title: Restoration of adipose function in obese glucose-tolerant men following pioglitazone treatment is associated with CCAAT enhancer-binding protein β up-regulation. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Beneficial effects of fenofibrate to improve endothelial dysfunction and raise adiponectin levels in patients with primary hypertriglyceridemia. Acute Exercise Increases Adiponectin Levels in Abdominally Obese Men Effects of combination lipid therapy in type 2 diabetes mellitus. Combination of niacin and fenofibrate with lifestyle changes improves dyslipidemia and hypoadiponectinemia in HIV patients on antiretroviral therapy: results of "heart positive," a randomized, controlled trial. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Plasma adiponectin levels and risk of myocardial infarction in men. Influence of PPAR-alpha agonist fenofibrate on insulin sensitivity and selected adipose tissue-derived hormones in obese women with type 2 diabetes. Significant differential effects of omega-3 fatty acids and fenofibrate in patients with hypertriglyceridemia. Attenuation of progression of insulin resistance in patients with coronary artery disease by bezafibrate. Peroxisome Proliferator–Activated Receptor Ligand Bezafibrate for Prevention of Type 2 Diabetes Mellitus in Patients With Coronary Artery Disease Apolipoprotein B-48 as a determinant of endothelial function in obese subjects with type 2 diabetes mellitus: effect of fenofibrate treatment. Bezafibrate Retard in Type II Diabetic Patients: Effects on Hemostasis and Glucose Homeostasis Fenofibrate and pioglitazone improve endothelial function and reduce arterial stiffness in obese glucose tolerant men. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Effects of fenofibrate therapy on circulating adipocytokines in patients with primary hypertriglyceridemia.
abstract: Obese AT ( adipose tissue ) exhibits increased macrophage number . Pro-inflammatory CD16 + peripheral monocyte numbers are also reported to increase with obesity . The present study was undertaken to simultaneously investigate obesity-associated changes in CD16 + monocytes and ATMs ( AT macrophages ) . In addition , a pilot r and omized placebo controlled trial using the PPAR ( peroxisome-proliferator-activated receptor ) agonists , pioglitazone and fenofibrate was performed to determine their effects on CD14+/CD16 + monocytes , ATM and cardiometabolic and adipose dysfunction indices . Obese glucose-tolerant men ( n=28 ) were r and omized to placebo , pioglitazone ( 30 mg/day ) and fenofibrate ( 160 mg/day ) for 12 weeks . A blood sample was taken to assess levels of serum inflammatory markers and circulating CD14+/CD16 + monocyte levels via flow cytometry . A subcutaneous AT biopsy was performed to determine adipocyte cell surface and ATM number , the latter was determined via assessment of CD68 expression by IHC ( immunohistochemistry ) and real-time PCR . Subcutaneous AT mRNA expression of CEBPβ ( CCAAT enhancer-binding protein β ) , SREBP1c ( sterol-regulatory-element-binding protein 1c ) , PPARγ2 , IRS-1 ( insulin receptor substrate-1 ) , GLUT4 ( glucose transporter type 4 ) and TNFα ( tumour necrosis factor α ) were also assessed . Comparisons were made between obese and lean controls ( n=16 ) at baseline , and pre- and post-PPAR agonist treatment . Obese individuals had significantly increased adipocyte cell surface , percentage CD14+/CD16 + monocyte numbers and ATM number ( all P=0.0001 ) . Additionally , serum TNF-α levels were significantly elevated ( P=0.017 ) and adiponectin levels reduced ( total : P=0.0001 ; high : P=0.022 ) with obesity . ATM number and percentage of CD14+/CD16 + monocytes correlated significantly ( P=0.05 ) . Pioglitazone  improved adiponectin levels significantly ( P=0.0001 ) , and result ed in the further significant enlargement of adipocytes ( P=0.05 ) , without effect on the percentage CD14+/CD16 + or ATM number  . Pioglitazone treatment also significantly increased subcutaneous AT expression of CEBPβ mRNA . The finding that improvements in obesity-associated insulin resistance following pioglitazone were associated with increased adipocyte cell