title: Effects of Fenofibric Acid on Carotid Intima-Media Thickness in Patients With Mixed Dyslipidemia on Atorvastatin Therapy: Randomized, Placebo-Controlled Study (FIRST) Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Lopid Coronary Angiography Trial (LOCAT) Study Group. Gemfibrozil for secondary prevention of cardiovascular events in mild to moderate chronic renal insufficiency. Bezafibrate in men with lower extremity arterial disease: randomised controlled trial Design and intermediate results of the Lower Extremity Arterial Disease Event Reduction (LEADER)* trial of bezafibrate in men with lower extremity arterial disease [ISRCTN41194621] Cardiovascular Outcomes in Type 2 Diabetes: A double-blind placebo-controlled study of bezafibrate: the St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study The influence of statin-fibrate combination therapy on lipids profile and apolipoprotein A5 in patients with acute coronary syndrome Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients Reduction in Stroke With Gemfibrozil in Men With Coronary Heart Disease and Low HDL Cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT) Effects of combination lipid therapy in type 2 diabetes mellitus. Diabetes Intervention Study: Multi-Intervention Trial in Newly Diagnosed NIDDM A one year double blind study of the effect of halofenate and clofibrate in patients with hyperlipoproteinemia. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Rationale and design of a secondary prevention trial of increasing serum high-density lipoprotein cholesterol and reducing triglycerides in patients with clinically manifest atherosclerotic heart disease (the Bezafibrate Infarction Prevention Trial). Treatment of Hypercholesterolemia and Combined Hyperlipidemia With Simvastatin and Gemfibrozil in Patients With NIPPM: A multicenter comparison study 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. Efficacy of gemfibrozil in dyslipidaemic subjects with suspected heart disease. An ancillary study in the Helsinki Heart Study frame population. Controlled trial of clofibrate in cerebral vascular disease. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Comparison of fluvastatin + fenofibrate combination therapy and fluvastatin monotherapy in the treatment of combined hyperlipidemia, type 2 diabetes mellitus, and coronary heart disease: a 12-month, randomized, double-blind, controlled trial. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. THE TROMSØHEART-STUDY: HIGH-DENSITY LIPOPROTEIN AND CORONARY HEART-DISEASE: A PROSPECTIVE CASE-CONTROL STUDY
abstract: Objective —To assess whether adding a fibrate to statin therapy reduces residual cardiovascular risk associated with elevated triglycerides and low high-density lipoprotein cholesterol , The Evaluation of Choline Fenofibrate ( ABT-335 ) on Carotid Intima-Media Thickness ( cIMT ) in Subjects with Type IIb Dyslipidemia with Residual Risk in Addition to Atorvastatin Therapy ( FIRST ) trial evaluated the effects of fenofibric acid ( FA ) treatment on cIMT in patients with mixed dyslipidemia on atorvastatin . Approach and Results —This multicenter , double-blind , placebo-controlled study was performed in patients with mixed dyslipidemia ( fasting triglycerides , ≥150 mg/dL ; high-density lipoprotein cholesterol , ⩽45 [ men ] or 55 mg/dL [ women ] ; low-density lipoprotein cholesterol , ⩽100 mg/dL once and averaging ⩽105 mg/dL ) and a history of coronary heart disease or risk equivalent . Patients on background atorvastatin ( continued on starting dose or titrated to 40 mg , if needed ) were r and omized to FA 135 mg or placebo . The primary end point was rate of change from baseline through week 104 of the mean posterior-wall cIMT , measured by ultrasound . In patients with controlled low-density lipoprotein cholesterol while on atorvastatin background therapy , rate of change in posterior-wall cIMT was similar with FA plus atorvastatin ( −0.006 mm/y ) versus atorvastatin monotherapy ( 0.000 mm/y ; P=0.22 ) . FA plus atorvastatin was favored ( P<0.05 ) in 5 of 24 prespecified subgroups : age ≥60 years , history of coronary artery disease , cIMT > 0.795 mm , triglycerides 170 to 235 mg/dL , and statin use at entry . Adverse events were consistent with the known safety profiles of both drugs ; however , FA plus atorvastatin was associated with a greater incidence of renal-related adverse events compared with atorvastatin monotherapy ( 6.5 % versus 0.9 % ) . Conclusions —Compared with atorvastatin monotherapy , FA plus atorvastatin did not further decrease cIMT progression in high-risk patients with mixed dyslipidemia BACKGROUND Studies have shown that treatment of hyperlipidemia , especially lowering of plasma LDL levels , retards the progression of coronary atherosclerosis and prevents clinical cardiovascular events . No such studies have focused on subjects with low levels of HDL cholesterol . METHODS AND RESULTS We r and omly assigned 395 post-coronary bypass men , who had an HDL cholesterol concentration < or = 1.1 mmol/L and LDL cholesterol < or = 4.5 mmol/L , to receive gemfibrozil 1200 mg/d or placebo . Coronary angiography was performed at baseline and after , on average , 32 months of therapy . Changes in coronary dimensions were assessed by computer-assisted analysis . Average on-trial serum triglyceride concentrations were 1.69+/-0.68 and 1.02+/-0.37 , total cholesterol 5.48+/-0.68 and 4.83+/-0.63 , LDL cholesterol 3.84+/-0.59 and 3.39+/-0.56 , and HDL cholesterol 0.88+/-0.15 and 0.98+/-0.17 mmol/L in the placebo and gemfibrozil groups , respectively ( mean+/-SD , each P<.001 ) . The change in per-patient means of average diameters of native coronary segments was -0.04+/-0.11 mm in the placebo group and -0.01+/-0.10 mm in the gemfibrozil group ( P=.009 ) . The equivalent changes in minimum luminal diameters of stenoses were -0.09+/-0.18 and -0.04+/-0.15 mm , respectively ( P=.002 ) . A similar , albeit nonsignificant , trend toward treatment benefit was found in the predefined primary study end point , segments unaffected by grafts and those distal to graft insertions . In aortocoronary bypass grafts , 23 subjects ( 14 % ) assigned to placebo had new lesions in the follow-up angiogram , compared with 4 subjects ( 2 % ) assigned to gemfibrozil ( P<.001 ) . CONCLUSIONS Gemfibrozil therapy retarded the progression of coronary atherosclerosis and the formation of bypass-graft lesions after coronary bypass surgery in men with low HDL cholesterol as their main lipid abnormality BACKGROUND Although cardiovascular disease and low high-density lipoprotein ( HDL ) cholesterol are common in people with renal insufficiency , data addressing the cardiovascular benefits of fibric acid derivatives in this population are sparse . We conducted a post hoc subgroup analysis of a r and omized double-blind , placebo-controlled trial to determine whether gemfibrozil is effective and safe for secondary prevention of cardiovascular events in individuals with chronic renal insufficiency ( CRI ) . METHODS Using an analysis plan that was developed a priori , we analyzed data from the Veterans ' Affairs High-Density Lipoprotein Intervention Trial ( VA-HIT ) study ; a r and omized trial of gemfibrozil versus placebo in 2531 men with established coronary disease , an HDL cholesterol level of 40 mg/dL ( 1.0 mmol/L ) or less , and a low-density lipoprotein ( LDL ) cholesterol level of 140 mg/dL ( 3.6 mmol/L ) or less . Of these , 1046 men had CRI as defined by creatinine clearance < /=75 mL/min using the Cockcroft-Gault equation , 99.8 % of whom had either mild or moderate renal impairment ( creatinine clearance 60 - 75 or 30 - 59.9 mL/min , respectively ) . RESULTS The incidence of the primary outcome ( coronary death or nonfatal myocardial infa rct ion ) was lower in participants with CRI who received gemfibrozil compared to placebo [ hazard ratio ( HR ) 0.73 ; 95 % CI 0.56 - 0.96 , P= 0.02 ) . The cumulative incidence of the primary end point was reduced from 24.3 % to 18.2 % . In subjects with CRI , gemfibrozil also significantly reduced the risk of the combined outcome of coronary death , nonfatal myocardial infa rct ion , or stroke ( HR 0.74 , 95 % CI 0.58 - 0.95 , P= 0.02 ) , but not the need for coronary revascularization ( HR 0.85 , 95 % CI 0.66 - 1.10 , P= 0.21 ) or total