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Background: Dyslipidemia is commonly observed in polycystic ovary syndrome (PCOS) patients. Bezafibrate is a drug for dyslipidemia acting through peroxisome proliferator-activated receptors. We investigated the effects of bezafibrate for ovulation induction in patients with PCOS with dyslipidemia who were resistant to clomiphene citrate (CC)., Methods: This was a prospective pilot study. Seven infertile, CC-resistant, PCOS patients with dyslipidemia were enrolled in this study. The participants received bezafibrate at 400 mg/day from day 1 of menses and CC at 100 mg/day from day 5 of menses simultaneously until one follicle measuring at least 18 mm in diameter was found by transvaginal ultrasound. The main outcome was ovulation rate., Results: Five of 7 patients successfully ovulated. The mean number of days of menses until the follicle reached 18 mm in diameter was 16 ± 3 (range 13-20). Monofollicular development was observed in all patients that ovulated. One woman became pregnant and delivered a healthy baby., Conclusion: Bezafibrate may be effective for ovulation induction in CC-resistant PCOS patients with dyslipidemia., (Copyright © 2010 S. Karger AG, Basel.)

Background: The majority of acute myeloid leukaemia (AML) patients are over sixty years of age. With current treatment regimens, survival rates amongst these, and also those younger patients who relapse, remain dismal and novel therapies are urgently required. In particular, therapies that have anti-leukaemic activity but that, unlike conventional chemotherapy, do not impair normal haemopoiesis., Principal Findings: Here we demonstrate the potent anti-leukaemic activity of the combination of the lipid-regulating drug bezafibrate (BEZ) and the sex hormone medroxyprogesterone acetate (MPA) against AML cell lines and primary AML cells. The combined activity of BEZ and MPA (B/M) converged upon the increased synthesis and reduced metabolism of prostaglandin D(2) (PGD(2)) resulting in elevated levels of the downstream highly bioactive, anti-neoplastic prostaglandin 15-deoxy Delta(12,14) PGJ(2) (15d-PGJ(2)). BEZ increased PGD(2) synthesis via the generation of reactive oxygen species (ROS) and activation of the lipid peroxidation pathway. MPA directed prostaglandin synthesis towards 15d-PGJ(2) by inhibiting the PGD(2) 11beta -ketoreductase activity of the aldo-keto reductase AKR1C3, which metabolises PGD(2) to 9alpha11beta-PGF(2alpha). B/M treatment resulted in growth arrest, apoptosis and cell differentiation in both AML cell lines and primary AML cells and these actions were recapitulated by treatment with 15d-PGJ(2). Importantly, the actions of B/M had little effect on the survival of normal adult myeloid progenitors., Significance: Collectively our data demonstrate that B/M treatment of AML cells elevated ROS and delivered the anti-neoplastic actions of 15d-PGJ(2). These observations provide the mechanistic rationale for the redeployment of B/M in elderly and relapsed AML.

Lipoprotein glomerulopathy (LPG) is a rare hereditary disease characterized by the accumulation of much thrombi material consisting of lipoproteins at the glomerular capillary lumen. Most patients show nephrotic syndrome; nearly half progress to chronic renal failure. Intensive therapy with lipid-lowering agents reportedly engenders clinical remission with histological resolution. We report the case of a 14-year-old Japanese female patient who had been in a nephrotic condition with hematuria from 4 years old and who had been diagnosed based on pathological and molecular examination at 7 years old. We initially treated the patient with probucol, enalapril (angiotensin-converting enzyme inhibitor: ACEI), and dipyridamole from age 7, but achieved no improvement in her nephrotic status. Subsequently, we replaced probucol with bezafibrate at age 11 and added atorvastatin calcium hydrate and valsartan (angiotensin II receptor blocker: ARB) the following year. The next 3 years' treatment improved her nephrotic status, decreased serum apolipoprotein E, and markedly decreased intraglomerular lipoprotein thrombi. Early and intensive therapy with antilipidemic drugs combined with ACEI and ARB is inferred to be effective for LPG.

Combined assessment of serum uric acid (UA) and C-reactive protein (CRP) compared with single-marker evaluation in patients with coronary artery disease (CAD) was performed. CRP is an independent predictor of cardiac events in patients with or without CAD. Data regarding the prognostic value of UA in patients with CAD are conflicting. The primary end point (fatal or nonfatal myocardial infarction or sudden cardiac death) was related to levels of UA and CRP in 2,966 patients with CAD enrolled in the Bezafibrate Infarction Prevention trial who were followed for a mean period of 6.2 years. Primary end-point rates were directly related to increasing tertiles (from tertile 1 [T1] to tertile 3 [T3]) of UA (12.7%, 12.8%, and 17.6% respectively, p for trend <0.0001) and CRP (11.5%, 14.2%, and 17.3% respectively, p for trend <0.002). By multivariable analysis, T3 UA (>6.25 mg/dl) and T3 CRP (>5.37 mg/dl) were shown to be independently associated with a significant increase in risk for the primary end point (hazard ratio 1.30, 1.01 to 1.68, p = 0.04; hazard ratio 1.31, 1.02 to 1.69, p = 0.03, respectively). Primary end-point rates were similarly high in those patients with a combination of T3 UA and T1 CRP levels (hazard ratio 1.68, 1.05 to 2.66) or a combination of T3 CRP and T1 serum UA levels (hazard ratio 1.64, 1.04 to 2.58) or in patients with T3 of the 2 markers (hazard ratio 1.66, 1.07 to 2.59). In conclusion, combined assessment of UA and CRP levels provides incremental information for risk stratification of patients with CAD with low levels of a single marker.

Eruptive xanthoma with unexpected granuloma annulare-like microscopic appearance - Case report Abstract: Eruptive xanthoma and granuloma annulare are dermatological diseases with different clinical findings that, sometimes, exhibit histopathological similarities with potential for misinterpretation. We report a case of an eruption of yellow-orange papules with erythematous borders in a 34-year-old male with high levels of serum triglycerides and cholesterol. The skin biopsy specimen has diagnosed granuloma annulare. Review of the histologic material revealed eruptive xanthoma. Remission of the eruption after treatment of dyslipidemia confirmed the diagnosis of the eruptive xanthoma and motivated research about the histological similarities and differences between these diseases.

