human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 ; 9 
    Output:
    
agent
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
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 ; 9 
    Output:
    