mortality ( HR 1.03 , 95 % CI 0.78 - 1.35 , P= 0.85 ) . The overall incidence of adverse effects was similar in individuals receiving gemfibrozil and placebo . However , the risk of sustained increases in serum creatinine was increased in gemfibrozil recipients compared with placebo ( 5.9 vs. 2.8 % , P= 0.02 ) . CONCLUSION Gemfibrozil appears effective for secondary prevention of cardiovascular events in individuals with mild to moderate chronic renal insufficiency and HDL cholesterol of 40 mg/dL or less . However , the benefit and safety of gemfibrozil in people with more severe impairment of kidney function requires further study Objective : To assess the effect of bezafibrate on the risk of coronary heart disease and stroke in men with lower extremity arterial disease . Design : Double blind placebo controlled r and omised trial . Setting : 85 general practice s and nine hospital vascular clinics . Participants : 1568 men , mean age 68.2 years ( range 35 to 92 ) at recruitment . Interventions : Bezafibrate 400 mg daily ( 783 men ) or placebo ( 785 men ) . Main outcome measures : Combination of coronary heart disease and of stroke . All coronary events , fatal and non-fatal coronary events separately , and strokes alone ( secondary end points ) . Results : Bezafibrate did not reduce the incidence of coronary heart disease and stroke . There were 150 and 160 events in the active and placebo groups respectively ( relative risk 0.96 , 95 % confidence interval 0.76 to 1.21 ) . There were 90 and 111 major coronary events in the active and placebo groups respectively ( 0.81 , 0.60 to 1.08 ) , of which 64 and 65 were fatal ( 0.95 , 0.66 to 1.37 ) and 26 and 46 non-fatal ( 0.60 , 0.36 to 0.99 ) . Beneficial effects on non-fatal events were greatest in men aged < 65 years at entry , in whom benefit was also seen for all coronary events ( 0.38 , 0.20 to 0.72 ) . There were no significant effects in older men . There were 60 strokes in those on active treatment and 49 in those on placebo ( 1.34 , 0.80 to 2.01 ) . There were 204 and 195 deaths from all causes in the two groups respectively ( 1.03 , 0.83 to 1.26 ) . Bezafibrate reduced the severity of intermittent claudication for up to three years . Conclusions : Bezafibrate has no effect on the incidence of coronary heart disease and of stroke combined but may reduce the incidence of non-fatal coronary events , particularly in those aged < 65 years at entry , in whom all coronary events may also be reduced Background Raised levels of both triglycerides and fibrinogen , each of which are reduced by bezafibrate , may contribute to lower extremity arterial disease ( LEAD ) . This condition is characterized by a particularly high incidence of coronary heart disease ( CHD ) and stroke , but is little studied thus far in r and omised controlled trials . Method Patients were recruited through 85 practice s in the British Medical Research Council General Practice Research Framework and through nine hospital vascular clinics . The treatment regimen , which is double-blind and placebo-controlled , is bezafibrate 400 mg/day . The 1568 patients recruited represent 86 % of those eligible at screening . Results None of the anticipated side effects ( mainly gastrointestinal ) differed between the two groups . Nearly 80 % of the total person-years accrued at 3 years were spent on trial treatment . Bezafibrate significantly reduced total cholesterol by approximately 8.0 % and low-density lipoprotein (LDL)-cholesterol by approximately 9.0 % , and increased high-density lipoprotein (HDL)-cholesterol by approximately 11.0 % initially , falling to about 6.0 % at 3 years . Triglycerides were significantly reduced by about 23.0 % and fibrinogen by about 14.0 % . Plasma creatinine rose by approximately 11 % in those on active treatment . All of these effects were highly significant ( P < 0.0001 ) . Bezafibrate had no effect on the level of C-reactive protein ( CRP ) . Conclusion The trial recruited an unusually high proportion of eligible patients , ensuring the general applicability of its results . The fibrinogen-lowering and lipid-modifying effects of bezafibrate were confirmed . Although bezafibrate lowers fibrinogen , it has no effect on CRP ; this suggests that the reduction in fibrinogen is due to an effect on its metabolism rather than suppression of an inflammatory response OBJECTIVE To determine whether serum lipid intervention , in addition to conventional diabetes treatment , could alter cardiovascular outcomes in type 2 diabetes . RESEARCH DESIGN AND METHODS There were 164 type 2 diabetic subjects ( 117 men , 47 women ) without a history of clinical cardiovascular disease r and omized to receive either bezafibrate or placebo daily on a double-blind basis in addition to routine diabetes treatment and followed prospect ively for a minimum of 3 years . Serial biochemical and noninvasive vascular assessment s , carotid and femoral artery B-mode ultrasound measurements , and those pertaining to coronary heart disease (CHD)— clinical history , the World Health Organization ( WHO ) cardiovascular question naire , and resting and exercise electrocardiogram (ECG)—were recorded . RESULTS Bezafibrate treatment was associated with significantly greater reductions over 3 years in median serum triglyceride ( −32 vs. 4 % , P = 0.001 ) , total cholesterol ( −7 vs. −0.3 % , P = 0.004 ) , and total−to-HDL cholesterol ratio ( −12 vs. −0.0 % , P = 0.001 ) , and an increase in HDL cholesterol ( 6 vs. −2 % , P = 0.02 ) as compared with placebo . There was a trend toward a greater reduction of fibrinogen ( −18 vs. −6 % , P = 0.08 ) at 3 years . No significant differences between the two groups were found in the progress of ultrasonically measured arterial disease . In those treated with bezafibrate , there was a significant reduction ( P = 0.01 , log-rank test ) in the combined incidence of Minnesota-coded probable ischemic change on the resting ECG and of documented myocardial infa rct ion . CONCLUSIONS Improving dyslipidemia in type 2 diabetic subjects had no effect on the progress of ultrasonically measured arterial disease , although the lower rate of “ definite CHD events ” in the treated group suggests that this might result in a reduction in the incidence of coronary heart disease Background Statin-fibrate combination therapy has been used to treat patients with acute coronary syndrome ( ACS ) complicated by elevated triglycerides ( TG ) and decreased high density lipoprotein cholesterol ( HDL-C ) . The purpose of this study was to evaluate the influence of the combination therapy on lipids profile and apolipoprotein A5 ( apoA5 ) level in patients with ACS . Methods One hundred and four patients with ACS were recruited and r and omly assigned into two groups : one was statin group ( n = 52 ) , given atorvastatin ( 20 mg QN ) or other statins with equivalent dosages ; the other was combination group ( n = 52 ) , given the same dose of statin plus bezafibrate ( 200 mg BID ) . Follow-up visits were scheduled at the end of 6 and 12 weeks post treatment . Serum apoA5 levels were determined using a commercial available ELISA kit . Results ( 1 ) Compared with that of statin monotherapy , statin-bezafibrate combination treatment not only result ed in a significant reduction of TG , TC and LDL-C levels , ( all p < 0.05 ) , but also led to increases in HDL-C and apoA5 levels ( p < 0.05).(2 ) The percentage changes of TC , TG , LDL-C and apoA5 levels in both groups were even bigger at 12 weeks after treatment than that at 6 weeks ( all p < 0.05 ) . Similarly , the rates of achieving lipid-control target were higher in statin-bezafibrate combination treatment group than those in statin monotherapy group ( all p < 0.05).(3 ) Spearman rank correlation analysis showed that the pre-treatment apoA5 level was positively correlated with TG ( r = 0.359 , p = 0.009 ) . However , a negative correlation was observed between apoA5 and TG ( r = -0.329 , p = 0.017 ) after 12 weeks treatment . Conclusions Statin and fibrate combination therapy is more effective than statin alone in achieving a comprehensive lipid control for ACS patients .  