Objective: The purpose of this study was to test the hypothesis that bezafibrate, an approved fibrate, can prevent or delay type 2 diabetes., Research Design and Methods: This was a retrospective cohort study using data from routine medical practice in the U.K., as captured by the General Practice Research Database (GPRD). Individuals chronically exposed to bezafibrate were compared with individuals chronically exposed to other fibrates. Hazard ratios (HRs) for incident type 2 diabetes were calculated using a Cox proportional hazards model. A post hoc analysis was used to examine the effect of bezafibrate on progression to use of oral antidiabetic medications or insulin in individuals with diabetes at baseline., Results: Bezafibrate users had a lower hazard for incident diabetes than users of other fibrates (HR 0.66 [95% CI 0.53-0.81]). This effect became stronger with increasing duration of therapy. Post hoc analysis of the effect of bezafibrate on progression of preexisting diabetes also showed a lower hazard for progression to use of antidiabetic medication (0.54 [0.38-0.76]) or progression to use of insulin (0.78 [0.55-1.10])., Conclusions: Bezafibrate appears to have clinically important antidiabetic properties. Randomized controlled trials should be considered to assess the utility of bezafibrate in treating patients with diabetes or in preventing diabetes in high-risk patients.

Background: Major randomized trials of fibrate therapy demonstrate an inverse relationship between on-treatment high-density lipoprotein cholesterol (HDL-C) increments and clinical outcome. We hypothesized that the degree of HDL-C response to bezafibrate is independently associated with subsequent long-term mortality., Methods: The risk of death at 16 years of follow-up among 3026 patients with coronary heart disease allocated to the original bezafibrate (n = 1509) and placebo (n = 1517) arms of the Bezafibrate Infarction Prevention (BIP) trial was related to HDL-C response to bezafibrate therapy, categorized as upper-tertile (>8 mg/dL) or lower-tertile (< or =8 mg/dL) on-treatment HDL-C change., Results: Multivariate analysis demonstrated that patients allocated to bezafibrate therapy experienced a significant 11% reduction (P = .06) in the risk of long-term mortality compared with placebo-allocated patients. Mortality reduction among bezafibrate-allocated patients was related to a significant 22% (P = .008) reduction in the risk of death in patients with an upper-tertile HDL-C response to therapy, whereas among patients with a lower HDL-C response, the risk of death was similar to that of the placebo group (hazard ratio, 0.95; P = .43). Accordingly, the cumulative probability of death at 16 years was significantly lower among bezafibrate-allocated patients with an upper-tertile HDL-C response (32.1%) compared with the placebo group (37.9%; P = .02), whereas patients with a lower HDL-C response to treatment displayed a mortality rate (36.8%) similar to the placebo group (P = .57)., Conclusion: Our findings suggest that HDL-C level-raising therapy with bezafibrate is associated with long-term mortality reduction that may be related to the degree of HDL-C response to treatment.

Background: The effects of pan-peroxisome proliferator-activated receptor (PPAR) ligand bezafibrate on N-terminal pro-B type natriuretic peptide (ProBNP) level in patients with coronary artery disease (CAD) is unknown. The current study aimed to investigate the long-term effects of bezafibrate on ProBNP level in patients with pre-existing CAD and advanced functional capacity impairment., Methods: Metabolic and inflammatory parameters were analyzed from stored frozen serum samples obtained from 108 patients enrolled in the Bezafibrate Infarction Prevention (BIP) Study. They presented with New York Heart Association (NYHA) functional class III, comprising 58 patients in the bezafibrate group and 50 in the placebo groups, and completed a 2-year prospective, double-blind, placebo-controlled follow-up., Results: During follow-up ProBNP level did not change significantly in the placebo group, whereas it increased slightly in the bezafibrate group, which was older and with lower baseline ProBNP values. No significant differences between the groups were found for ProBNP levels after 2 year of follow-up. Analysis-of-covariance (ANCOVA) -taking into account age and baseline ProBNP level- showed that bezafibrate was not associated with longitudinal ProBNP changes during the follow-up period (p = 0.3)., Conclusion: Long-term treatment by bezafibrate was not associated with longitudinal ProBNP changes in patients with pre-existing CAD and advanced functional capacity impairment.

Low high-density lipoprotein (HDL) cholesterol is a strong independent predictor of cardiovascular risk. The present study was designed to assess the relation between the clinical response to HDL cholesterol modification and serum levels of low-density lipoprotein (LDL) cholesterol in patients with coronary artery disease (CAD). The risk for a major cardiac event (defined as nonfatal myocardial infarction or cardiac death) during a median 7.9-year follow-up period in 3,020 patients with CAD enrolled in the Bezafibrate Infarction Prevention (BIP) trial was related to changes in lipid levels during the study. Baseline LDL cholesterol levels were categorized according to National Cholesterol Education Program Adult Treatment Panel III criteria. Multivariate analysis demonstrated that the benefit of HDL cholesterol increase was most pronounced in patients with low baseline LDL cholesterol (or=160 mg/dl; hazard ratio 0.94, 95% confidence interval 0.75 to 1.17, p = 0.14). A similar relation was shown for risk reduction-associated triglyceride decrements, whereas the benefit of LDL cholesterol reduction was more pronounced in patients with baseline LDL cholesterol >or=130 mg/dl. In conclusion, these data suggest that the clinical response to HDL cholesterol and triglyceride modification is inversely related to baseline LDL cholesterol levels. Thus, combined assessment of baseline and follow-up lipid levels to direct therapeutic goals in patients with CAD may provide incremental prognostic information to secondary prevention that is based solely on LDL cholesterol modification.

No appropriate pharmaceutical therapy has been established for dyslipidemia with cholestasis in progressive familial intrahepatic cholestasis (PFIC)-1. We evaluated the efficacy of bezafibrate in PFIC-1. We monitored the clinical presentation and lipoprotein metabolism of 3 patients, aged 3, 4, and 8 years, with FIC1 deficiency, manifesting PFIC-1, over 12 months of bezafibrate therapy. Pruritus was substantially alleviated in the 3 patients after initiation of bezafibrate. Cholestasis was alleviated in 2 of them. Serum high-density lipoprotein cholesterol and low-density lipoprotein cholesterol increased 1.6- to 2.0-fold and 1.1- to 1.2-fold, respectively; but the values remained low and normal, respectively. Serum lipoprotein X, which was at normal levels before treatment, was elevated to levels above the upper limit of the reference range. High serum triglyceride levels decreased by 15% to 30%, to normal levels, after treatment initiation. The activities of lipoprotein lipase and hepatic triglyceride lipase were increased, but those of high-density lipoprotein regulators remained unchanged. Liver expression of multidrug resistance protein-3, which regulates lipoprotein X synthesis, was enhanced by bezafibrate therapy. Bezafibrate treatment favorably affected pruritus, dyslipidemia, and cholestasis in PFIC-1.

