all employed laborious ultracentrifugation and gradient gel electrophoresis methodologies to quantify lipoprotein subclasses, a new technology utilizing proton nuclear magnetic resonance (NMR) has drawn more attentions recently [5], [6]. This new method uses signals emitted from methyl groups of lipids. Overall NMR signals from these lipids were computationally decomposed to yield 16 lipoproteins subclasses concentrations, together with particle numbers and sizes. The NMR method does not require fractionation of lipoproteins, is rapid measurement, and NMR-determined lipoprotein subclasses concentrations correspond well to those by the established methods [7]. Furthermore, recent studies [8], [9], [10] have shown clinical values of NMR-measured lipoprotein subclasses concentrations as the risk of CAD. In the present study, we, for the first time, utilized NMR method to investigate the effect of bezafibrate on lipoprotein metabolism in hypertriglyceridemic patients. We also focused on potential effects of bezafibrate on inflammatory markers.
Section snippets
Methods
Twenty four hypertriglyceridemic patients were recruited for this study from out-patients clinic of Jikei University School of Medicine Hospital. Eligibility criteria included age between 30 and 70 years, body mass index (BMI) less than 30 kg/m2 and fasting triglyceride values ≥150 mg/dl both at screening and at the end of run-in period. None of the study subjects had poorly controlled diabetes (HbA1c>8%) or evidence of thyroid, liver or renal dysfunction (creatinine>2 mg/dl) and none were
Baseline demographic measures
Baseline characteristics of the study subjects are summarized in Table 1. The study subjects were mostly comprised of men (91.7%) and the average age of 53.8 years old. The average BMI of 25.1 kg/m2 was equal to the cut-off point to define obesity in Japan and, in fact, 10 patients (42%) were obese. Percentage of hypertension and diabetes are 50% and 25%, respectively. Current smokers comprised 42%. All patients, except for one patient who underwent coronary artery bypass surgery, were free
Discussion
In addition to elevated LDL-C, increased TG-rich lipoproteins (increased remnants), decreased HDL-C and small dense LDL comprise a new cluster of atherogenic dyslipidemia. Unlike hypercholesterolemia in which HMG-CoA reductase inhibitors are now widely accepted as the first choice, fibrate derivatives are considered to be an ideal treatment for this type of dyslipidemia. A recent intervention trials further supported this strategy by demonstrating that gemfibrozil provided a benefit when used
Acknowledgements
This study was funded by a grant from Kissei Pharmaceutical, Tokyo, Japan and Health and Labor Sciences Research Grants for Comprehensive Research on Aging and Health (H15-Choju-012), Japan.
References (27)
- et al.
Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT)
J. Am. Coll. Cardiol.
(1998) - et al.
Long-term efficacy of bezafbrate in reductionof small, dense low-density lipoprotein by hypotriglyceridemic action
Curr. Ther. Res. Clin. Exp.
(2000) - et al.
Effects of bezafibrate therapy on subfractions of plasma low-density lipoprotein and high-density lipoprotein, and on activities of lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein in patients with hyperlipoproteinemia
Atherosclerosis
(1994) - et al.
Relation of hypertriglyceridemia to plasma concentrations of biochemical markers of inflammation and endothelial activation (C-reactive protein, interleukin-6, soluble adhesion molecules, von Willebrand factor, and endothelin-1)
Am. J. Cardiol.
(2003) - et al.
Effect of atorvastatin and bezafibrate on plasma levels of C-reactive protein in combined (mixed) hyperlipidemia
Atherosclerosis
(2002) - et al.
Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: reversal with bezafibrate therapy in a randomized controlled trial
Am. J. Med.
(2002) - et al.
Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men. Prospective results from the Quebec Cardiovascular Study
Circulation
(1997) Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study
Circulation
(2000)- et al.
Quantification of plasma lipoproteins by proton nuclear magnetic resonance spectroscopy
Clin. Chem.
(1991) Measurement of lipoprotein subclass profiles by nuclear magnetic resonance spectroscopy
Clin. Lab.
(2002)
Development of a proton nuclear magnetic resonance spectroscopic method for determining plasma lipoprotein concentrations and subspecies distributions from a single, rapid measurement
Clin. Chem.
Relation of lipoprotein subclasses as measured by proton nuclear magnetic resonance spectroscopy to coronary artery disease
Arterioscler. Thromb. Vasc. Biol.
Low-density lipoprotein particle concentration and size as determined by nuclear magnetic resonance spectroscopy as predictors of cardiovascular disease in women
Circulation
Cited by (30)
Comparison of statin alone versus bezafibrate and statin combination in patients with diabetes mellitus and acute coronary syndrome
2014, American Journal of CardiologyCitation Excerpt :Nonetheless, despite the almost universal use of statins in the setting of ACS, significant residual cardiovascular risk is still present, especially in patients with DM. Bezafibrate significantly increased high-density lipoprotein cholesterol level; reduced plasma triglycerides, free fatty acids, small dense low-density lipoprotein particles, remnants, glucose, and insulin resistance; and induced atherosclerotic plaque regression in the thoracic and abdominal aorta.10–15,17,25 In addition, bezafibrate has important fibrinogen-related properties and anti-inflammatory effects.
Quantum chemical computations including intermolecular interactions, natural bond orbital analysis and scaled quantum mechanical force field calculations on bezafibrate - A cholesterol drug for HIV infected
2012, Vibrational SpectroscopyCitation Excerpt :Healthcare professionals use fibrates as first-line therapy for patients with isolated severe hypertriglyceridemia [1]. It also helps to lower LDL (low-density lipoprotein) cholesterol and triglyceride in the blood and increase HDL (high-density lipoprotein) [2]. Basically, fibrates are hypolipemic drugs which are used to reduce the flow of fatty acids to the liver, stimulate lipoprotein-lipase activity and increase the biliary excretion of hepatic cholesterol.
Effect of bezafibrate therapy on atherosclerotic aortic plaques detected by MRI in dyslipidemic patients with hypertriglyceridemia
2008, AtherosclerosisCitation Excerpt :The BECAIT trial [22] also showed that bezafibrate increased small HDL levels and that an increase in small HDL levels was associated with less progression of coronary stenosis. Small HDL particles are believed to be better acceptors for cholesterol than large HDL particles [24,25]. Since atorvastatin increases HDL particle size [26], the reduction in HDL particle size and the increase in HDL particles by bezafibrate may play an important role in the regression of abdominal aortic plaques, which could not be regressed by atorvastatin.
Atherogenic Lipoproteins for the Statin Residual Cardiovascular Disease Risk
2022, International Journal of Molecular SciencesAnti-unicorn principle: Appropriate biomarkers don’t need to be rare or hard to find
2020, Biomarkers in Drug Discovery and Development: A Handbook of Practice, Application, and StrategyDeterminants of bezafibrate-induced improvements in LDL cholesterol in dyslipidemic patients with diabetes: A subgroup analysis of the J-BENEFIT study
2015, Journal of Atherosclerosis and Thrombosis
H⋯O intermolecular interaction (O
O of secondary amide group). The current study provides complete vibrational assignments for all the vibrational modes, which is supported by normal coordinate analysis, force constants and potential energy distributions. In the scaled quantum mechanical (SQM) approach the systematic errors of the computed harmonic force field have been corrected by multiple scale factors and the theoretical spectrogram for the infrared and Raman spectra of the title molecule have been constructed. Natural bond orbital analysis has been carried out to understand the nature of different interactions responsible for the electron delocalization and the intramolecular charge transfer between the orbitals (n → π*, n → σ*, π → π*).