Serum apoA5 elevation after statin and fibrate combination treatment could be due to the synergistic effect of both drugs on hypertriglyceridemia control BACKGROUND Bezafibrate has effects on lipid metabolism and haemostatic function . We undertook a double-blind , placebo-controlled intervention trial , the Bezafibrate Coronary Atherosclerosis Intervention Trial ( BECAIT ) , to establish whether bezafibrate ( 200 mg three times daily ) could retard or prevent the progression of atherosclerotic lesions in dyslipidaemic male survivors of myocardial infa rct ion who were younger than 45 years at the time of the event . METHODS 92 patients completed an initial 3-month period of dietary intervention  and were r and omly assigned to treatment with bezafibrate or placebo . Dietary intervention continued throughout the trial . Coronary angiography was done at baseline and after 2 and 5 years . 81 patients ( 42 bezafibrate treated and 39 placebo treated ) who underwent baseline angiography and at least one post-treatment angiogram were included in the efficacy analysis . The primary endpoint was change in mean minimum lumen diameter . FINDINGS The mean minimum lumen diameter decreased from baseline to the last angiographic assessment ( 2 or 5 years ) by 0.06 mm ( 95 % CI 0.15 reduction to 0.01 increase ) in the bezafibrate group and by 0.17 mm ( 0.33 reduction to 0.09 increase ) in the placebo group . The treatment effect was therefore 0.13 mm ( 95 % CI 0.10 to 0.15 ; p=0.049 ) . Parallel treatment effects , although not statistically significant , were observed for the secondary angiographic endpoints ( mean segment diameter 0.02 mm [ 0.01 - 0.04 ] and percentage stenosis -3.41 % [ -4.00 to -2.98 ] ) . The cumulative coronary event rate was significantly lower among bezafibrate-treated than among placebo-treated patients ( three vs 11 patients ; p=0.02 ) . There were significant treatment effects of bezafibrate for serum concentrations of cholesterol ( -9 % ; p<0.001 ) , very-low-density-lipoprotein ( VLDL ) cholesterol ( -35 % ; p<0.001 ) , serum triglycerides ( -31 % ; p<0.001 ) , VLDL triglycerides ( -37 % ; p<0.001 ) , and plasma fibrinogen ( -12 % ; p=0.001 ) , whereas low-density ( LDL ) cholesterol concentrations did not change . High density lipoprotein ( HDL ) cholesterol increased significantly with bezafibrate ( 9 % ; p=0.02 ) . INTERPRETATION The results show that bezfibrate improves dyslipidaemia , lowers plasma fibrinogen , slows the progression of focal coronary atherosclerosis , and reduces coronary events in young survivors of myocardial infa rct ion Background —A low level of HDL cholesterol has been identified as a risk factor for stroke in observational studies . Methods and Results —Our objective was to determine whether treatment aim ed at raising HDL cholesterol and lowering triglycerides reduces stroke in men with coronary heart disease and low levels of both HDL and LDL cholesterol . The study was a placebo-controlled , r and omized trial conducted in 20 Veterans Affairs medical centers . A total of 2531 men with coronary heart disease , with mean HDL cholesterol 0.82 mmol/L ( 31.5 mg/dL ) and mean LDL cholesterol 2.9 mmol/L ( 111 mg/dL ) , were r and omized to gemfibrozil 1200 mg/d or placebo  and were followed up for 5 years . Strokes were confirmed by a blinded adjudication committee . Relative risks were derived from Cox proportional hazards models . There were 134 confirmed strokes , 90 % of which were ischemic . Seventy-six occurred in the placebo group ( 9 fatal ) and 58 in the gemfibrozil group ( 3 fatal ) , for a relative risk reduction , adjusted for baseline variables , of 31 % ( 95 % CI , 2 % to 52 % , P = 0.036 ) . The reduction in risk was evident after 6 to 12 months . Patients with baseline HDL cholesterol below the median may have been more likely to benefit from treatment than those with higher HDL cholesterol . Conclusions —In men with coronary heart disease , low HDL cholesterol , and low LDL cholesterol , gemfibrozil reduces stroke incidence 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 . Objective In a r and omized 5-yr multi-intervention trial , we tested the efficacy of intensified health education ( IHE ) in improving metabolic control and reducing the level of coronary risk factors and incidence of ischemic heart