Background: Epidemiologic studies have suggested that hypertriglyceridemia and insulin resistance are related to the development of colon cancer. Nuclear peroxisome proliferator-activated receptors (PPAR), which play a central role in lipid and glucose metabolism, had been hypothesized as being involved in colon cancerogenesis. In animal studies the lipid-lowering PPAR ligand bezafibrate suppressed colonic tumors. However, the effect of bezafibrate on colon cancer development in humans is unknown. Therefore, we proposed to investigate a possible preventive effect of bezafibrate on the development of colon cancer in patients with coronary artery disease during a 6-year follow-up., Methods: Our population included 3011 patients without any cancer diagnosis who were enrolled in the randomized, double blind Bezafibrate Infarction Prevention (BIP) Study. The patients received either 400 mg of bezafibrate retard (1506 patients) or placebo (1505 patients) once a day. Cancer incidence data were obtained by matching a subject's identification numbers with the National Cancer Registry. Each matched record was checked for correct identification., Results: Development of new cancer (all types) was recorded in 177 patients: in 79 (5.25%) patients from the bezafibrate group vs. 98 (6.51%) from the placebo group. Development of colon cancer was recorded in 25 patients: in 8 (0.53%) patients from the bezafibrate group vs. 17 (1.13%) from the placebo group, (Fisher's exact test: one side p = 0.05; two side p = 0.07). A difference in the incidence of cancer was only detectable after a 4 year lag and progressively increased with continued follow-up. On multivariable analysis the colon cancer risk in patients who received bezafibrate tended to be lower with a hazard ratio of 0.47 and 95% confidence interval 0.2-1.1., Conclusion: Our data, derived from patients with coronary artery disease, support the hypothesis regarding a possible preventive effect of bezafibrate on the development of colon cancer.

Background: Mixed hyperlipidemia is a common disorder characterized by elevated VLDL and LDL levels. Patients with this syndrome usually are in need of combination therapy, comprising a fibric acid derivate with a statin drug in order to achieve LDL and triglyceride target values. Atorvastatin is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor demonstrated to be effective in reducing both cholesterol (CHOL) and triglyceride (TG) levels in humans. We examined the efficacy of atorvastatin as monotherapy in achieving a better or the same lipid profile in patients with mixed hyperlipidemia treated with combination therapy., Design: We compared atorvastatin with a combination of a fibric acid derivate and a statin drug (other than atorvastatin) in a 24-week, prospective randomized, open-label study of 27 patients with mixed hyperlipidemia., Methods: All 27 patients had been treated with statin-fibrate therapy in different regimens for at least a year. Atorvastatin at a daily dose of 20 mg was substituted for statin-fibrate therapy. Lipid and safety profiles were assessed., Results: Atorvastatin significantly reduced total cholesterol, LDL-C, and HDL-C compared to statin-fibrate therapy. In contrast, TG and glucose levels were significantly elevated with atorvastatin. Target LDL-C and TG was achieved in 10 patients with the single therapy of atorvastatin vs. 6 patients under statin-fibrate. In 16 patients, atorvastatin was at least as effective as, or better than, the combination therapy, and was recommended for continuation of treatment., Conclusion: Atorvastatin is an adequate monotherapy for many mixed hyperlipidemia patients. We recommend atorvastatin be considered for every patient suffering from mixed hyperlipidemia.

Several factors have been incriminated in the genesis of diabetic nephropathy. To elucidate their interplay, we have used a hypertensive, obese, diabetic rat model with nephropathy (SHR/NDmcr-cp) that mimics human type 2 diabetes. This model is characterized by hypertension, obesity with the metabolic syndrome, diabetes with insulin resistance, and intrarenal advanced glycation end product (AGE) accumulation. In order to achieve renoprotection, which was evaluated by histology and albuminuria, various therapeutic approaches were used: caloric restriction, antihypertensive agents (angiotensin II receptor blocker [ARB] and calcium channel blocker), lipid- (bezafibrate) or glucose-lowering (insulin and pioglitazone) agents, and cobalt chloride (a hypoxia-inducible factor activator). Altogether, renoprotection is not necessarily associated with blood pressure or glycemic control. By contrast, it is almost always associated with decreased AGE formation, with the exception of insulin, which induces hyperinsulinemia, eventually leading to an overproduction of transforming growth factor-beta. AGE formation is reduced directly by in vitro active compounds (e.g., ARBs) or indirectly by in vitro inactive compounds (e.g., pioglitazone and cobalt). In the latter cases, AGE reduction may reflect a decreased oxidative stress as it is concomitant with a marked reduction of oxidative stress markers. It remains to be seen whether the renoprotection offered by these various approaches may be additive.

Context: The mitochondrial respiratory chain (RC) disorders are the largest group of inborn errors of metabolism and still remain without treatment in most cases., Objective: We tested whether bezafibrate, a drug acting as a peroxisome proliferator-activated receptor (PPAR) agonist, could stimulate RC capacities., Design: Fibroblasts or myoblasts from controls or patients deficient in complex I (CI), complex III (CIII), or complex IV (CIV) were cultured with or without bezafibrate., Main Outcome Measures: Enzyme activities, mRNA and protein expression, and respiration rates were measured., Results: In control cells, bezafibrate increased the CI, CIII, and CIV enzyme activities (+42 to +52%), as well as RC mRNAs (+40 to +120%) and RC protein levels (+50 to +150%). Nine of 14 patient cell lines tested exhibited a significant increase in the activity of the deficient RC complex after bezafibrate treatment (+46 to +133%), and full pharmacological correction could be achieved in seven cell lines. Similar effects were obtained using a PPARdelta agonist. These changes were related to a drug-induced increase in the mutated mRNAs and RC protein levels. Finally, the molecular mechanisms by which the PPAR pathway could induce the expression of genes encoding structural subunits or ancillary proteins of the RC apparatus, leading to stimulate the activity and protein levels of RC complex, likely involved the PPARgamma coactivator-1alpha., Conclusions: This study suggests a rationale for a possible correction of moderate RC disorders due to mutations in nuclear genes, using existing drugs, and brings new insights into the role of PPAR in the regulation of the mitochondrial RC in human cells.

