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Bezafibrate reduces the incidence of MI in patients with MS during long-term follow-up.

Background-Recent studies have shown that type 2 diabetes is preventable by both lifestyle interventions and medications that influence primary glucose metabolism. Whether pharmacological interventions that influence primary lipid metabolism can also delay development of type 2 diabetes is unknown. The goal of this study was to evaluate the effect of the peroxisome proliferator-activated receptor ligand bezafibrate on the progression of impaired fasting glucose phase to type 2 diabetes in patients with coronary artery disease over a 6.2-year follow-up period. Methods and Results-The study sample comprised 303 nondiabetic patients 42 to 74 years of age with a fasting blood glucose level of 110 to 125 mg/dL (6.1 to 6.9 mmol/L).

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Background-The independent association between elevated triglycerides and all-cause mortality among patients with established coronary heart disease is controversial. The aim of this study was to investigate this association in a large cohort of patients with proven coronary heart disease. Methods and Results-The study cohort comprised 15 355 patients who were screened for the Bezafibrate Infarction Prevention (BIP) trial. Twenty-two-year mortality data were obtained from the national registry. Patients were divided into 5 groups according to strata of fasting serum triglycerides: (1) low-normal triglycerides (<100 mg/dL); (2) highnormal triglycerides (100-149 mg/dL); (3) borderline hypertriglyceridemia triglycerides (150-199 mg/dL); (4) moderate hypertriglyceridemia triglycerides (200-499 mg/dL); (5) severe hypertriglyceridemia triglycerides (≥500 mg/dL). Ageand sex-adjusted survival was 41% in the low-normal triglycerides group than 37%, 36%, 35%, and 25% in groups with progressively higher triglycerides (P<0.001). In an adjusted Cox-regression for various covariates including high-density lipoprotein cholesterol, each 1 unit of natural logarithm (Ln) triglycerides elevation was associated with a corresponding 6% (P=0.016) increased risk of 22-year all-cause mortality. The 22-year mortality risk for patients with severe hypertriglyceridemia was increased by 68% when compared with patients with low-normal triglycerides (P<0.001). Conclusions-In patients with established coronary heart disease, higher triglycerides levels are independently associated with increased 22-year mortality. Even in patients with triglycerides of 100 to 149 mg/dL, the elevated risk for death could be detected than in patients with lower triglycerides levels, whereas severe hypertriglyceridemia denotes a population with particularly increased mortality risk. (Circ Cardiovasc Qual Outcomes. 2016;9:100-108.

Background-Calcification of the thoracic aorta is associated with atherosclerotic risk factors, yet its pathogenesis and clinical implications are not yet elucidated. The goal of the present study was to assess whether thoracic aorta calcification is associated with an increased risk of cardiovascular events and death in patients with stable angina pectoris. Methods and Results-A prospective cohort of 361 stable angina pectoris patients (307 men, 54 women; age range, 37 to 83 years) underwent chest spiral computed tomography and were evaluated for aortic calcification. We recorded the incidence of cardiovascular events and death during a 4.5-to 6-year follow-up.

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 PPAR␣ 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 PPAR␣-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 PPAR␣ was knocked down by PPAR␣-RNAi. Conclusions-Our results suggest that fibrates enhance adiponectin partly through adipose PPAR␣ and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes. Key Words: adipocyte Ⅲ adiponectin Ⅲ fibrate Ⅲ metabolic syndrome Ⅲ peroxisome proliferator-activated receptor F ibrates have been used in clinical practice for Ͼ4 decades as a class of agents known to decrease triglyceride levels. Fibrates are also known to be peroxisome proliferator-activated receptor (PPAR)␣ ligands. Several clinical studies of fibrates have been performed in large populations. The Bezafibrate Infarction Prevention study (BIP) suggested that bezafibrate prevented cardiovascular events in the subgroup of coronary artery disease patients with high triglycerides. 1 Moreover, further subanalyses demonstrated that the administrations of bezafibrate significantly reduced new-onset diabetes 2,3 and myocardial infarction in the patients with the metabolic syndrome (MS). 4 The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study showed that fenofibrate significantly reduced nonfatal myocardial infarctions and coronary revascularizations, a secondary endpoint, among patients with type 2 diabetes. 5 These favorable clinical outcomes in fibrate studies might be explained by not only its triglyceride-lowering effect but also its various PPAR␣-mediated pleiotropic effects.Adiponectin is an adipose-specific secretory protein and acts as an anti-diabetic and anti-atherosclerotic molecule. 6 Furthermore, a number of clinical trials showed that subjects with high levels of circulating adiponectin tend to be protected against type 2 diabetes and myocardial infarction. 7,8 Thiazolidi...

There are three peroxisome proliferator-activated receptors (PPARs) subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases high density lipoprotein (HDL) cholesterol synthesis, stimulates "reverse" cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Until recently, the biological role of PPAR beta/delta remained unclear. However, treatment of obese animals by specific PPAR delta agonists results in normalization of metabolic parameters and reduction of adiposity. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies "pure" PPAR gamma ligands. The new generation of dual-action PPARs -the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar) are on deck in latestage clinical trials and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown. A number of glitazars have presented problems at a late stage of clinical trials because of serious side-effects (including ragaglitazar and farglitazar). The old and well known lipid-lowering fibric acid derivative bezafibrate is the first clinically tested pan -(alpha, beta/delta, gamma) PPAR activator. It is the only pan-PPAR activator with more than a quarter of a century of therapeutic experience with a good safety profile. Therefore, bezafibrate could be considered (indeed, as a "post hoc" understanding) as an "archetype" of a clinically tested pan-PPAR ligand. Bezafibrate leads to considerable raising of HDL cholesterol and reduces triglycerides, improves insulin sensitivity and reduces blood glucose level, significantly lowering the incidence of cardiovascular events and new diabetes in patients with features of metabolic syndrome. Clinical evidences obtained from bezafibrate-based studies strongly support the concept of pan-PPAR therapeutic approach to conditions which comprise the metabolic syndrome. However, from a biochemical point of view, bezafibrate is a PPAR ligand with a relatively low potency. More powerful new compounds with pan-PPAR activity and proven long-term safety should be highly effective in a clinical setting of patients with coexisting relevant lipid and glucose metabolism disorders.