surface and systemic adiponectin levels , supports the central ity of AT to the cardiometabolic derangement underlying the development of T2D ( Type 2 diabetes ) and CVD ( cardiovascular disease ) The insulin-sensitizing effects of thiazolidinediones are thought to be mediated through peroxisome proliferator-activated receptor-gamma , a nuclear receptor that is highly abundant in adipose tissue . It has been reported that adipocytes secrete a variety of proteins , including tumor necrosis factor-alpha , resistin , plasminogen activator inhibitor-1 , and adiponectin . Adiponectin is a fat cell-secreted protein that has been reported to increase fat oxidation and improve insulin sensitivity . Our aim was to study the effects of troglitazone on adiponectin levels in lean , obese , and diabetic subjects . Ten diabetic and 17 nondiabetic subjects ( 8 lean , BMI < 27 kg/m(2 ) and 9 obese , BMI > 27 kg/m(2 ) ) participated in the study . All subjects underwent an 80 mU. m(-2 ) . min(-1 ) hyperinsulinemic-euglycemic glucose clamp before and after 3 months ' treatment with the thiazolidinedione ( TZD ) troglitazone ( 600 mg/day ) . Fasting plasma glucose significantly decreased in the diabetic group after 12 weeks of treatment compared with baseline ( 9.1 + /- 0.9 vs. 11.1 + /- 0.9 mmol/l , P < 0.005 ) but was unchanged in the lean and obese subjects . Fasting insulin for the entire group was significantly lower than baseline ( P = 0.02 ) after treatment . At baseline , glucose disposal rate ( R(d ) ) was lower in the diabetic subjects ( 3.4 + /- 0.5 mg . kg(-1 ) . min(-1 ) ) than in the lean ( 12.3 + /- 0.4 ) or obese subjects ( 6.7 + /- 0.7 ) ( P < 0.001 for both ) and was significantly improved in the diabetic and obese groups ( P < 0.05 ) after treatment , and it remained unchanged in the lean subjects . Baseline adiponectin levels were significantly lower in the diabetic than the lean subjects ( 9.0 + /- 1.7 vs. 16.7 + /- 2.7 micro g/ml , P = 0.03 ) and rose uniformly in all subjects ( 12.2 + /- 2.3 vs. 25.7 + /- 2.6 micro g/ml , P < 10(-4 ) ) after treatment , with no significant difference detected among the three groups . During the glucose clamps , adiponectin levels were suppressed below basal levels in all groups ( 10.2 + /- 2.3 vs. 12.2 + /- 2.3 micro g/ml , P < 0.01 ) . Adiponectin levels correlated with R(d ) ( r = 0.46 , P = 0.016 ) and HDL cholesterol levels ( r = 0.59 , P < 0.001 ) and negatively correlated with fasting insulin ( r = -0.39 , P = 0.042 ) and plasma triglyceride ( r = -0.61 , P < 0.001 ) . Our findings show that TZD treatment increased adiponectin levels in all subjects , including normal subjects in which no other effects of TZDs are observed . Insulin also appears to suppress adiponectin levels . We have confirmed these results in normal rats . These findings suggest that adiponectin can be regulated by obesity , diabetes , TZDs , and insulin , and it may play a physiologic role in enhancing insulin sensitivity OBJECTIVE Improvement in endothelial function is predicted to improve insulin sensitivity , and this may be one mechanism by which fenofibrate decreases the incidence of coronary heart disease . We hypothesize fenofibrate improves endothelial function by enhancing insulin sensitivity . RESEARCH DESIGN AND METHODS We administered placebo or fenofibrate 200 mg daily for 8 weeks to 46 patients with primary hypertriglyceridemia ( 24 had metabolic syndrome ) . This study was r and omized , double blind , placebo controlled , and crossover in design . RESULTS Compared with placebo , fenofibrate decreased total cholesterol , non-HDL cholesterol , apolipoprotein B , and triglycerides and increased HDL cholesterol and apolipoprotein A-I ( all P < 0.001 ) while tending to decrease LDL cholesterol ( P = 0.069 ) . Fenofibrate significantly improved percent flow-mediated dilator response to hyperemia by 48 + /- 5 % ( P < 0.001 ) and lowered plasma levels of high-sensitivity C-reactive protein ( hsCRP ) relative to baseline measurements from 0.80 to 0.70 mg/l ( P = 0.001 ) and fibrinogen levels by 16 + /- 3 % ( P < 0.001 ) . Compared with placebo , fenofibrate therapy significantly increased plasma levels