Oxidative stress may initiate significant hepatocyte injury in subjects with fatty liver. We characterized changes in hepatic oxidative anti-oxidative parameters in rats given a fructose-enriched diet (FED) with and without medications to reduce blood pressure or plasma triglycerides. FED rats had an increase in malondialdehyde (MDA) concentration, a reduction in alpha-tocopherol concentration, a reduction in paraoxonase (PON) activity, an increase in glutathione peroxidase (GSH-Px), and glutathione reductase (GSSG-R) activity. Amlodipine increased PON and GSH-Px, but decreased GSSG-R activity and alpha-tocopherol concentration. Captopril decreased MDA concentration and the activity of both GSH-Px and GSSG-R, but increased alpha-tocopherol concentration and PON activity. Bezafibrate increased alpha-tocopherol concentration and PON activity, but decreased the activity of GSSG-R. Animals with fatty liver exhibit an increase in peroxidative stress but also a defect in anti-oxidative pathways. Drugs administered to treat hypertension and hypertriglyceridemia could lead to a variety of changes in the hepatic oxidative, anti-oxidative milieu.

Background: Patients with coronary heart disease (CHD) are at increased risk of stroke. We investigated in a large cohort of patients with CHD the relationship between functional status, as assessed by the New York Heart Association (NYHA) classification, and incident ischemic stroke., Methods: We followed up 15,524 patients with documented CHD, screened for inclusion in a clinical trial (Bezafibrate Infarction Prevention), for 4.8 to 8.1 years. Functional status at baseline was categorized according to the NYHA classification. Among 14,703 patients, free of stroke, with recorded NYHA functional class, 1086 (7.4%) developed an ischemic cerebrovascular event, of whom 604 (4.1%) patients were confirmed to have an ischemic stroke or transient ischemic attack., Results: The cumulative rate of ischemic cerebrovascular events increased from 6.7% in patients with NYHA functional class I to 9.2% and 9.7% for patients with NYHA functional classes II and III, respectively (P < .001). Adjustments were made in Cox proportional hazard models for age, sex, body mass index, past myocardial infarction, current smoking, diabetes, hypertension, peripheral vascular disease, percent of cholesterol in high-density lipoprotein, and triglyceride levels. The adjusted hazard ratios associated with NYHA functional class II and III were 1.29 (95% confidence interval 1.12-1.48) and 1.71 (95% confidence interval 1.36-2.15), respectively, as compared with patients with NYHA class I., Conclusions: Our findings indicate that stable coronary patients with even a slight limitation based on the NYHA functional class are exposed to an increased risk of ischemic stroke.

Objectives: This study was designed to evaluate the long-term cardiovascular benefit of bezafibrate therapy in coronary heart disease patients enrolled in the BIP (Bezafibrate Infarction Prevention) trial., Background: The BIP trial yielded a nonsignificant 7.3% reduction in the rate of major cardiac events after a mean follow-up period of 6.2 years, possibly owing to an increasing unbalanced usage of nonstudy lipid-lowering drugs (LLDs) during the course of the trial., Methods: The adjusted risk for the combined end point of cardiac death or nonfatal myocardial infarction during an extended mean 8.2-year follow-up period of the BIP trial was assessed in 3,090 patients allocated to the original bezafibrate (n = 1,548) and placebo (n = 1,542) groups of the trial., Results: During the extended follow-up period, nonstudy LLDs were administered to a significantly greater proportion of placebo-allocated patients (57%) than bezafibrate-allocated patients (53%; p = 0.02). Interaction-term analysis demonstrated that the benefit of bezafibrate therapy was pronounced (18% risk reduction; p = 0.03) without or before treatment with nonstudy LLDs initiated during follow-up and attenuated (hazard ratio 1.05; p = 0.85) after therapy with nonstudy LLDs initiated during the observation period. Consistent with these findings, treatment with bezafibrate was shown to be associated with a significant 17% risk reduction (p = 0.03) when study patients were censored from the analysis upon initiation of therapy with nonstudy LLDs., Conclusions: The data demonstrate that bezafibrate therapy in the BIP trial was associated with significant long-term cardiovascular protection that was attenuated by an unbalanced usage of nonstudy LLDs during the course of the trial.

Very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency is an inborn mitochondrial fatty-acid beta-oxidation (FAO) defect associated with a broad mutational spectrum, with phenotypes ranging from fatal cardiopathy in infancy to adolescent-onset myopathy, and for which there is no established treatment. Recent data suggest that bezafibrate could improve the FAO capacities in beta-oxidation-deficient cells, by enhancing the residual level of mutant enzyme activity via gene-expression stimulation. Since VLCAD-deficient patients frequently harbor missense mutations with unpredictable effects on enzyme activity, we investigated the response to bezafibrate as a function of genotype in 33 VLCAD-deficient fibroblasts representing 45 different mutations. Treatment with bezafibrate (400 microM for 48 h) resulted in a marked increase in FAO capacities, often leading to restoration of normal values, for 21 genotypes that mainly corresponded to patients with the myopathic phenotype. In contrast, bezafibrate induced no changes in FAO for 11 genotypes corresponding to severe neonatal or infantile phenotypes. This pattern of response was not due to differential inductions of VLCAD messenger RNA, as shown by quantitative real-time polymerase chain reaction, but reflected variable increases in measured VLCAD residual enzyme activity in response to bezafibrate. Genotype cross-analysis allowed the identification of alleles carrying missense mutations, which could account for these different pharmacological profiles and, on this basis, led to the characterization of 9 mild and 11 severe missense mutations. Altogether, the responses to bezafibrate reflected the severity of the metabolic blockage in various genotypes, which appeared to be correlated with the phenotype, thus providing a new approach for analysis of genetic heterogeneity. Finally, this study emphasizes the potential of bezafibrate, a widely prescribed hypolipidemic drug, for the correction of VLCAD deficiency and exemplifies the integration of molecular information in a therapeutic strategy.

