This study demonstrated that bezafibrate significantly improved postprandial endothelial dysfunction and reduced both exogenous and endogenous postprandial TG levels in patients with metabolic syndrome. The potential association between the improvement in endothelial dysfunction and the decrease in TRLs suggests that bezafibrate may have vascular protective effects. Consequently, the risk of cardiovascular disease, especially the risk associated with postprandial TGs, may be reduced with bezafibrate treatment.
Our results are consistent with previous studies demonstrating reduced postprandial TG in response to fibrate treatment [12, 21]. Evans et al. reported that ciprofibrate treatment for 3 months improved postprandial endothelial dysfunction and postprandial TG levels after ingestion of a test meal containing 80 g fat in patients with type 2 diabetes mellitus . Rosenson et al. reported that fenofibrate treatment for 6 weeks significantly ameliorated postprandial hypertriglyceridemia, oxidative stress and inflammatory response after ingestion of a test meal containing standardized fat (50 g/m2) in patients with hypertriglyceridemia and the metabolic syndrome . Blood TG concentrations reflect the balance between uptake of TG into and clearance from the circulation. The majority of TG secreted into the bloodstream after a high-fat meal is from fat absorption via enterocytes . We demonstrated that intestinal TGs in chylomicrons and TG in VLDLs are decreased by bezafibrate. This is consistent with the findings of an experimental study, which found that postprandial chylomicrons and VLDLs were reduced in the plasma of bezafibrate-treated mice . CM and VLDL-sized particles have been reported to include chylomicron remnants, suggesting that the postprandial TG-lowering effects of bezafibrate are mainly due to decreased uptake of TG into the circulation and increased clearance of TGs from the bloodstream . However, a formal kinetic approach is required to confirm these findings and to evaluate the precise underlying mechanisms.
In this study, the changes in TRLs were moderately correlated with changes in FMD, although these correlations did not reach statistical significance. The sample size (n = 10) may have been too small to detect statistical significance, or bezafibrate may have a direct favorable effect on vascular function. Alternatively, improvements in vasodilation following fibrate therapy may have been due to changes in lipoprotein profiles. Indeed, bezafibrate can protect endothelial function in various populations including patients with metabolic syndrome  or coronary artery disease,  and we found that fasting % FMD was significantly improved in the bezafibrate group compared with the control group. Furthermore, bezafibrate increases the expression of endothelial nitric oxide synthase in cultured endothelial cells and increases nitric oxide bioactivity [25, 26]. Suppression of systemic inflammation by peroxisome proliferator-activated receptor α activation is an additional mechanism whereby bezafibrate may enhance nitric oxide synthase activity . Thus, bezafibrate treatment for 4 weeks may have preventive effects against postprandial endothelial dysfunction. Postprandial TRL-induced inflammation and oxidative stress, which affect the metabolism of nitric oxide and the release of vasoconstrictive mediators, result in endothelial dysfunction [6, 28]. In our study, we evaluated the levels of pentraxin 3 as a marker of inflammation. Pentraxin 3 is produced by vascular endothelial cells and may more directly reflect the inflammatory status of the vasculature [29–31]. Therefore, an increase in pentraxin 3 after the cookie test was expected, but no significant changes were observed both in the control and bezafibrate groups. Therefore, further studies are necessary to determine whether the administration of bezafibrate limits postprandial inflammation and oxidative stress and to evaluate the interplay between these stresses and endothelial function.
Our finding showed that the baseline triglyceride concentration was much lower in the bezafibrate than in the control group and that baseline TG was significantly correlated with baseline ApoB-48 concentration (r > 0.9, p < 0.01, data not shown). Baseline ApoB-48 may affect the peak TG concentration after the cookie test, because the assembly of CM in enterocytes depends on baseline apoB-48 concentration. Thus, baseline TG may represent the postprandial response.
Previous large studies reported that bezafibrate increases HDL-cholesterol concentrations by over 10% [32–35]. In this study, bezafibrate increased HDL-cholesterol concentration by 3 mg/dl (about 7 %), although this difference did not reach statistical significance. The four-week duration of bezafibrate treatment may have been too short to significantly increase HDL-cholesterol concentrations. Bezafibrate has been shown to benefit patients with atherogenic dyslipidemia. As our study population consisted of patients with the metabolic syndrome, it was not unexpected that the increase in HDL-cholesterol would be less than observed in patients with diabetes mellitus and atherogenic dyslipidemia. In contrast, a recent study showed that bezafibrate treatment of patients with type 2 diabetes mellitus increased cholesterol efflux, but had no effect on the anti-inflammatory activity of HDL . Thus, bezafibrate may have specific effects on HDL concentrations and functions.
In clinical trials, bezafibrate has been highly effective at reducing cardiovascular disease risk in patients with metabolic syndrome or atherogenic dyslipidemia [32, 37]. A prospective observational study found that bezafibrate significantly improved HbA1c in dyslipidemic patients with diabetes in Japan . At present, statins are the most widely applied therapy for the treatment and prevention of cardiovascular diseases related to atherosclerosis [38, 39]. Despite the increased use of statins as a monotherapy for elevated LDL-C, a significant residual risk of cardiovascular disease remains for patients with atherogenic dyslipidemia and insulin resistance, which are typical in patients with type 2 diabetes mellitus and metabolic syndrome. Combined bezafibrate–statin therapy is more effective for achieving comprehensive lipid control and reducing cardiovascular disease risk [8, 37, 40, 41].
Our study has several limitations. First, this was a single-blind study, and the number of participants enrolled was small. Therefore, some selection bias may have occurred. Second, no widely accepted method has been established for assessing postprandial hyperlipemia. The oral cookie test—with a defined quantity of fat per body surface area—may be a reliable method for detecting postprandial metabolic disturbances. The oral cookie test used in this study contains a greater content of carbohydrates than fat loading meals. These high-carbohydrate meals have a greater effect on glycemic parameters, including glucose and insulin concentrations, than high-fat meals. These metabolic differences may affect postprandial endothelial function and the effects of bezafibrate. Finally, because patients were only treated with bezafibrate for 4 weeks, we were not able to evaluate the long-term effects of bezafibrate on postprandial lipid dynamics.