of adiponectin by 14 + /- 5 % ( P = 0.008 ) and increased insulin sensitivity ( assessed by quantitative insulin sensitivity check index [ QUICKI ] ) by 6 + /- 2 % ( P = 0.048 ) . There were significant correlations between percent changes in adiponectin levels and percent changes in flow-mediated dilation ( r = 0.401 , P = 0.006 ) , hsCRP ( r = -0.443 , P = 0.002 ) , or QUICKI ( r = 0.292 , P = 0.049 ) . Multivariate regression analysis showed that only changes in adiponectin levels persisted as an independent predictor of changes in flow-mediated dilation ( r = 0.504 , P = 0.013 ) . Overall , we observed similar results in 24 patients with metabolic syndrome . CONCLUSIONS Fenofibrate therapy significantly improved percent flow-mediated dilator response to hyperemia , reduced inflammation marker levels , increased adiponectin levels , and improved insulin sensitivity in hypertriglyceridemic or metabolic syndrome patients Objective . To examine the effect of acute and short-term ( ~1 week ) aerobic exercise training on plasma adiponectin levels in inactive , abdominally obese men . Material s and Methods . Inactive and abdominally obese men ( n = 38 , waist circumference ≥102 cm ) recruited from Kingston , Canada were r and omly allocated to perform three bouts of aerobic treadmill exercise at either low ( 50 % VO2 peak ) or high ( 75 % VO2 peak ) intensity during a 1-week period  . Blood sample s were taken before and after the first exercise session and 24–72 hours following the completion of the final exercise session . Results . Adiponectin levels were elevated immediately following an acute bout of exercise at both high and low intensities ( High : 5.79 ± 0.42 versus 5.05 ± 0.41 ug/mL ; Low : 5.24 ± 0.44 versus 4.37 ± 0.44 ug/mL , P < 0.05 ) and remained elevated following 30 minutes of rest . In comparison to baseline , adiponectin levels were also elevated 24–72 hours following the final exercise session ( High : 5.47 ± 0.48 versus 4.88 ± 0.48 ug/mL ; Low : 5.18 ± 0.49 versus 4.47 ± 0.49 ug/mL , P < 0.05 ) . Conclusion . Both acute and short-term aerobic exercise result in a significant increase in plasma adiponectin levels in inactive , abdominally obese men independent of intensity BACKGROUND We investigated whether combination therapy with a statin plus a fibrate , as compared with statin monotherapy , would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease . METHODS We r and omly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo .  The primary outcome was the first occurrence of nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes . The mean follow-up was 4.7 years . RESULTS The annual rate of the primary outcome was 2.2 % in the fenofibrate group and 2.4 % in the placebo group ( hazard ratio in the fenofibrate group , 0.92 ; 95 % confidence interval [ CI ] , 0.79 to 1.08 ; P=0.32 ) . There were also no significant differences between the two study groups with respect to any secondary outcome . Annual rates of death were 1.5 % in the fenofibrate group and 1.6 % in the placebo group ( hazard ratio , 0.91 ; 95 % CI , 0.75 to 1.10 ; P=0.33 ) . Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex , with a benefit for men and possible harm for women ( P=0.01 for interaction ) , and a possible interaction according to lipid subgroup , with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol ( P=0.057 for interaction ) . CONCLUSIONS The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events , nonfatal myocardial infa rct ion , or nonfatal stroke , as compared with simvastatin alone . These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes . ( Clinical Trials.gov number , NCT00000620 . CONTEXT HIV patients on antiretroviral therapy ( ART ) have a unique dyslipidemia [ elevated triglycerides and non-high-density lipoprotein-cholesterol ( HDL-C ) , low HDL-C ] with insulin resistance ( characterized by hypoadiponectinemia ) . OBJECTIVE The aim was to test a targeted , comprehensive , additive approach to treating the dyslipidemia . DESIGN AND SETTING We conducted a r and omized , double-blind , placebo-controlled , 24-wk trial of lifestyle modification , fenofibrate , and niacin in multiethnic