Background: Elevated C-reactive protein (CRP) levels are related to increased coronary risk in healthy subjects and in patients with acute coronary syndromes. The aims of the present study were to assess the following: (1) the association between CRP and subsequent coronary risk in patients with chronic coronary heart disease (CHD), (2) the effect of long-term bezafibrate treatment on CRP levels, and (3) to evaluate the consequences of change in CRP level over time on subsequent risk., Methods: Patients with chronic CHD (n = 3122) were recruited to a secondary prevention study that assessed the efficacy of bezafibrate versus placebo. C-reactive protein was measured in plasma samples collected at prerandomization and after 2 years of follow-up. Mean follow-up time was 6.2 years. Primary end point was fatal and nonfatal myocardial infarction and sudden cardiac death., Results: Increased baseline CRP levels were associated with increased risk (hazard ratios [HRs] per unit of log-transformed CRP level change) of myocardial infarction (HR 1.17, 95% CI 1.03-1.33), the primary end point (HR 1.19, 95% CI 1.06-1.34), total death (HR 1.19, 95% CI 1.02-1.40) and cardiac death (HR 1.28, 95% CI 1.04-1.59). After 2 years, CRP levels increased by 3.0% (from a mean level of 3.44 mg/L) in the bezafibrate group and by 3.7% (from 3.49 mg/L) in the placebo group. C-reactive protein levels after 2 years were associated with increased subsequent cardiovascular risk., Conclusions: Baseline CRP and 2-year CRP levels were associated with subsequent risk of myocardial infarction and death in patients with chronic CHD. Bezafibrate did not reduce CRP levels as compared with placebo.

Metabolic myopathies are inborn errors of intermediate muscle metabolism, presenting either by exercise intolerance, or by progressive muscle weakness. Growing knowledge concerning the pathophysiology of these rare disorders, and the development of new technologies, opens new avenues for the treatment of this group of myopathies. Recent studies showed improvement in exercise capacity after regular aerobic exercise training in patients with McArdle's disease and mitochondrial myopathies. In late-onset Pompe disease enzyme replacement therapy trials with recombinant acid alpha-glucosidase (Myozyme) are currently in progress, the first trials conducted in childhood onset Pompe disease having previously shown a clear improvement in life expectancy and cardiac function. The demonstration that fibrates can induce correction of carnitine palmitoyl-transferase II deficiency in patients cells, lead to the development of an open-labelled therapeutic trial with bezafibrate in patients with CPTII deficiency, which is actually ongoing.

Background: Beyond total low-density-lipoproteins (LDL) levels, increasing evidence suggests that the 'quality' of LDL exerts a great influence on the cardiovascular risk. Several studies have also shown that the therapeutic modulation of LDL size is of benefit in reducing the risk of cardiovascular events. Hypolipidaemic treatment is able to alter LDL subclass distribution but strong variations have been noticed among different agents. Fibrates have a major impact on triglyceride metabolism and in modulating LDL size and subclasses, but variations exist among the different molecules., Methodology: A literature search (by Medline and Scopus) was performed using the following headings: 'small dense LDL', 'LDL size', 'LDL subfractions', 'LDL subclasses', 'LDL distribution' and 'fenofibrate', 'bezafibrate', 'ciprofibrate' and 'gemfibrozil' up to 20 January 2007. The authors also manually reviewed the references of selected articles for any pertinent material., Results: Analysis of all published studies revealed that treatment with fenofibrate, ciprofibrate, bezafibrate and gemfibrozil is usually beneficial, and fenofibrate may be more efficacious than the other molecules. This is supported by using all the available techniques in subjects with a very wide range of lipid alterations., Conclusion: Among the different agents, fenofibrate has been found to be particularly effective in modulating LDL size and subclasses in patients at higher cardiovascular risk, such as those with type 2 diabetes or the metabolic syndrome.

Bacterial endotoxin/lipopolysaccharide (LPS)-induced cachexia is characterized by weight loss, anorexia, and a disturbance in lipid metabolism, namely, hypertriacylglycerolemia. The aim of this study in rats with acute endotoxicity induced by an injection of LPS was to investigate whether bezafibrate, a ligand for peroxisome proliferator-activated receptor alpha and a lipoprotein lipase (LPL) activator, improved cachectic conditions, including impaired lipid metabolism. Short-term administration of LPS in the rats resulted in impairment of triacylglycerol clearance in plasma after the intake of fresh cream. In addition, LPS increased whole-body energy expenditure, reduced fasting body weight and caused anorexia in the rats. Bezafibrate treatment resulted in significant improvements in LPS-induced dyslipidemia and anorexia, but had no effect on energy expenditure, respiratory quotient, or fasting body weight in the endotoxic rats. Administration of LPS was also associated with a decrease in the level of messenger RNA (mRNA) expression for LPL in white adipose tissue and skeletal muscle and an increase in the mRNA levels for uncoupling protein 3 in skeletal muscle. Bezafibrate treatment reversed the decline in LPL mRNA levels in white adipose tissue but not in the skeletal muscle tissue of the rats. The enhanced uncoupling protein 3 mRNA level in the endotoxic rats was not affected by bezafibrate treatment. Plasma concentration of leptin was increased by short-term LPS treatment. Bezafibrate decreased the level of plasma leptin significantly without affecting the level of leptin mRNA expression. These results suggest that bezafibrate may be an effective drug not only for impaired triacylglycerol metabolism, but also for anorexia in cachectic states induced by bacterial infections.

We tested the ability of simvastatin, atorvastatin, fenofibrate and bezafibrate (two synthetic peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists) to prevent dopaminergic cell death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Tyrosine hydroxylase (TH) immunochemistry was performed 8 days after acute MPTP intoxication. When orally administered for the week prior to intoxication and a week thereafter, fenofibrate prevented the MPTP-induced dopaminergic cell loss in the substantia nigra pars compacta (SNpc) and attenuated the loss of tyrosine hydroxylase immunoreactivity in the striatum. The dosage of 1-methyl-4-phenyl pyridinium (MPP+) in the striatum by high-performance liquid chromatography indicated that fenofibrate did not affect MPTP metabolism. Bezafibrate had no effect and, strikingly, simvastatin and atorvastatin had a negative effect. We also demonstrated the presence of PPAR-alpha in the dopaminergic neurons of the murine substantia nigra. Our data suggest that PPAR-alpha activation by fenofibrate could have a neuroprotective effect in PD through inhibition of inflammation, oxidative stress and/or apoptosis.

