title: Plasma homocysteine and the risk of venous thromboembolism: insights from the FIELD study Hemostatic effects of bezafibrate and ω-3 fatty acids in isolated hypertriglyceridemic patients. Bezafibrate lowers plasma lipids, fibrinogen and platelet aggregability in hypertriglyceridaemia Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial Effects of short-term fenofibrate treatment on circulating markers of inflammation and hemostasis in patients with impaired glucose tolerance. Ideal Cardiovascular Health: Associations With Biomarkers and Subclinical Disease and Impact on Incidence of Cardiovascular Disease in the Framingham Offspring Study Effects of combination lipid therapy in type 2 diabetes mellitus. Relationships between plasma insulin triglyceride, body mass index, and plasminogen activator inhibitor 1. Effect of micronized fenofibrate on plasma lipoprotein levels and hemostatic parameters of hypertriglyceridemic patients with low levels of high-density lipoprotein cholesterol in the fed and fasted state. Effects of gemfibrozil on insulin sensitivity and on haemostatic variables in hypertriglyceridemic patients. Effects of fluvastatin and bezafibrate combination on plasma fibrinogen, t-plasminogen activator inhibitor and C reactive protein levels in coronary artery disease patients with mixed hyperlipidaemia (FACT study). Fluvastatin Alone and in Combination Treatment. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial Pleiotropic Action of Short-Term Metformin and Fenofibrate Treatment, Combined With Lifestyle Intervention, in Type 2 Diabetic Patients With Mixed Dyslipidemia Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. Effects of fenofibrate on lipoproteins, vasomotor function, and serological markers of inflammation, plaque stabilization, and hemostasis. Fibrinolytic proteins and progression of coronary artery disease in relation to gemfibrozil therapy. Gemfibrozil treatment of combined hyperlipoproteinemia. No improvement of fibrinolysis despite marked reduction of plasma triglyceride levels. Effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator, plasminogen activator inhibitor-1 and fibrinogen in hyperlipidaemic patients. Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipoproteinaemia. Gemfibrozil treatment increases low-density lipoprotein particle size in Type 2 diabetes mellitus but does not alter in vitro oxidizability. 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 gemfibrozil on lipids and haemostasis after myocardial infarction.
abstract: Abstract Background : The lipid-lowering effect of fenofibrate is accompanied by a rise in plasma homocysteine ( HCY ) , a potential risk factor for venous thromboembolism ( VTE ) . This study investigated the relationship between HCY and the risk of VTE in patients treated with fenofibrate .  Methods : The relationship between HCY and deep-vein thrombosis or pulmonary embolism was investigated in 9522 participants of the 5-year Fenofibrate Intervention and Event Lowering in Diabetes ( FIELD ) trial . All subjects received fenofibrate during a 6-week active run-in phase before r and omization . A Cox proportional-hazards model was used to assess the effect of HCY on risk of venous thromboembolic events . Results : During active-drug run-in , HCY rose on average by 6.5 μmol/L , accompanied by a substantial rise in plasma creatinine ( + 12 % ) . Fenofibrate-induced  changes in HCY and creatinine were fully reversible in the placebo group but persisted in the treatment group until reversing at the end of therapy . During follow-up , 1.8 % had at least one episode of deep-vein thrombosis or pulmonary embolism : 103 on fenofibrate and 68 on placebo ( log-rank p=0.006 ) . In multivariate analysis , every 5 μmol/L higher baseline HCY was associated with 19 % higher risk of VTE . Fenofibrate treatment was associated with 52 % higher risk , but the change in HCY with fenofibrate was not significantly associated with VTE after adjustment for baseline HCY . Conclusions : Hyperhomocysteinemia is prospect ively associated with  VTE . Fenofibrate may predispose individuals with high pretreatment HCY towards VTE . The fenofibrate-induced increase in HCY did not , however , explain the risk associated with fenofibrate therapy This study aim ed to compare the effects of ω-3 fatty acids and fibrate treatment on plasma levels and activities of hemostatic risk factors on glucose and lipid metabolism in subjects with isolated hypertriglyceridemia . Seventy-three subjects with elevated triglyceride levels were allocated into one of the following treatment options : bezafibrate ( 200 mg twice daily ) , ω-3 fatty acids ( 1 g twice daily ) or placebo . Plasma lipids , glucose homeostasis markers ( fasting and 2-h post-glucose load plasma glucose levels and HOMA ) , as well as plasma levels/activities of fibrinogen , factor VII and PAI-1 were determined at baseline , on the day of r and omization , and after 4 and 12 weeks of the treatment . Not only did bezafibrate  improve plasma lipids , but it also increased glucose sensitivity and tended to reduce post-glucose loads of plasma glucose . Except for the reduction in plasma triglycerides , ω-3 fatty acids produced no effect on the lipid profile and insulin sensitivity . Both treatment options reduced , to similar extents , plasma levels of fibrinogen and PAI-1 and factor VII coagulant activity . Our study indicates that , although fibrates exhibit more-pronounced metabolic effects than do ω-3 fatty acids , both these treatment options are equipotent in producing a complex beneficial effect on hemostasis in isolated hypertriglyceridemic subjects Summary The effects of bezafibrate 400 mg/day ( slow release formulation ) on plasma lipids/lipoproteins and on selected haemostatic parameters were evaluated in a double blind cross-over study in patients with Type IIb and IV hyperlipoproteinaemia .  