HIV clinics at an academic center . PARTICIPANTS Hypertriglyceridemic adult patients were stratified on three combinations of ART classes . Subjects retained at the first measurement ( 2 wk ) after entry were included in the analysis ( n = 191 ) . INTERVENTIONS Subjects were r and omized into five treatment groups : usual care ( group 1 ) ; low-saturated-fat diet and exercise ( D/E ; group 2 ) ; D/E + fenofibrate ( group 3 ) ; D/E + niacin ( group 4 ) ; or D/E + fenofibrate + niacin ( group 5 ) . MAIN OUTCOME MEASURES We measured changes in fasting triglycerides , HDL-C , and non-HDL-C ( primary ) , and in insulin sensitivity , glycemia , adiponectin , C-reactive protein , energy expenditure , and body composition ( secondary ) . Data were analyzed as a factorial set of treatment combinations using a mixed repeated measures model , last observation carried forward , and complete case approaches ( groups 2 - 5 ) , and as an unstructured set of treatments ( groups 1 - 5 ) . RESULTS Fenofibrate improved triglycerides ( P = 0.002 ) , total cholesterol ( P = 0.02 ) , and non-HDL-C ( P = 0.003 ) , whereas niacin improved HDL-C ( P = 0.03 ) , and both drugs decreased the total cholesterol-to-HDL-C ratio ( P = 0.005 - 0.01 ) . The combination of D/E , fenofibrate , and niacin provided maximal benefit , markedly reducing triglycerides ( -52 % compared to usual care ; P = 0.003 ) , increasing HDL-C ( + 12 % ; P < 0.001 ) , and decreasing non-HDL-C ( -18.5 % ; P = 0.003 ) and total cholesterol-to-HDL-C ratio ( -24.5 % ; P < 0.001 ) . Niacin doubled adiponectin levels . CONCLUSIONS A combination of fenofibrate and niacin with low-saturated-fat D/E is effective and safe in increasing HDL-C , decreasing non-HDL-C and hypertriglyceridemia , and ameliorating hypoadiponectinemia in patients with HIV/ART-associated dyslipidemia BACKGROUND Coronary heart disease patients with low high-density lipoprotein cholesterol ( HDL-C ) levels , high triglyceride levels , or both are at an increased risk of cardiovascular events , but the clinical impact of raising HDL-C or decreasing triglycerides remains to be confirmed . METHODS AND RESULTS In a double-blind trial , 3090 patients with a previous myocardial infa rct ion or stable angina , total cholesterol of 180 to 250 mg/dL , HDL-C < or = 45 mg/dL , triglycerides < or = 300 mg/dL , and low-density lipoprotein cholesterol < or = 180 mg/dL were r and omized to receive either 400 mg of bezafibrate per day or a placebo ; they were followed for a mean of 6.2 years . The primary end point was fatal or nonfatal myocardial infa rct ion or sudden death .  Bezafibrate increased HDL-C by 18 % and reduced triglycerides by 21 % . The frequency of the primary end point was 13 . 6 % on bezafibrate versus 15.0 % on placebo ( P=0.26 ) . After 6.2 years , the reduction in the cumulative probability of the primary end point was 7.3 % , ( P=0.24 ) . In a post hoc analysis in the subgroup with high baseline triglycerides ( > or = 200 mg/dL ) , the reduction in the cumulative probability of the primary end point by bezafibrate was 39.5 % ( P=0.02 ) . Total and noncardiac mortality rates were similar , and adverse events and cancer were equally distributed . CONCLUSIONS Bezafibrate was safe and effective in elevating HDL-C levels and lowering triglycerides . An overall trend in a reduction of the incidence of primary end points was observed . The reduction in the primary end point in patients with high baseline triglycerides ( > or = 200 mg/dL ) requires further confirmation CONTEXT Adiponectin , a recently discovered adipocyte-derived peptide , is involved in the regulation of insulin sensitivity and lipid oxidation and , purportedly , in the development of atherosclerosis and coronary heart disease in humans . OBJECTIVE To assess prospect ively whether plasma adiponectin concentrations are associated with risk of myocardial infa rct ion ( MI ) . DESIGN , SETTING , AND PARTICIPANTS Nested case-control study among 18 225 male participants of the Health Professionals Follow-up Study aged 40 to 75 years who were free of diagnosed cardiovascular disease at the time of blood draw ( 1993 - 1995 ) . During 6 years of