Cerebral sinus thrombosis is a rare but severe complication during treatment for acute lymphoblastic leukaemia (ALL). It mostly has been reported during treatment with asparaginase and dexamethasone. Hypertriglyceridemia has - albeit very rarely - also been associated with asparaginase therapy. The combination of cerebral sinus thrombosis and hypertriglyceridemia however, has not yet been reported. Here we describe a 15-year-old boy who presented with clinical symptoms and radiologic findings of a cerebral sinus thrombosis. In addition, a life-threatening hypertriglyceridemia was present. The complication was successfully treated by anticoagulation with low molecular weight heparin and the lipid regulator bezafibrate.

Objective: Adiponectin is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule. We previously found peroxisome proliferators response element in adiponectin promoter region, suggesting that peroxisome proliferator-activated receptor (PPAR) ligands elevate adiponectin. Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease. Effect of fibrates on adiponectin has not been clarified, whereas thiazolidinediones enhance adiponectin. Thus, we explored the possibility and mechanism that fibrates enhance adiponectin in humans, mice, and cells., Methods and Results: Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The Bezafibrate Infarction Prevention study. Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes. Fibrates, bezafibrate and fenofibrate, significantly elevated adiponectin levels in wild-type mice and 3T3-L1 adipocytes. Such an effect was not observed in PPARalpha-deficient mice and adipocytes. Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha-RNAi., Conclusions: Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes.

We have prospectively evaluated the risk of incident coronary events in association with serum total homocysteine in patients with preexisting chronic coronary heart disease. A nested case-control design was used. Total homocysteine concentration was measured in baseline fasting serum samples from patients with chronic coronary heart disease enrolled in the Bezafibrate Infarction Prevention Study (n = 3,090) who developed coronary events during 6.2 years of follow-up (n = 69). They were matched for age and gender with controls without subsequent cardiovascular events. Elevated homocysteine levels were associated with 2.5 times higher risk of subsequent coronary events and each 5 mumol/l increment was associated with a 25% higher risk.

Background: Large randomized, controlled clinical trials of lovastatin and gemfibrozil for heart disease prevention have reported statistically significantly lower melanoma incidences in persons receiving these medications. Results of in vitro animal model and human case-control studies also suggest that statins and fibrates may reduce the risk of melanoma., Methods: We performed a systematic review of trials that randomly assigned participants to receive statins or fibrates versus an alternative therapy for a minimum of 6 months. Trials were identified by searching five electronic databases and the reference lists of eligible publications. Unpublished data were solicited from trial investigators and pharmaceutical companies. A meta-analysis was performed using a fixed-effects model, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate pooled treatment effects. All statistical tests were two-sided., Results: We obtained data on incident melanomas from 20 of 36 qualifying randomized controlled trials (12 statin trials and eight fibrate trials), with a total of 70,820 participants. A total of 127 melanomas occurred among the 39,426 participants in the statin trials (59 among the 19,872 statin group participants and 68 among the 19,554 control group participants). A total of 27 melanomas occurred among the 31,394 participants enrolled in the fibrate trials (seven among the 12,324 fibrate group participants and 20 among the 19,070 control group participants). Overall, incidence of melanoma was not statistically significantly associated with the use of either statins (OR = 0.87, 95% CI = 0.61 to 1.23) or fibrates (OR = 0.45, 95% CI = 0.20 to 1.01). In a subgroup analysis by drug, only lovastatin use (in one trial) was statistically significantly associated with lower incidence of melanoma (OR = 0.52, 95% CI = 0.27 to 0.99)., Conclusions: These findings do not validate the possibility that statins or fibrates prevent melanoma.

Sjögren-Larsson syndrome (SLS) is caused by a deficiency of fatty aldehyde dehydrogenase (FALDH), encoded by the ALDH3A2 gene. In animal studies, the expression of the murine ortholog of FALDH, has been shown to be under the control of peroxisome proliferator-activated receptor alpha (PPARalpha). In the present study, we investigated whether the hypolipidemic drug bezafibrate, which is a pan-agonist of all PPAR-isoforms, might induce FALDH activity in human fibroblasts of control subjects and SLS patients that still have some residual FALDH activity. Our results show that FALDH activity was induced 1.4-fold after a 3-day treatment with 800 microM bezafibrate in fibroblasts of control subjects. Interestingly, in fibroblasts of two SLS patients homozygous for the p.R228C substitution, FALDH activity could be induced to 37% of control values by bezafibrate treatment. mRNA analysis in fibroblasts of these patients also revealed a mean 1.8-fold induction of FALDH mRNA after bezafibrate treatment. No induction was observed in fibroblasts of patients with mutations that cause instability of FALDH mRNA or that result in a protein without any residual activity. These data suggest that bezafibrate treatment could be effective in patients with expression of FALDH protein and some residual enzyme activity. Further research is needed to resolve whether patients could benefit from treatment with bezafibrate.

Background: Fibrates were reported to be effective in reducing recurrent coronary events in coronary heart disease patients with elevated triglycerides. It is not known whether this effect is related to the extent of triglyceride reduction., Methods: Participants comprised 3090 coronary heart disease patients enrolled in the Bezafibrate Infarction Prevention study, which showed a nonsignificant reduction (9.4%; P=0.26) in fatal or nonfatal myocardial infarction and sudden death during a mean follow-up time of 6.2 years., Results: Significant reduction in triglyceride serum level was evident only among patients allocated to bezafibrate, ranging between 0.06 mmol/l (5 mg/dl) in the lowest decile of baseline triglycerides level and 0.68 mmol/l (60 mg/dl) in the highest baseline decile. The extent of triglyceride reduction with bezafibrate was significantly associated with the reduction of risk; relative risk reduction of 55% (hazards ratio: 0.45; 95% confidence interval: 0.24-0.84) was observed among patients with baseline triglycerides>or=2.26 mmol/l who reduced triglyceride level to >0.50 mmol/l (>44.3 mg/dl). In contrast, the risk of recurrent events among patients treated with bezafibrate and achieving less triglyceride reduction or failing to reduce triglyceride level was not significantly different from that of patients treated with placebo., Conclusion: Bezafibrate treatment was associated with significant risk reduction among coronary heart disease patients with elevated triglyceride levels that substantially reduced their triglyceride level with treatment.