Placebo treatment did not influence any of those parameters , but the drug significantly reduced plasma triglycerides ( −45 % ) and VLDL cholesterol , as well as causing a 12 % fall in total cholesterol and a 20 % increase in HDL cholesterol . Apo AI levels were significantly increased following bezafibrate and Apo B was reduced by about 20 % . In addition to changes in the plasma lipid profile , bezafibrate reduced the sensitivity of platelets to the aggregatory effect of collagen , with no effect on TXB2 production . Fibrinogen levels  after bezafibrate treatment were significantly lowered , the effect being more marked in patients with hyperfibrinogenaemia  . Bezafibrate did not influence the plasma fibrinolytic profile . It is concluded that bezafibrate , besides its beneficial effects on the plasma lipoprotein profile , can exert beneficial changes on specific haemostatic parameters Summary Background Amputations in people with type 2 diabetes mellitus substantially impair their quality of life and impose high costs on health-care systems . Our aim was to assess the effect of fenofibrate on amputation events in a large cohort of patients with type 2 diabetes . Methods In the Fenofibrate Intervention and Event Lowering in Diabetes ( FIELD ) study , 9795 patients aged 50–75 years with type 2 diabetes were r and omly assigned by computer-generated r and omisation sequence to receive fenofibrate 200 mg per day ( n=4895 ) or matching placebo ( n=4900 ) for 5 years ' duration . Information about non-traumatic amputation — a prespecified tertiary endpoint of the study —was routinely gathered . Clinicians who were masked to treatment allocation adjudicated amputations as minor or major ( below or above the ankle , respectively ) . Amputations were also classified on the basis of whether or not large-vessel disease was present in the limb , to distinguish those related to large-artery atherosclerosis from those predominantly related to microvascular disease . Analysis was by intention to treat ( ITT ) . The FIELD study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N64783481 . Findings All 9795 patients were included in the ITT population . 115 patients had one or more non-traumatic lower-limb amputations due to diabetes .  Previous cardiovascular disease , microvascular disease , previous non-traumatic amputation or skin ulcer , smoking , and longer duration of diabetes were more frequent in patients who had amputations during the trial than in those who had other cardiovascular events or in those who had neither event ( all p<0·001 for three-way comparison ) . Mean lipid concentrations differed between patients who had on- study amputations and those who had other cardiovascular events or neither event , but by no more than 0·2 mmol/L. The risks of first amputation ( 45 vs 70 events ; hazard ratio [ HR ] 0·64 , 95 % CI 0·44–0·94 ; p=0·02 ) and minor amputation events without known large-vessel disease ( 18 vs 34 events ; 0·53 , 0·30–0·94 ; p=0·027 ) were lower for patients assigned to fenofibrate than for patients assigned to placebo , with no difference between groups in risk of major amputations ( 24 vs 26 events ; 0·93 , 0·53–1·62 ; p=0·79 ) . Interpretation Classic markers of macrovascular and microvascular risk were associated with lower extremity amputations in patients with type 2 diabetes . Treatment with fenofibrate was associated with a lower risk of amputations , particularly minor amputations without known large-vessel disease , probably through non-lipid mechanisms . These findings could lead to a change in st and ard treatment for the prevention of diabetes-related lower-limb amputations . Funding Laboratoires Fournier SA ( now part of Solvay Pharmaceuticals ) and National Health and Medical Research Council of Australia CONTEXT Apart from lowering lipid levels , peroxisome proliferator-activated receptor ( PPAR ) alpha activators ( fibrates ) produce many other favorable effects that may contribute to their clinical effectiveness in dyslipidemic and diabetic patients . OBJECTIVE The objective of this study was to compare the impact of a short-term treatment with fenofibrate and the American Heart Association ( AHA ) step 1 diet on systemic inflammation , hemostasis , and monocyte secretory function in relationship with their metabolic actions . DESIGN , SETTING , PARTICIPANTS , AND INTERVENTIONS This was a prospect i ve , r and omized , placebo-controlled trial involving the