follow-up through January 31 , 2000 , 266 men subsequently developed nonfatal MI or fatal coronary heart disease . Using risk set sampling , controls were selected in a 2:1 ratio matched for age , date of blood draw , and smoking status ( n = 532 ) . MAIN OUTCOME MEASURE Incidence of nonfatal MI and fatal coronary heart disease by adiponectin level . RESULTS After adjustment for matched variables , participants in the highest compared with the lowest quintile of adiponectin levels had a significantly decreased risk of MI ( relative risk [ RR ] , 0.39 ; 95 % confidence interval [ CI ] , 0.23 - 0.64 ; P for trend < .001 ) . Additional adjustment for family history of MI , body mass index , alcohol consumption , physical activity , and history of diabetes and hypertension did not substantively affect this relationship ( RR , 0.41 ; 95 % CI , 0.24 - 0.70 ; P for trend < .001 ) . Further adjustment for hemoglobin A1c or C-reactive protein levels also had little impact , but additional adjustment for low- and high-density lipoprotein cholesterol levels modestly attenuated this association ( RR , 0.56 ; 95 % CI , 0.32 - 0.99 ; P for trend = .02 ) . CONCLUSIONS High plasma adiponectin concentrations are associated with lower risk of MI in men . This relationship can be only partly explained by differences in blood lipids and is independent of inflammation and glycemic status PPAR-alpha agonists improve insulin sensitivity in rodent models of obesity/insulin resistance , but their effects on insulin sensitivity in humans are less clear . We measured insulin sensitivity by hyperinsulinemic-isoglycemic clamp in 10 obese females with type 2 diabetes before and after three months of treatment with PPAR-alpha agonist fenofibrate  and studied the possible role of the changes in endocrine function of adipose tissue in the metabolic effects of fenofibrate . At baseline , body mass index , serum glucose , triglycerides , glycated hemoglobin and atherogenic index were significantly elevated in obese women with type 2 diabetes , while serum HDL cholesterol and adiponectin concentrations were significantly lower than in the control group ( n=10 ) . No differences were found in serum resistin levels between obese and control group .  Fenofibrate treatment decreased serum triglyceride concentrations , while both blood glucose and glycated hemoglobin increased after three months of fenofibrate administration . Serum adiponectin or resistin concentrations were not significantly affected by fenofibrate treatment . All parameters of insulin sensitivity as measured by hyperinsulinemic-isoglycemic clamp were significantly lower in an obese diabetic group compared to the control group before treatment and were not affected by fenofibrate administration . We conclude that administration of PPAR-alpha agonist fenofibrate for three months did not significantly affect insulin sensitivity or resistin and adiponectin concentrations in obese subjects with type 2 diabetes mellitus . The lack of insulin-sensitizing effects of fenofibrate in humans relative to rodents could be due to a generally lower PPAR-alpha expression in human liver and muscle BACKGROUND Omega-3 fatty acids and fenofibrate are both used to treat patients with hypertriglyceridemia .  However , a head-to-head comparison of the lipoprotein and metabolic effects of these two medicines has not been published . METHODS This was a r and omized , single-blind , placebo-controlled , parallel study . Age , sex , and body mass index were matched among groups . All patients were recommended to maintain a low fat diet . Fifty patients in each group were given placebo , omega-3 fatty acids 2 g ( most commonly used dosage in Korean patients ) , or fenofibrate 160 mg , respectively daily for 2 months . RESULTS Omega-3 fatty acids therapy decreased triglycerides by 21 % and triglycerides/HDL cholesterol and improved flow-mediated dilation ( P<0.01 ) , however , did not significantly change insulin , plasma adiponectin levels , and insulin sensitivity ( determined by QUICKI ) relative to baseline measurements . Fenofibrate therapy decreased total cholesterol , triglycerides by 29 % , and triglycerides/HDL-cholesterol ( all P<0.01 ) and improved flow-mediated dilation when compared with baseline . When compared with placebo and omega-3 fatty acids , fenofibrate therapy decreased non-HDL cholesterol ( P<0.001 ) and triglycerides/HDL cholesterol ( P=0.016 ) while increasing HDL cholesterol ( P<0.001 ) and apolipoprotein AI ( P=0.001 ) . Of note , when compared with omega-3 fatty acids , fenofibrate therapy decreased fasting insulin ( P=0.023 ) and increased plasma adiponectin ( P=0.002 ) and insulin sensitivity ( P=0.015 ) . CONCLUSIONS Omega-3 fatty acids and fenofibrate therapy promoted similar changes in triglycerides and endothelium-dependent dilation . However , fenofibrate therapy had substantially better effects on lipoprotein and metabolic profiles in patients with hypertriglyceridemia 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 lig and bezafibrate on IR , and its long-term effect is unknown . The present analysis aim ed to investigate the effect of bezafibrate on IR in patients with coronary artery disease enrolled in the Bezafibrate Infa rct ion Prevention Study . METHODS Metabolic and inflammatory parameters were analyzed from stored frozen plasma sample s obtained from patients who completed a 2-year , r and omized , 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 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 lig and 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 ) . The patients received either 400 mg bezafibrate retard ( 156 patients ) or placebo ( 147 patients ) once a day . No patients were using statins , and use of ACE inhibitors , which also reduce diabetes incidence , was relatively low . During follow-up , development of new-onset diabetes was recorded in 146 patients : in 80 ( 54.4 % ) from the placebo group and 66 ( 42.3 % ) from the bezafibrate group ( P = 0.04 ) . The mean time until onset of new diabetes was significantly delayed in patients on bezafibrate compared with patients on placebo : 4.6±2.3 versus 3.8±2.6 years ( P = 0.004 ) . Multivariate analysis identified bezafibrate treatment as an independent predictor of reduced risk of new diabetes development ( hazard ratio , 0.70 ; 95 % CI , 0.49 to 0.99 ) . Other significant variables associated with future overt type 2 diabetes in patients with impaired fasting glucose were total cholesterol level ( hazard ratio , 1.22 ; 95 % CI 1.0 to 1.51 ) and body mass index ( hazard ratio , 1.10 ; 95 % CI , 1.05 to 1.16 ) . Conclusions —Bezafibrate reduces the incidence and delays the onset of type 2 diabetes in patients with impaired fasting glucose . Whether the combination of bezafibrate with other recommended drugs for secondary prevention ( statins and ACE inhibitors ) would be as efficacious as suggested by our results remains to be determined OBJECTIVE Elevated triglyceride-rich lipoproteins may contribute to endothelial dysfunction in obese diabetic subjects . We investigated the association between plasma concentrations of chylomicron-related particles and endothelial function , and the corresponding responses to fenofibrate treatment . METHODS Plasma apolipoprotein ( apo ) B-48 and remnant-like particle (RLP)-cholesterol concentrations were measured in 28 obese subjects with T2DM .  Flow-mediated endothelium-dependent dilation ( FMD ) and glyceryl-trinitrate mediated dilatation ( GTNMD ) in the brachial artery during reactive hyperaemia were examined by high-resolution ultrasound technique . RESULTS In univariate analysis , plasma apoB-48 and RLP-cholesterol concentrations were inversely associated with brachial artery FMD ( r = -0.425 and -0.423 , respectively , P<0.05 ) , but not with GTNMD . In regression models including BMI and HOMA score , plasma apoB-48 was an independent predictors ( P<0.05 ) of brachial artery FMD ( β coefficient = -0.384 ) . Replacing HOMA-IR score with plasma triglyceride , adiponectin or CRP concentrations did not alter the findings . The subjects were then r and omized to a 12-week treatment period of either 200 mg micronized fenofibrate or matching placebo . Compared with the placebo group , fenofibrate treatment ( 200 mg daily for 12 weeks ) achieved significant increase in FMD ( + 34 % ) and