Background and Purpose: C-reactive protein (CRP) has emerged as an important predictor of cardiovascular disease, but there are few prospective data on its association with risk of ischemic stroke in patients at high risk., Methods: We examined the association between CRP levels and subsequent risk of incident ischemic stroke among 2979 patients with stable coronary heart disease included in a controlled clinical trial (Bezafibrate Infarction Prevention) that assessed the efficacy of bezafibrate, a fibric acid derivative, versus placebo for secondary prevention. CRP was measured by a high-sensitivity assay in plasma samples collected before randomization and again at the second follow-up year of an overall mean follow-up of 6.2 years., Results: Risk of ischemic stroke per 1000 person-years increased from 4.1% for baseline CRP in the lowest tertile (<2.3 mg/L; n=982) to 5.9% for levels at the middle tertile (2.3 to 5.4 mg/L; n=1013) and 10.5% for CRP levels at the upper tertile (>5.4 mg/L; n=984; P<0.001). With adjustment for potential confounders, baseline CRP levels in the top versus bottom tertile were associated with a 2.16-fold increased hazard (95% CI, 1.32 to 3.53) for ischemic stroke, and CRP levels measured after 2 years were associated with a hazard ratio of 2.43 (95% CI, 1.30 to 4.57). The risk of an incident ischemic stroke did not differ between the bezafibrate group compared with the placebo group regardless of baseline CRP levels., Conclusions: These findings, based on a large prospective study, demonstrate the risk prediction for incident ischemic stroke conferred by CRP levels in patients at high risk.

Background: Bezafibrate is a commonly used medicine for hyperlipidemia, and recently several reports have suggested the efficacy of bezafibrate for the treatment of primary biliary cirrhosis (PBC). To assess its efficacy for other liver diseases, we administered bezafibrate to patients with various categories of hepatobiliary impairment., Methods: Bezafibrate (400 mg/day) was orally administered to 67 patients with chronic liver disease [22 with PBC, six with primary sclerosing cholangitis (PSC), 20 with chronic liver disease associated with hepatitis C virus (HCV) infection (CLD-C), seven with auto immune hepatitis (AIH), ten with alcoholic liver injury, and two with drug-induced liver injury]., Results: The levels of biliary enzymes, such as alkaline phosphatase and gamma-glutamyltranspeptidase, decreased promptly and dramatically. The abnormally high level of alanine aminotransferase also showed a gradual decrease over 6 months in five of the eight PBC patients, all three PSC patients, eight of the 17 CLD-C patients, and all seven alcoholic liver injury patients. The level of immunoglobulin M showed a gradual decrease in 17 of the 22 PBC patients., Conclusions: Bezafibrate significantly reduced the level of biliary enzymes in various chronic liver diseases and may be useful for the treatment of certain liver disease subsets.

An association of hepatitis C virus (HCV) with low-density lipoproteins (LDL) in serum of patients with chronic hepatitis C (CHC) has been suggested. We conducted a prospective study in CHC patients complicated with hyperlipidaemia, to examine whether bezafibrate, which is commonly used for treatment of hyperlipidaemia, reduces serum HCV-RNA titre and improves liver dysfunction. Fifteen patients received daily oral bezafibrate treatment (400 mg/day) for 8 weeks, and its effects on serum lipids, transaminases, HCV-RNA titres, and HCV-RNA titres bound to LDL were evaluated. Fifteen untreated patients with CHC and hyperlipidaemia were used as controls. The mean serum alanine aminotransferase levels and HCV-RNA titres significantly decreased at the end of bezafibrate therapy in the treated group (105 +/- 34 to 80 +/- 32 IU/L, P = 0.02 and 2.23 +/- 2.71 to 1.78 +/- 2.38 x 10(7) copies/mL, P < 0.01 respectively), but no changes were observed in the control group. Serum HCV-RNA titres bound to LDL, as quantified by immunoprecipitation using anti-LDL antibody, also decreased in all 15 treated patients [5.55 +/- 6.59 to 1.07 +/- 1.58 x 10(6) copies/ml, P < 0.01 (mean reduction rate was -78.5 +/- 17.0%)]. Sucrose density-gradient ultracentrifugation study revealed that HCV-RNA-decreased density fractions after the bezafibrate were identical to LDL-density fractions (1.015-1.062 g/mL). Eight CHC patients were treated with bezafibrate, interferon, and ribavirin triple therapy for 32 weeks, and four patients achieved sustained virological response to therapy. This pilot study provides further evidence of an association between HCV and LDL in serum and suggests the potential usefulness of bezafibrate as an anti-HCV reagent for the treatment of CHC patients.

The short-term effects of bezafibrate on high-density lipoprotein cholesterol quality and triglyceride-rich lipoprotein metabolism in 186 postmenopausal hypertriglyceridemic women were investigated. Patients were randomized to an untreated group and to bezafibrate (400 mg/d) for 6 months. Fasting lipid concentrations, high-density lipoprotein 2, and high-density lipoprotein 3 levels were measured at baseline and after 3 and 6 months. At 3 months, bezafibrate had significantly decreased mean serum triglycerides and remnant-like particle cholesterol levels (105.7 +/- 43.4 mg/dL and 5.33 +/- 2.1 mg/dL, P < .001, respectively) from baseline values (232.5 +/- 63.9 mg/dL and 9.69 +/- 3.8 mg/dL, respectively). It also maintained lower total cholesterol, low-density lipoprotein cholesterol, triglycerides, and remnant-like particle cholesterol concentrations to 6 months. After 3 months, it significantly increased mean serum high-density lipoprotein cholesterol (55.1 +/- 14.7 vs 64.8 +/- 12.1 mg/dL; P < .0001) and maintained higher high-density lipoprotein cholesterol at 6 months. The high-density lipoprotein 2-high-density lipoprotein 3 ratio was decreased after 3 months of therapy with bezafibrate (2.13 +/- 0.68) from the baseline (2.42 +/- 0.71) (P < .01).