group of 91 ambulatory patients with impaired glucose tolerance ( IGT ) ( diagnosed on the basis of the American Diabetes Association criteria ) , r and omly divided into three groups , simultaneously treated for 30 d with the AHA step 1 diet ( n = 30 ) , micronized fenofibrate ( 267 mg/d , n = 31 ) , or placebo ( n = 30 ) . The control group included 34 age- , sex- , and weight-matched subjects with normal glucose tolerance . Eighty-six ( 95 % ) patients and all control subjects completed the study . MAIN OUTCOME MEASURES Plasma markers of inflammation and hemostasis and monocyte release of proinflammatory cytokines were measured . RESULTS Compared with subjects with normal glucose tolerance , IGT patients exhibited higher plasma levels/activities of fibrinogen , factor VII , plasminogen activator inhibitor-1 , high-sensitivity C-reactive protein , and oxidized low-density lipoproteins . Lipopolysaccharide-activated monocytes from IGT patients released significantly more TNF-alpha , IL-1beta , IL-6 , and monocyte chemoattractant protein-1 in comparison with monocytes from control subjects . Thirty-day treatment with fenofibrate but not with the AHA step 1 diet : 1 ) improved lipid/lipoprotein profile and glucose metabolism , and 2 ) reversed or alleviated all the above-mentioned abnormalities . The favorable effects of fenofibrate on plasma high-sensitivity C-reactive protein and on monocyte release of TNF-alpha , IL-1beta , IL-6 , and monocyte chemoattractant protein-1 did not correlate with its action on plasma lipids but was related to the improvement in insulin sensitivity and weakly to free fatty acid-lowering action . CONCLUSIONS Our study is the first to show that relatively small disturbances in glucose metabolism are associated with marked and multidirectional abnormalities in plasma markers of inflammation and hemostasis and in monocyte secretory function . Moreover , fenofibrate may exhibit early pleiotropic effects in patients with IGT Background — The American Heart Association Cardiovascular Health score ( CVH score ) is inversely associated with cardiovascular disease ( CVD ) incidence , but the mechanisms underlying this association warrant exploration . Methods and Results — We related the CVH score to circulating biomarkers and prevalent sub clinical CVD ( defined as ≥1 of the following : increased carotid intima-media thickness or stenosis , left ventricular hypertrophy [ by ECG or echocardiography ] , left ventricular systolic dysfunction , microalbuminuria , and a reduced ankle-brachial index ) in 2680 Framingham Study participants ( mean age , 58 years ; 55 % women ) . After adjustment for age and sex , an ideal CVH score ( nonsmoking status , ideal body mass index , regular physical activity , healthy diet , and an optimal profile of serum cholesterol , blood pressure , and glucose ; 1 point for each ) was associated with higher circulating concentrations of natriuretic peptides ( N-terminal pro-atrial natriuretic peptide and B-type natriuretic peptide ) and lower blood concentrations of plasminogen activator inhibitor-1 , aldosterone , C-reactive protein , D-dimer , fibrinogen , homocysteine , and growth differentiation factor-15 levels ( P<0.001 for all ) , as well as lower odds of sub clinical disease ( odds ratio , 0.74 per 1-unit increase in CVH score ; 95 % confidence interval , 0.68–0.80 ) . The incidence of CVD ( 267 events over 16 years ) was inversely associated with the CVH score in age- and sex-adjusted models ( hazard ratio , 0.77 per 1-unit increase in CVH score ; 95 % confidence interval , 0.70–0.86 ) , which was slightly attenuated upon adjustment for biomarkers and sub clinical disease ( hazard ratio , 0.87 ; 95 % confidence interval , 0.78–0.97 ) . Conclusion — In our prospect i ve community-based study , the inverse association between an ideal cardiovascular health score and CVD incidence was partly attributable to its favorable impact on CVD biomarker levels and sub clinical disease 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 . Low fibrinolytic activity , as measured by euglobulin ( EFA ) , has been observed in obese subjects , and hypofibrinolysis may play a role in the pathogenesis of atherosclerosis and its complications . Blood fibrinolytic activity is regulated through a complex system of activators and inhibitors , especially plasminogen activator inhibitors ( PA Inhibitors ) . In a group of 35 non-diabetic subjects with a wide range of body mass index ( BMI ) , EFA was negatively correlated , and PA Inhibitor activity positively correlated , with BMI and plasma insulin levels . In a population of 49 non-diabetic obese women ( differing from a control group of normal weight by lower EFA and higher level , of PA Inhibitor activity , plasma insulin and triglyceride ) , the PA Inhibitor activity was positively correlated with BMI , insulin and triglyceride . The increase in PA Inhibitor activity was associated with a high value of PA Inhibitor 1 antigen measured by an immuno-radiometric assay , indicating that the increased activity was due to a high level of circulating PA Inhibitor 1 . Plasma insulin was lowered in obese non-diabetic subjects , without modification of the body weight , by a 24 hour fast or by treatment with Metformin . After 24 hours ' fast , ten obese subjects had lower levels of insulin and PA Inhibitor activity and an increase in EFA . Treatment for 15 days by 1.75 g Metformin ( or placebo ) , on a weight maintaining diet , induced , in the Metformin group , a decrease in plasma insulin , triglyceride and PA Inhibitor activity and an increase in EFA , while no change was observed in the placebo group . ( ABSTRACT TRUNCATED AT 250 WORDS A r and omized , double-blind , placebo-controlled study was undertaken in 20 hypertriglyceridemic men [ plasma triglyceride ( TG ) , > 2.3 mM ] with low levels ( < 0.9 mM ) of high-density lipoprotein cholesterol ( HDL-C ) to investigate the ability of micronized fenofibrate ( Tricor or Lipidil ; 200 mg/day ) to affect atherogenic and thrombogenic plasma risk factors in the fed and fasted state . Each patient underwent ( a ) 4 weeks of dietary stabilization , ( b ) 8 weeks of treatment with fenofibrate or placebo , ( c ) a 5-week washout period , and ( d ) 8-weeks of treatment with the alternative medication . An oral fat-loading test ( 1 g fat/kg body weight ) was carried out after both treatment periods . Before treatment , patients had a mean ( + /- SD )  total plasma TG of 3.31+/-0.93 mM ; total  C , 5.75+/-0.89 mM ; HDL-C , 0.71+/-0.09 mM ; and low-density lipoprotein (LDL)-C , 3.40+/-0.68 mM. Compared with placebo , fenofibrate reduced fasting TG levels by 36 % , and triglyceride-rich lipoprotein ( TRL , d<1.006 g/ml ) -TG , and TRL-C levels by approximately 40 % . In the postpr and ial state , fenofibrate reduced total TG , TRL-TG , TRL-C , TRL-apoC-III , and TRL-apoE levels by -35 % ( all values of p<0.01 ) . Fasted and fed HDL-C and apoA-I levels were increased -10 % , and total cholesterol/HDL cholesterol ratios were decreased -15 % by fenofibrate . No significant differences were observed in mean LDL-C and LDL-apoB levels . A 6 % increase in the LDL-C/LDL-apoB ratio during fenofibrate treatment indicated a shift to larger , more buoyant LDL particles . A small , but statistically significant ( p<0.01 ) increase was observed in fasted and fed Lp(a ) levels during fenofibrate treatment . Hemostatic parameters were not significantly affected by fenofibrate , except for a 12 - 15 % decrease ( p<0.05 ) in fibrinogen levels in the fasted and fed state , and a significant increase ( 43 % ; p<0.05 ) in fasting levels of plasminogen activator-inhibitor-1 . These data demonstrate that micronized fenofibrate is highly effective , in both the fed and fasted state , in reducing TRL lipids and apolipoproteins , and in reducing plasma fibrinogen levels of men with an atherogenic lipoprotein profile In order to assess the efficacy of gemfibrozil on lipid and haemostatic parameters in patients with plurimetabolic syndrome , a multicenter double-blind placebo controlled , parallel study was carried out in 56 patients with primary hypertriglyceridemia and glucose intolerance . These patients had elevated PAI activity and antigen and t-PA antigen levels at rest and after venous occlusion . Gemfibrozil reduced plasma triglyceride levels ( P<0.001 ) , whereas it increased free fatty acids ( P<0.05 ) and high density lipoprotein cholesterol levels ( P<0.05 ) . In those patients reaching normalization of plasma triglyceride levels ( triglyceride reduction > or = 50 % ) ( n=15 ) , insulin levels ( P<0.05 ) as well as the insulin resistance index were reduced by gemfibrozil treatment , suggesting an improvement of the insulin resistance index in this patient subgroup . Gemfibrozil treatment did not affect plasma fibrinolysis or fibrinogen levels , despite marked reduction of plasma triglycerides and improvement of the insulin sensitivity associated with triglyceride normalization AIM OF THE STUDY We studied the effects of fluvastatin and bezafibrate in monotherapy and in combination on plasma fibrinogen , t-plasminogen activator inhibitor ( PAI-1 ) and C reactive protein ( CRP ) in patients with coronary artery disease ( CAD ) and mixed hyperlipidaemia . DESIGN In this r and omised , double blind , multicentre trial 333 patients with stable angina pectoris or previous myocardial infa rct ion or coronary revascularisation and mixed hyperlipidaemia ( LDL-cholesterol 135 - 250 mg/dl and triglycerides ( TG ) 180 - 400 mg/dl ) were r and omised to fluvastatin 40 mg , bezafibrate 400 mg , fluvastatin 20 mg + bezafibrate 400 mg or fluvastatin 40 mg + bezafibrate 400 mg treatments for 24 weeks . RESULTS Plasma fibrinogen significantly decreased after treatment with the combinations fluvastatin+bezafibrate ( -14 and -16 % ) and with bezafibrate monotherapy ( -9 % ) . No significant reduction was observed after fluvastatin monotherapy ( -4 % ) . No significant changes were observed in PAI-1 and CRP plasma levels . Combination therapy significantly decreased both LDL-C and TG , and significantly increased HDL-C. CONCLUSIONS The combined effects on fibrinogen and plasma lipids achieved by fluvastatin and bezafibrate combination treatment might be more useful than the simple reduction of cholesterol in preventing