reduction in plasma triglyceride ( -42 % ) , apoB-48 ( -52 % ) and RLP-cholesterol ( -51 % ) concentrations . The increase in FMD with fenofibrate was significantly associated with the corresponding decrease in plasma apoB-48 ( r = -0.644 , P<0.02 ) concentrations . CONCLUSIONS Our findings demonstrate an association between changes in lipid metabolism and improvement in endothelial function in patients with diabetic dyslipidaemia treated with fenofibrate that may involve the effect of apoB-48 on endothelium-dependent vasodilator function A double-blind , placebo-controlled trial assessed the effect of a slow-release formulation of bezafibrate ( Bezalip Mono , 400 mg daily for 3 months ) on lipid profile , glucose homeostasis , platelet function , and plasma fibrinogen concentration in non-insulin-dependent ( type II ) diabetics . Twenty-four patients completed the trial . There was a significant improvement in the cholesterol ( p < 0.02 ) , triglyceride ( p < 0.01 ) , and nonesterified fatty acid ( p < 0.05 ) concentrations and in the fasting blood glucose ( p < 0.03 ) and glycosylated hemoglobin ( p < 0.01 ) levels of those ( n = 11 ) who received the active preparation but not in those ( n = 13 ) who received placebo . Treatment , but not placebo , also result ed in a significant ( p < 0.01 ) fall in plasma fibrinogen concentration and a trend towards inhibition of platelet aggregation .  Bezafibrate was well tolerated ; only one patient ( not included in the analysis of results ) withdrew from the trial possibly because of side effects of the drug . A larger study is needed to establish whether bezafibrate can reduce nonlipid risk factors ( e.g. , plasma fibrinogen concentration , glucose intolerance , and hyperinsulinemia ) in normo- and hyperlipidemic subjects Obesity is a low grade inflammatory state associated with premature cardiovascular morbidity and mortality . Along with traditional risk factors the measurement of endothelial function , insulin resistance , inflammation and arterial stiffness may contribute to the assessment of cardiovascular risk . We conducted a r and omised placebo controlled trial to assess the effects of 12 weeks treatment with a PPAR alpha agonist ( fenofibrate ) and a PPAR gamma agonist ( pioglitazone ) on these parameters in obese glucose tolerant men .  Arterial stiffness was measured using augmentation index and pulse wave velocity ( PWV ) . E-selectin , VCAM-1 and ICAM-1 were used as markers of endothelial function . Insulin sensitivity improved with pioglitazone treatment ( p=0.001 ) and , in keeping with this , adiponectin increased by 85.2 % ( p<0.001 ) . Pro-inflammatory cytokine levels ( TNFalpha , IL-6 and IL-1 beta ) fell with both treatments ( p<0.01 for TNFalpha and IL-1 beta , p<0.001 for IL-6 ) . VCAM-1 and ICAM-1 were reduced with both treatments ( p<0.001 for VCAM-1 , p<0.05 for ICAM-1 ) and E-selectin improved with pioglitazone treatment ( p=0.05 ) . Both treatments result ed in a fall in augmentation index . PWV fell by 17.4 % with fenofibrate treatment ( p<0.001 ) and 16.3 % with pioglitazone treatment ( p<0.001 ) . Pioglitazone and fenofibrate treatment of obese , glucose tolerant men reduces inflammation , improves markers of endothelial function and reduces arterial stiffness . These results suggest that treatment with PPAR agonists has potential to reduce the incidence of premature cardiovascular disease associated with obesity BACKGROUND Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease , partly owing to dyslipidaemia , which can be amenable to fibrate therapy . We design ed the Fenofibrate Intervention and Event Lowering in Diabetes ( FIELD ) study to assess the effect of fenofibrate on cardiovascular disease events in these patients . METHODS We did a multinational , r and omised controlled trial with 9795 participants aged 50 - 75 years , with type 2 diabetes mellitus , and not taking statin therapy at study entry . After a placebo and a fenofibrate run-in phase , we r and omly assigned patients ( 2131 with previous cardiovascular disease and 7664 without ) with a total-cholesterol concentration of 3.0 - 6.5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4.0 