The use of highly active antiretroviral therapy (HAART) in HIV-infected patients has been associated with the development of risk factors for cardiovascular diseases (CD) including dyslipidemia and insulin resistance, hypertriglyceridemia being the most frequent metabolic disturbance in these patients. Fibrates are indicated when hypertriglyceridemia is accentuated and persists for over six months. We evaluated the efficacy and safety of bezafibrate for the treatment of hypertriglyceridemia in HIV-infected individuals on HAART. All patients received 400mg/day of bezafibrate and were evaluated three times: Mo (pre-treatment), M1 (one month after treatment), and M2 (six months after treatment). Fifteen adult individuals, eight males and seven females with mean age = 41.2 +/- 7.97 years and triglyceride serum levels > 400mg/dL were included in the study. Smoking, alcohol ingestion and sedentarism rates were 50%, 6.66% and 60%, respectively. Family history of CD, hypertension and diabetes mellitus was reported in 33.3%, 40% and 46.7% of the cases, respectively, while dyslipidemia was reported by only 13.3%. More than half of the patients were using a protease inhibitor plus a nucleotide analog transcriptase inhibitor. Eutrophy and tendency toward overweight were observed at all three study time points. There were significant reductions in triglyceride serum levels from Mo to M1 and from Mo to M2. No significant changes were observed in the serum levels of creatine phosphokinase, hepatic enzymes, CD4+, CD8+ and viral load. Therefore, bezafibrate seems to be safe and effective for the reduction of hypertriglyceridemia in HIV-infected patients on HAART.

Background: Development of insulin resistance (IR) may be important in the pathogenesis of both metabolic syndrome and type 2 diabetes mellitus. Few data are available regarding the short-term efficacy of the peroxisome proliferator-activated receptor ligand bezafibrate on IR, and its long-term effect is unknown. The present analysis aimed to investigate the effect of bezafibrate on IR in patients with coronary artery disease enrolled in the Bezafibrate Infarction Prevention Study., Methods: Metabolic and inflammatory parameters were analyzed from stored frozen plasma samples obtained from patients who completed a 2-year, randomized, double-blind, placebo-controlled study. The homeostatic indexes of IR (HOMA-IRs) were calculated according to the homeostasis model of assessment., Results: Both the patients taking bezafibrate (n = 1262) and those taking placebo (n = 1242) displayed similar baseline characteristics. The HOMA-IRs significantly correlated at baseline and during follow-up with glucose (r = 0.35 and 0.31, respectively) and triglycerides (r = 0.16 and 0.19, respectively). In a subgroup of 351 patients with diabetes, HOMA-IR at baseline was 88% higher than in their counterparts with normal glucose levels (P<.001). In the placebo group, during follow-up there was a significant 34.4% rise in HOMA-IR. In contrast, in the bezafibrate group there was only a nonsignificant 6.6% change in HOMA-IR. The intergroup differences in percentage changes of HOMA-IR were in favor of bezafibrate (P<.001)., Conclusions: In patients with coronary artery disease enrolled in our study, as represented by the placebo group, HOMA-IR increased over time. During the 2 years of the follow-up, bezafibrate significantly attenuated this process.

Fibrates are drugs of choice in patients with hypertriglyceridemia (HTG), but may increase the risk for gallstones by decreasing bile acid synthesis. Fish oil might be a therapeutic alternative, but its effect on bile acid metabolism in humans is unknown. We compared the effects of triglyceride-lowering therapy by fish oil or bezafibrate on cholesterol synthesis and bile acid metabolism in HTG. Cholesterol synthesis, bile acid pool sizes, and synthesis rates were compared between 9 male HTG patients and 10 normolipidemic controls matched for age, sex, and BMI. Effects of bezafibrate or fish oil were studied only in HTG patients in a randomized crossover trial. Patients had 14-fold higher serum triglyceride concentrations and greater cholesterol synthesis, as indicated by a 107% higher ratio of serum lathosterol to cholesterol (P < 0.01) than controls. The groups did not differ in bile acid metabolism. Both bezafibrate and fish oil reduced serum TG concentration (-68 and -51% vs. baseline, respectively). Compared with baseline, bezafibrate therapy was associated with reduced cholesterol synthesis (-25%, P = 0.009) without changes in bile acid synthesis rate and pool size. In contrast, fish oil increased bile acid synthesis (+31% vs. baseline, P = 0.07 and +53% vs. bezafibrate, P = 0.02) and altered bile acid distribution, as reflected by an increased ratio of the cholic acid (CA) synthesis rate to the chenodeoxycholic acid (CDCA) synthesis rate (+35% vs baseline, P = 0.05 and + 32% vs bezafibrate, P = 0.07) without effects on bile acid pool size or cholesterol synthesis. In conclusion, cholesterol synthesis is greater in HTG patients than in controls, whereas bile acid synthesis does not differ. Bezafibrate and fish oil have similar triglyceride-lowering capacities, but distinct effects on cholesterol synthesis. Bile acid synthesis is increased by fish oil, but not by bezafibrate therapy.

Aims: Platelets participate in the pathogenesis of arterial thrombosis and it has been demonstrated that enhanced platelet activation occurs in patients with diabetes mellitus (DM). Dyslipidaemia is a common feature of diabetes. We investigated the association between certain lipid fractions and plasma platelet-derived microparticle (PMP) levels in patients with type-2 DM., Methods and Results: We measured fasting serum levels of remnant-like lipoprotein particles-cholesterol (RLP-cholesterol) and assessed in vivo platelet activation by quantifying the number of PMP in the plasma detected as CD42b-positive microparticles by flow cytometry in Japanese type-2 DM patients without obstructive coronary artery disease who were more slender when compared with Western diabetic patients. The levels of total cholesterol, triglycerides, RLP-cholesterol, and plasma glucose were significantly higher in patients with type-2 DM (n = 105) than in non-diabetic patients (n = 92). The plasma levels of PMP were elevated significantly in type-2 DM patients when compared with non-diabetic control subjects [7.41(5.39-10.50) x 10(6) vs. 3.44(2.43-4.41)x10(6), P < 0.001]. We found that RLP-cholesterol levels were the best predictor of PMP in multivariable linear regression analyses (beta = 0.375, P < 0.001). Lipid-lowering medication with bezafibrate successfully reduced levels of both RLP-cholesterol and PMP in patients with type-2 DM (P < 0.05)., Conclusions: RLP-cholesterol and platelet microparticles are both elevated in type-2 DM patients when compared with controls. RLP-cholesterol is the primary and only predictor of platelet microparticles in the multivariable analysis, which include several standard atherosclerosis risk factors. This suggested that reducing elevated RLP-cholesterol with lipid-lowering therapy may be an effective strategy to prevent thrombogenic vascular complications in type-2 DM.