disease ( IHD ) . Research Design and Methods Within the intervention group , the benefit of clofibric acid was evaluated in a double-blind study . One thous and one hundred thirty-nine newly diagnosed middle-aged ( 30- to 55-yr-old ) patients with non-insulindependent diabetes mellitus ( NIDDM ) entered the study . They were classified as diet controlled after a 6- wk screening phase with conventional dietary treatment . During the follow-up , the control group ( n = 378 ) was cared for at different diabetes outpatient clinics with a st and ardized surveillance . The intervention group ( n = 761 ) had a structured IHE that included dietary advice , antismoking and antialcohol education , and ways to enhance physical activity . Results R and omly , 379 of the IHE patients received 1.6 g clofibric acid/day , and the others received placebo . IHE result ed in improved glucose control ( adjusted fasting blood glucose ) levels after 5 yr ( control subjects 9.27 mM , IHE group 8.71 mM , and IHE plus clofibric acid group 8.60 mM , P < 0.01 ) . The better glycemic control was achieved with fewer antidiabetic drugs . After 5 yr , antidiabetic drugs were prescribed to 47 % of the control subjects , 28 % of the IHE group , and 34 % of the IHE plus clofibric acid group ( cutoff limit for drug application was postpr and ial blood glucose of ≥13.87 mM ) . The ratio of polyunsaturated to saturated fatty acids ( 0.26 vs. 0.40 , P < 0.01 ) and physical activity ( 174 vs. 327 scores , P < 0.01 ) were increased , and blood pressure , tobacco , and alcohol consumption were significantly reduced by IHE . However , IHE had no effect on calorie intake , percentage of fat in the diet ( 45 % ) , and body weight . The most important finding was the significant increase of blood cholesterol in all three groups ( + 0.47 , + 0.36 , and + 0.34 mM , respectively ) . Clofibric acid only prevented the increase of triglyceride levels ( + 0.56 , + 0.24 , and + 0.05 mM , respectively ) . The incidence rate per 1000 for myocardial infa rct ion was 30.3 for control subjects , 53.6 for the IHE group , and 55.6 for the IHE plus clofibric acid group . The corresponding rates for IHD incidence were 90.9 , 97.8 , and 98.8 , respectively . Men suffered more frequently from myocardial infa rct ion , whereas women developed ECG criteria for IHD more frequently . Among the 35 cases of death , besides cardiovascular diseases , liver cirrhosis and neoplasia were the predominant causes . The death rate per 1000 in control subjects was 46.2 , 30.6 in the IHE group , and 27 among patients with IHE plus clofibric acid . Conclusions IHE was of substantial benefit for the control of glycemia , significantly diminished the need for antidiabetic drugs , and reduced a cluster of risk factors but had no effect on the control of blood lipids . This could be one major reason for the failure of IHE , effective lowering of blood pressure , and clofibric acid to prevent cardiovascular complications .  Clofibric acid was only effective in reducing triglycerides Summary A double blind clinical trial of one year duration was performed to compare the activity of halofenate ( 1 000 mg once a day ) and of clofibrate ( 1 000 mg twice a day ) on plasma levels of cholesterol , triglycerides and uric acid in 20 hyperlipidaemic patients .Statistical analysis showed that clofibrate provokes a significant decrease of cholesterol and triglycerides , a slight ( p>0.05 ) increase of uric acid .  Halofenate did not influence significantly any of three levels . Noteworthy is the decrease in uric acid,.caused by halofenate ( 18 % after 24 weeks -p<0.05 ) , although the basal uric acid values were normal . Clinical ly both drugs were well tolerated . Alkaline phosphatase levels significantly decreased during treatment with clofibrate BACKGROUND Atherosclerosis is the most common complication of diabetes . Correction of hyperglycaemia helps to prevent microvascular complications but has little effect on macrovascular disease . Post-hoc analyses of diabetic sub population s in lipid intervention trials suggest that correction of lipoprotein abnormalities will lead to a decrease in coronary-artery disease . The Diabetes Atherosclerosis Intervention Study ( DAIS ) was specifically design ed to assess the effects of correcting lipoprotein abnormalities on coronary atherosclerosis in type 2 diabetes . METHODS 731 men and women with type 2 diabetes were screened by metabolic and angiographic criteria . 