ischaemic cardiovascular disease BACKGROUND Laser treatment for diabetic retinopathy is often associated with visual field reduction and other ocular side-effects . Our aim was to assess whether long-term lipid-lowering therapy with fenofibrate could reduce the progression of retinopathy and the need for laser treatment  in patients with type 2 diabetes mellitus . METHODS The Fenofibrate Intervention and Event Lowering in Diabetes ( FIELD ) study was a multinational r and omised trial of 9795 patients aged 50 - 75 years with type 2 diabetes mellitus . Eligible patients were r and omly assigned to receive fenofibrate 200 mg/day ( n=4895 ) or matching placebo ( n=4900 ) . At each clinic visit , information concerning laser treatment for diabetic retinopathy-a prespecified tertiary endpoint of the main study -was gathered . Adjudication by ophthalmologists masked to treatment allocation defined instances of laser treatment for macular oedema , proliferative retinopathy , or other eye conditions . In a sub study of 1012 patients , st and ardised retinal photography was done and photographs grade d with Early Treatment Diabetic Retinopathy Study ( ETDRS ) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions . Analyses were by intention to treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N64783481 . FINDINGS  Laser treatment  was needed more frequently in participants with poorer glycaemic or blood pressure control than in those with good control of these factors , and in those with a greater burden of clinical microvascular disease , but the need for such treatment was not affected by plasma lipid concentrations . The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group ( 164 [ 3.4 % ] patients on fenofibrate vs 238 [ 4.9 % ] on placebo ; hazard ratio [ HR ] 0.69 , 95 % CI 0.56 - 0.84 ; p=0.0002 ; absolute risk reduction 1.5 % [ 0.7 - 2.3 ] ) . In the ophthalmology sub study , the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups overall ( 46 [ 9.6 % ] patients on fenofibrate vs 57 [ 12.3 % ] on placebo ; p=0.19 ) or in the subset of patients without pre-existing retinopathy ( 43 [ 11.4 % ] vs 43 [ 11.7 % ] ; p=0.87 ) . By contrast , in patients with pre-existing retinopathy , significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo ( three [ 3.1 % ] patients vs 14 [ 14.6 % ] ; p=0.004 ) . An exploratory composite endpoint of 2-step progression of retinopathy grade , macular oedema , or laser treatments was significantly lower in the fenofibrate group than in the placebo group ( HR 0.66 , 95 % CI 0.47 - 0.94 ; p=0.022 ) . INTERPRETATION Treatment with fenofibrate in individuals with type 2 diabetes mellitus reduces the need for laser treatment for diabetic retinopathy , although the mechanism of this effect does not seem to be related to plasma concentrations of lipids OBJECTIVE To compare the effect of short-term metformin and fenofibrate treatment , administered alone or in sequence , on glucose and lipid metabolism , cardiovascular risk factors , and monocyte cytokine release in type 2 diabetic patients with mixed dyslipidemia . RESEARCH DESIGN AND METHODS We studied 128 type 2 diabetic patients with mixed dyslipidemia complying throughout the study with lifestyle intervention who were r and omized twice , initially to either  metformin or placebo  , and then to micronized fenofibrate or placebo . RESULTS Fenofibrate alleviated diabetic dyslipidemia – induced changes in plasma high-sensitivity C-reactive protein , fibrinogen , and plasminogen activator inhibitor (PAI)-1 and in monocyte cytokine release , whereas metformin or lifestyle intervention improved mainly glucose and lipid metabolism . The strongest pleiotropic effect was observed when fenofibrate was added to metformin . CONCLUSIONS Fenofibrate , particularly administered together with metformin , is superior to metformin and lifestyle intervention in exhibiting beneficial effects on systemic inflammation , hemostasis , and monocyte secretory function in type 2 diabetic patients with mixed dyslipidemia In a r and omized , double-blind five-year trial , we tested the efficacy of simultaneously elevating serum levels of high-density lipoprotein ( HDL ) cholesterol and lowering levels of non-HDL cholesterol with gemfibrozil in reducing the risk of coronary heart disease in 4081 asymptomatic middle-aged men ( 40 to 55 years of age ) with primary dyslipidemia ( non-HDL cholesterol greater than or equal to 200 mg per deciliter [ 5.2 mmol per liter ] in two consecutive pretreatment measurements ) . One group ( 2051 men ) received 600 mg of gemfibrozil twice daily , and the other ( 2030 men ) received placebo . Gemfibrozil caused a marked increase in HDL cholesterol and persistent reductions in serum levels of total , low-density lipoprotein ( LDL ) , and non-HDL cholesterol and triglycerides . There were minimal changes in serum lipid levels in the placebo group . The cumulative rate of cardiac end points at five years was 27.3 per 1,000 in the gemfibrozil group and 41.4 per 1,000 in the placebo group -- a reduction of 34.0 percent in the incidence of coronary heart disease ( 95 percent confidence interval , 8.2 to 52.6 ; P