or more or plasma triglyceride of 1.0 - 5.0 mmol/L to micronised fenofibrate 200 mg daily ( n=4895 ) or matching placebo ( n=4900 ) . Our primary outcome was coronary events ( coronary heart disease death or non-fatal myocardial infa rct ion ) ; the outcome for prespecified subgroup analyses was total cardiovascular events ( the composite of cardiovascular death , myocardial infa rct ion , stroke , and coronary and carotid revascularisation ) . Analysis was by intention to treat . The study was prospect ively registered ( number IS RCT N 64783481 ) . FINDINGS Vital status was confirmed on all but 22 patients . Averaged over the 5 years ' study duration , similar proportions in each group discontinued study medication ( 10 % placebo vs 11 % fenofibrate ) and more patients allocated placebo ( 17 % ) than fenofibrate ( 8 % ; p<0.0001 ) commenced other lipid treatments , predominantly statins . 5.9 % ( n=288 ) of patients on placebo and 5.2 % ( n=256 ) of those on fenofibrate had a coronary event ( relative reduction of 11 % ; hazard ratio [ HR ] 0.89 , 95 % CI 0.75 - 1.05 ; p=0.16 ) . This finding corresponds to a significant 24 % reduction in non-fatal myocardial infa rct ion ( 0.76 , 0.62 - 0.94 ; p=0.010 ) and a non-significant increase in coronary heart disease mortality ( 1.19 , 0.90 - 1.57 ; p=0.22 ) . Total cardiovascular disease events were significantly reduced from 13.9 % to 12.5 % ( 0.89 , 0.80 - 0.99 ; p=0.035 ) . This finding included a 21 % reduction in coronary revascularisation ( 0.79 , 0.68 - 0.93 ; p=0.003 ) . Total mortality was 6.6 % in the placebo group and 7.3 % in the fenofibrate group ( p=0.18 ) . Fenofibrate was associated with less albuminuria progression ( p=0.002 ) , and less retinopathy needing laser treatment ( 5.2%vs 3.6 % , p=0.0003 ) . There was a slight increase in pancreatitis ( 0.5%vs 0.8 % , p=0.031 ) and pulmonary embolism ( 0.7%vs 1.1 % , p=0.022 ) , but no other significant adverse effects . INTERPRETATION Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events . It did reduce total cardiovascular events , mainly due to fewer non-fatal myocardial infa rct ions and revascularisations . The higher rate of starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit BACKGROUND We investigated effects of fenofibrate therapy on endothelial dysfunction and adipocytokine profiles . METHODS A r and omized , single-blind , placebo-controlled , cross-over study was conducted in 53 patients with primary hypertriglyceridemia . We administered placebo or fenofibrate 160 mg daily for 8 weeks . RESULTS When compared with placebo , fenofibrate therapy substantially lowered plasma levels of TNF-α by 6±3 % ( P=0.014 ) and hsCRP from 1.10 to 0.90mg/l ( P=0.004 ) . When compared with placebo , fenofibrate therapy increased plasma levels of adiponectin by 17±4 % ( P=0.001 ) , insulin sensitivity by 4±1 % ( as assessed by QUICKI , P=0.009 ) , and decreased plasma levels of leptin and resistin by 4±7 % ( P=0.022 ) and 10±3 % ( P=0.001 ) , respectively . There were correlations between percent changes in QUICKI and percent changes in adiponectin levels ( r=0.279 , P=0.043 ) or leptin ( r=-0.280 , P=0.042 ) . CONCLUSIONS Fenofibrate therapy significantly reduced pro-inflammatory biomarkers and improved adipocytokines levels and insulin sensitivity in hypertriglyceridemic patients
target: The observed effect was robust in sensitivity analyses and independent of fibrate dose .
  The present meta- analysis suggests that fibrate therapy increases circulating levels of adiponectin .
background: BACKGROUND Several lines of evidence have indicated the insulin-sensitizing , anti-diabetic and anti-atherosclerotic properties of adiponectin , as well as the inverse association between circulating levels of this adipokine and development of cardiovascular outcomes .
  Improvement of adiponectin status has been reported as a pleiotropic effect of fibrate therapy , but the findings have not been conclusive .
  OBJECTIVE To systematic ally review and meta-analyze available evidence from r and omized placebo-controlled trials ( RCTs ) on the impact of fibrate therapy on circulating levels of adiponectin .