Effects of bezafibrate and pravastatin on remnant-like lipoprotein particles and lipoprotein subclasses in type 2 diabetes

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Abstract

The effects of bezafibrate and pravastatin on remnant-like lipoprotein particles (RLPs) and lipoprotein subclasses were compared in type 2 diabetes. Bezafibrate (400 mg/day) and pravastatin (10 mg/day) were given to 27 Japanese diabetics in a randomized crossover design. RLP cholesterol (RLP-C) and RLP triglyceride (RLP-TG) were measured by an immunoseparation technique. LDL and HDL were separated each into three subclasses (large, medium, small) and their cholesterol (C) contents were measured by an HPLC method. RLP-C was reduced more effectively by pravastatin (bezafibrate −16.0% vs. pravastatin −40.6%, P<0.05), whereas RLP-TG was reduced more effectively by bezafibrate (−55.2% vs. −35.0%, P<0.05). Further, pravastatin decreased large and small LDL-C levels equally (large; −23.6%; medium; −17.2%, small; −21.0%), while bezafibrate produced a relatively larger reduction in small LDL-C (−12.1; −16.9; −21.5%). Whereas bezafibrate significantly decreased large HDL-C and increased medium and small HDL-C (−49.6; 34.1; 35.8%), pravastatin significantly increased only medium HDL-C (5.2; 9.4; 5.9%). Bezafibrate reduced RLP-C and RLP-TG more effectively in patients with high TG levels, whereas pravastatin's effect was not markedly influenced by the initial TG level. Thus measurements of RLP-C, RLP-TG, and HPLC subclasses revealed that bezafibrate and pravastatin differently influence the lipoprotein status in type 2 diabetes.

Introduction

The lipoprotein status in patients with type 2 diabetes mellitus (DM) is generally characterized by hypertriglyceridemia, a low level of high density lipoprotein cholesterol (HDL-C), and a normal or mildly elevated low density lipoprotein cholesterol (LDL-C) [1]. It has been reported that in type 2 diabetes, LDL particles shift toward a smaller and denser form, which is more susceptible to oxidation, glycation and consequently, more atherogenic [2], [3].

Remnant-like lipoprotein particles cholesterol (RLP-C) and triglyceride (RLP-TG) levels in diabetics have been reported to be higher than in non-diabetics [4]. RLP-C has been recognized as an independent risk factor for coronary artery disease (CAD) in women by the Framingham Heart Study [5]. Although RLP-TG has not been recognized as an independent risk factor for CAD, RLP-TG levels in cases of sudden cardiac death were higher than individuals who died from sudden non-cardiac causes [6].

Bezafibrate and pravastatin are representatives of fibric acid derivatives and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors, respectively, and are frequently prescribed in Japan. However, which agent is more favorable for treating diabetic dyslipidemia is not known yet, because to our knowledge, there are only two reports which compared the effects of bezafibrate and pravastatin on lipoproteins in type 2 diabetics [7], [8]. Regarding the effects on RLP-C, only one study compared pravastatin with bezafibrate [8].

Recently, in clinical lipid research laboratories, the focus has been shifting from major lipoprotein classes to their subclasses. In this regard, the separation of LDL and HDL subclasses by ultracentrifugation (UC) based on hydrated density has been attempted [9]. However, lipoprotein analysis by UC is time-consuming and requires large amounts of test samples and special technical training. Recently, categorical classifications, not quantifications, of LDL and HDL subclasses by polyacrylamide gel electrophoresis (PAGE) have been widely attempted [10], [11]. The PAGE method gives the researchers information on particle size profiles, but cannot measure absolute cholesterol contents of subclasses. In view of this, Okazaki et al. have recently reported a high performance liquid chromatography (HPLC) method for lipoprotein subclass analysis [12]. The lipoprotein profiles obtained by the HPLC method can provide information on absolute cholesterol concentrations of both LDL and HDL subclasses simultaneously according to their particle sizes. The HPLC method is much less time-consuming and needs only a very small amount of test sample (5 μl of serum or plasma per measurement).

The objectives of this study were firstly to compare the effects of bezafibrate and pravastatin on lipoprotein metabolism including analyses of RLPs and lipoprotein subclasses in type 2 diabetics and secondly to evaluate the clinical usefulness of LDL and HDL subclasses as determined by the HPLC method.

Section snippets

Patients and study design

A total of 27 Japanese diabetic outpatients aged 51–80 year with hypercholesterolemia and/or hypertriglyceridemia according to the criteria of the Japan Atherosclerosis Society (total cholesterol level ≥5.69 mmol/l, triglyceride level ≥1.69 mmol/l) [13] were consecutively enrolled in this study. Diagnoses of hypercholesterolemia and hypertriglyceridemia were based on the mean value of at least three pre-treatment lipid measurements. A diagnosis of type 2 DM was made according to the World

Results

The baseline lipid profiles of two treatment groups were well matched and no carry-over effects were observed. Therefore, we conjugated the results of both treatment groups and made the subsequent analyses. Body mass indices and glycemic control levels of subjects did not change significantly during the study period. None of the patients discontinued the study and no serious adverse effects related to drugs were observed. Compliance with trial medication was over 90% during the study with no

Discussion

In this study, we compared the effects of bezafibrate and pravastatin on RLP-C, RLP-TG, and HPLC subclasses cholesterol of LDL and HDL in type 2 diabetic patients. To our knowledge, this is the first report that simultaneously compared the effects of bezafibrate and pravastatin on RLPs and LDL and HDL subclasses.

Both drugs significantly decreased RLP-C and RLP-TG levels, but RLP-C was reduced more effectively by pravastatin, while RLP-TG was by bezafibrate (Table 2, Fig. 1). Because

Acknowledgements

The authors would like to thank Dr Takamitsu Nakano (Japan Immunoresearch Laboratories) for measuring RLP-C and RLP-TG concentrations, Dr Abby R Saniabadi (Japan Immunoresearch Laboratories) for critical reading of the manuscript, and Dr Atsushi Araki, Dr Toshiyuki Horiuchi and Dr Tetsuro Nakamura (Tokyo Metropolitan Geriatric Hospital) for their support in recruiting the participants.

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