less than 0.02 ; two-tailed test ) . The decline in incidence in the gemfibrozil group became evident in the second year and continued throughout the study . There was no difference between the groups in the total death rate , nor did the treatment influence the cancer rates . The results are in accord with two previous trials with different pharmacologic agents and indicate that modification of lipoprotein levels with gemfibrozil reduces the incidence of coronary heart disease in men with dyslipidemia We investigated the effects of fenofibrate , peroxisome proliferator-activated receptors ( PPARs ) agonist , on endothelial function in patients with hypertriglyceridemia . We administered placebo or fenofibrate 200 mg daily to 25 patients with hypertriglyceridemia for 8 weeks . This study was r and omized , double-blind , placebo-controlled , crossover in design . Compared with placebo , fenofibrate significantly changed lipoprotein levels including non-HDL cholesterol and significantly improved the percent flow-mediated dilator response to hyperemia by 13 + /- 6 % ( P < 0.001 ) and lowered plasma levels of tumor necrosis factor-alpha by 13 + /- 3 % ( P < 0.001 ) . Fenofibrate reduced fibrinogen and plasminogen activator inhibitor type 1 antigen levels by 17 + /- 3 and 10 + /- 3 % , respectively ( P < 0.001 and P = 0.014 , respectively ) . However , fenofibrate did not significantly change plasma levels of nitrate , malondialdehyde , tissue factor activity , and serological markers of plaque stabilization . Fenofibrate significantly changed lipoprotein levels and improved the percent flow-mediated dilator response to hyperemia as well as lowered levels of tumor necrosis factor-alpha ( TNF-alpha ) , fibrinogen , and plasminogen activator inhibitor type 1 antigen Impaired fibrinolytic function , mainly due to increased plasma plasminogen activator inhibitor-1 ( PAI-1 ) activity , is common in patients with manifest coronary artery disease ( CAD ) and a predictor of recurrent cardiovascular events . We investigated the relationships of plasma tissue-type plasminogen activator ( tPA ) and PAI-1 antigen levels , plasma PAI-1 activity and PAI 4/5-guanosine ( 4G/5 G ) genotype to CAD progression in 203 middle-aged men participating in the Lopid Coronary Angiography Trial ( LOCAT ) . A higher tPA antigen concentration , whether baseline or on-trial , was associated with a more severe global angiographic response ( p < 0.05 ) , an association mainly accounted for by progression of diffuse lesions in graft-affected segments ( change in per-patient means of average diameters of segments haemodynamically related to bypass grafts ) . Plasma PAI-1 activity and mass concentration and 4G/5 G PAI-1 genotype were unrelated to angiographic outcome measurements . tPA and PAI-1 antigen increased significantly in the gemfibrozil group ( + 11.3 % and + 16.4 % , respectively , p < 0.001 ) , whereas there was no treatment effect on PAI-1 activity ( median change 0.0 % ) . It is concluded that fibrinolytic function does not substantially influence progression of CAD as assessed by angiography in middle-aged men . Furthermore , pronounced long-term lowering of serum triglycerides by gemfibrozil treatment does not significantly affect the plasma PAI-1 activity level but increases the plasma tPA and PAI-1 antigen concentrations Hypertriglyceridemia is linked to impaired fibrinolytic function , and lipid-lowering treatment with fibric acid derivatives could hypothetically improve fibrinolysis in this condition . We therefore conducted a double-blind , placebo-controlled , crossover study of gemfibrozil treatment on fibrinolytic function in 21 men with combined hyperlipoproteinemia . Measurements were performed at rest and during mental stress and after venous occlusion . The patients had clearly disturbed fibrinolytic function , with elevated plasminogen activator inhibitor-1 ( PAI-1 ) activity at rest ( approximately 25 U/mL ; reference , < 15 U/mL ) . Gemfibrozil reduced plasma total and VLDL cholesterol as well as all triglyceride fractions , whereas HDL cholesterol increased ( P < .001 for all ) . Total triglyceride levels were reduced by 57 + /- 4 % ( from 5.3 to 2.1 mmol/L ) . Fasting serum insulin levels were not altered by gemfibrozil treatment . Plasma levels of PAI-1 activity and tissue-type plasminogen activator ( TPA ) activity or antigen were unaffected by gemfibrozil treatment both at rest and during the provocations . The levels of D-dimer , plasmin/antiplasmin complex , and fibrinogen were also uninfluenced by gemfibrozil treatment . Mental stress elevated plasma TPA ( P=.0036 ) and lowered PAI-1 ( P=.0012 ) activity during placebo but not gemfibrozil treatment ( P=.28 and P=.17 , respectively ) , but treatment effects did not differ by ANOVA on delta values ( ie , stress minus rest ) . Venous occlusion reduced PAI-1 activity , whereas TPA and plasmin/antiplasmin complex increased during both treatments . Thus , gemfibrozil treatment did not improve fibrinolysis or lower fibrinogen levels in men with combined hyperlipoproteinemia despite marked reduction of plasma triglyceride levels . It seems unlikely that improved fibrinolysis explains the primary preventive effect of gemfibrozil Evaluation of fibrate treatment in humans has focused primarily on its anti-lipidaemic effects . A potentially favourable haemostasis-modulating activity of fibrates has also been recognized but the data are not consistent . We sought to learn more about this variability by examining the effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator ( t-PA ) , plasminogen activator inhibitor-1 ( PAI-1 ) and fibrinogen in primary hyperlipidaemic patients after six and twelve weeks of treatment using different assay systems for PAI-1 and fibrinogen . Although both fibrates effectively lowered triglyceride and cholesterol levels , no effect on the elevated baseline antigen levels of t-PA and PAI-1 was observed after fibrate treatment . However , both fibrates influenced plasma fibrinogen levels , albeit in a different way . Fibrinogen antigen levels were elevated by 17.6 % ( p < 0.05 ) and 24.3 % ( p < 0.001 ) with gemfibrozil after six and twelve weeks , respectively , whereas with ciprofibrate there was no effect . Using a Clauss functional assay with either a mechanical end point or a turbidity-based end point , no significant change in fibrinogen levels was seen after six weeks of gemfibrozil treatment . However , after twelve weeks , gemfibrozil enhanced functional fibrinogen levels by 7.2 % ( p < 0.05 ) as assessed by the Clauss mechanical assay , but decreased functional fibrinogen levels by 12.5 % ( p < 0.0001 ) when a Clauss assay based on turbidity was used . After six or twelve weeks of ciprofibrate treatment , functional fibrinogen levels were decreased by 10.1 % ( p < 0.001 ) and 10.5 % ( p < 0.0001 ) , respectively on the basis of Clauss mechanical and by 14.2 % ( p < 0.001 ) and 28.2 % ( p < 0.0001 ) , respectively with the Clauss turbidimetric assay . A remarkable and consistent finding with both fibrates was the decrease in functionality of fibrinogen as assessed by the ratio of functional fibrinogen ( determined by either of the two Clauss assays ) to fibrinogen antigen . Taken together , our results indicate that at least part of the variability in the effects of fibrates on haemostatic parameters can be explained by intrinsic differences between various fibrates , by differences in treatment period and /or by the different outcomes of various assay systems . Interestingly , the two fibrates tested both reduced the functionality of fibrinogen We have investigated the effects of two fibric acid derivatives , bezafibrate mono ( 400 mg daily ) and gemfibrozil ( 600 mg b.d . ) , in 29 patients with type IIb hyperlipoproteinaemia . All patients received placebo and each drug for 8 weeks in r and omised order in a double-blind , cross-over study design ed to evaluate any different effects of the drugs on serum lipoproteins , cholesteryl ester transfer protein ( CETP ) , cholesteryl ester transfer activity ( CETA ) , plasma fibrinogen , plasminogen activator inhibitor-I ( PAI-1 ) or paraoxonase . Serum cholesterol decreased ( P < 0.05 ) with gemfibrozil , but the effect of bezafibrate on serum cholesterol did not achieve statistical significance ( placebo 8.34 + /- 1.05 ( mean + /- S.D. ) , gemfibrozil 7.70 + /- 1.23 and bezafibrate 7.8 + /- 1.37 mmol/l ) . Both drugs decreased the serum triglyceride concentration ( both P < 0.001 ) ( placebo 4.39 ( 3.13 - 5.75 ) ( median ( interquartile range ) ) , bezafibrate 2.26 ( 1.89 - 3.89 ) and gemfibrozil 2.00 ( 1.30 - 3.30 ) mmol/l ) and very low density lipoprotein ( VLDL ) cholesterol ( both P < 0.001 ) ( placebo 1.18 ( 0.74 - 2.30 ) , bezafibrate 0.59 ( 0.34 - 0.85 ) and gemfibrozil 0.48 ( 0.34 - 0.68 ) mmol/l ) . Discontinuous gradient ultracentrifugation ( DGU ) revealed that Sf 60 - 400 ( large VLDL ) decreased by more than 50 % and Sf 20 - 60 ( small VLDL ) by more than 30 % with each of the drugs ( both P < 0.001 ) , neither of which affected the composition of these lipoproteins . Gemfibrozil decreased the concentration of Sf 12 - 20 lipoprotein ( intermediate density lipoprotein ; IDL ) by 23 % ( P < 0.01 ) , whereas the effect of bezafibrate on this lipoprotein did not achieve statistical significance . Neither drug altered the concentration of apolipoprotein B or of total Sf 0 - 12 lipoproteins ( low density lipoprotein , ( LDL ) ) . Both , however , significantly increased the quantity of free cholesterol in Sf 0 - 12 lipoproteins ( P < 0.05 ) . Overall the concentration of triglycerides decreased significantly in all lipoproteins isolated by DGU ( Sf 0 - 12 , Sf 12 - 20 , Sf 20 - 60 , Sf 60 - 400 ) on gemfibrozil treatment , but only in Sf 20 - 60 and Sf 60 - 400 on bezafibrate ( all P < 0.05 ) . Both drugs also increased serum high density lipoprotein ( HDL ) cholesterol ( placebo 1.15 + /- 0.29 , bezafibrate 1.27 + /- 0.38 ( P < 0.01 ) and gemfibrozil 1.26 + /- 0.49 ( P < 0.05 ) mmol/l ) and HDL3 cholesterol concentration ( placebo 0.59 + /- 0.12 , bezafibrate 0.72 + /- 0.23 ( P < 0.001 ) and gemfibrozil 0.70 + /- 0.24 ( P < 0.01 ) mmol/l ) . Serum apolipoprotein A1 ( apo A1 ) was increased ( P < 0.05 ) by bezafibrate compared to gemfibrozil ( placebo 103 + /- 26 , bezafibrate 111 + /- 28 and gemfibrozil 102 + /- 25 mg/dl ) and CETA from HDL to VLDL and LDL was decreased ( P < 0.05 ) by bezafibrate compared to placebo , but the apparent decrease with gemfibrozil did not achieve statistical significance ( placebo 39.6 + /- 17.7 , bezafibrate 32.3 + /- 14.7 and gemfibrozil 33.8 + /- 15.0 nmol/ml/h ) . Neither drug affected the circulating concentration of CETP . Plasma fibrinogen was increased ( P < 0.05 ) by gemfibrozil ( placebo 4.16 ( 3.38 - 4.71 ) and gemfibrozil 4.65 ( 4.05 - 5.77 ) g/l ) and was significantly lower ( P < 0.001 ) on bezafibrate ( 3.60 ( 3.18 - 4.54 ) g/l ) than on gemfibrozil treatment . There was a significant ( P < 0.05 ) increase in PAI-1 activity with bezafibrate and a similar trend with gemfibrozil ( placebo 41.2 ( 25.6 - 64.5 ) , bezafibrate 50.5 ( 35.1 - 73.9 ) and gemfibrozil 48.5 ( 31.5 - 5.4 U/l ) . Neither fibrate influenced plasma concentrations of PAI-1 nor were the activities of lecithin : cholesterol acyl transferase or paraoxonase affected . The major difference in the action of the two drugs on lipoprotein metabolism was the greater effect of gemfibrozil in decreasing the overall serum concentration of Sf 12 - 20 lipoproteins and the triglycerides in Sf 12 - 20 and 0 - 12 lipoproteins . Bezafibrate , however , increased serum apo A1 concentration and significantly decreased CETA . The two drugs also had different effects on the plasma fibrinogen levels , which increased with gemfibrozil and tended to The aim of this study was to determine the effect of the lipid modifying agent gemfibrozil on lipid and coagulation risk factors in patients with Type 2 diabetes mellitus ( Type 2 DM ) . Twenty-six subjects with Type 2 DM and dyslipidaemia were treated for 24 weeks with either gemfibrozil 600 mg orally twice daily or placebo in a double-blind r and omized trial . Lipid profiles , fibrinogen , Factor VII , and plasminogen activator inhibitor-1 ( PAI-1 ) were measured by routine laboratory methods . Low density lipoprotein ( LDL ) size was determined by gradient gel electrophoresis and the resistance of LDL to copper-induced oxidation was assessed by measuring absorbance at 234 nm . Gemfibrozil significantly reduced total cholesterol ( -0.9 ( -0.48 , -1.32 ) mmol l(-1 ) ; p < 0.05 ) and triglycerides ( -2.7 ( -1.55 , -1.35 ) mmol l(-1 ) ; p < 0.001 ) vs placebo . The fall in triglyceride was reflected by a fall in VLDL cholesterol levels in the gemfibrozil treated group vs placebo ( -1.31 mmol l(-1 ) ; p < 0.001 ) . LDL-cholesterol level did not change but LDL particle size increased by 0.5 nm ( 0.01 , 0.93 ) ; P < 0.02 . The increase in particle size was inversely correlated with the change of triglyceride level ( r = -0.79 , p < 0.0001 ) but did not result in any reduction of susceptibility to copper-induced oxidation . There were no significant changes in the coagulation parameters studied . Because of its ability to correct the lipid abnormalities associated with Type 2 DM particularly hypertriglyceridaemia , gemfibrozil provides a useful therapeutic option in the management of diabetic dyslipidaemia but it does not alter in vitro oxidizability of LDL 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 The effects of gemfibrozil on haemostatic variables were studied in 43 survivors of myocardial infa rct ion with serum triglycerides ( TG ) greater than or equal to 2 mmol/l 2 weeks prior to r and omization . The study was double-blind , placebo-controlled and stratified for chronic betablockade . Twenty-two individuals were given gemfibrozil 600 mg twice daily and 21 individuals received matching placebo . After 8 weeks the TG level was unchanged in the placebo group , whereas a 44 % reduction was noted in the gemfibrozil group ( p less than 0.001 ) . Fibrinogen increased in both groups , while bleeding time and platelet count were unchanged . Clotting factor VII-phospholipid complex decreased in both groups , but the change was more marked and attained statistical significance only in the gemfibrozil group ( 60 % reduction , p less than 0.01 ) . By DDAVP-stimulated D-Dimer agglutination test 8 in 21 patients in the placebo group ( 38 % ) still had reduced fibronolytic capacity versus none in the gemfibrozil group ( p = 0.001 ) . Thus , in this study , gemfibrozil improved reduced fibrinolytic capacity and may have reduced hypercoagulability by lowering the clotting factor VII-phospholipid complex
target: The estimated effects of fibrate therapy on plasma concentration and activity of PAI-1 were independent of treatment duration and changes in plasma triglyceride levels in the meta-regression analysis .
  This meta- analysis of RCTs suggested that fibrate therapy does not reduce plasma concentration or activity of PAI-I. The putative benefits of fibrate therapy in patients with cardiovascular disease appear to be exerted via mechanisms independent of effects on PAI-1
background: OBJECTIVE The aim of this systematic review was to perform a meta- analysis of r and omized controlled trials ( RCTs ) examining the efficacy of fibrate therapy in reducing plasma concentration or activity of plasminogen activator inhibitor 1 ( PAI-1 ) .