418 were r and omly assigned micronised fenofibrate ( 200 mg/day ) or placebo for at least 3 years . They were in good glycaemic control ( mean haemoglobin A1c 7.5 % ) , had mild lipoprotein abnormalities , typical of type 2 diabetes , and at least one visible coronary lesion . Half had no previous clinical coronary disease . Initial and final angiograms followed a st and ard protocol and were analysed by a computer-assisted quantitative approach . Missing data for the primary endpoints ( minimum lumen diameter , mean segment diameter , and mean percentage stenosis ) were imputed . Analyses were by intention to treat . FINDINGS Total plasma cholesterol , HDL-cholesterol , LDL-cholesterol , and triglyceride concentrations all changed significantly more from baseline in the fenofibrate group ( n=207 ) than in the placebo group ( n=211 ) . The fenofibrate group showed a significantly smaller increase in percentage diameter stenosis than the placebo group ( mean 2.11 [ SE 0.594 ] vs 3.65 [0.608]% , p=0.02 ) , a significantly smaller decrease in minimum lumen diameter ( -0.06 [ 0.016 ] vs -0.10 [ 0.016 ] mm , p=0.029 ) , and a non-significantly smaller decrease in mean segment diameter ( -0.06 [ 0.017 ] vs -0.08 [ 0.018 ] mm , p=0.171 ) . The trial was not powered to examine clinical endpoints , but there were fewer in the fenofibrate group than the placebo group ( 38 vs 50 ) . INTERPRETATION DAIS suggests that treatment with fenofibrate reduces the angiographic progression of coronary-artery disease in type 2 diabetes . This effect is related , at least partly , to the correction of lipoprotein abnormalities , even those previously judged not to need treatment 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 Controlled clinical trials have demonstrated the efficacy of reducing the blood levels of low-density lipoprotein cholesterol in reducing the incidence of coronary artery disease in hypercholesterolemic middle-aged men . However , a similar reversibility of the risk of coronary artery disease has not been demonstrated for high-density lipoprotein cholesterol elevation and triglyceride reduction . Therefore , the effect of administering 400 mg of bezafibrate retard daily versus placebo ( double blind ) to patients with myocardial infa rct ion preceding r and omization by 6 months to 5 years , or a clinical ly manifest anginal syndrome documented by objective evidence of dynamic myocardial ischemia , or both , is being investigated . Three thous and subjects ( aged 45 to 74 years ) are being enrolled from 19 cardiac departments in Israel , with total serum cholesterol between 180 and 250 mg/dl , high-density lipoprotein cholesterol < or = 45 mg/dl and triglycerides < or = 300 mg/dl . In addition , low-density lipoprotein cholesterol concentrations are required to be < or = 180 mg/dl ( < or = 160 mg/dl for patients aged < 50 years ) . Patients needing lipid-modifying therapy , exhibiting > or = 1 prespecified exclusion criterion or not giving informed consent , or a combination , are not r and omized . The primary end points for evaluating efficacy are the incidence of fatal and nonfatal myocardial infa rct ion , and sudden death . The hypothesized effect of bezafibrate administration under the aforementioned protocol is to reduce an estimated cumulative end point event incidence of > or = 15 % by 20 to 25 % over an average follow-up period of 6.25 years , through early 1998 , when the last patient recruited will have completed 5 years . ( ABSTRACT TRUNCATED AT 250 WORDS OBJECTIVE To compare the lipid-lowering efficacies of simvastatin and gemfibrozil in NIDDM patients with combined ( mixed ) hyperlipidemia ( CHL ) or isolated hypercholesterolemia ( IHC ) . RESEARCH DESIGN AND METHODS Patients with primary dyslipidemia and NIDDM were recruited for this double-blind , double-dummy comparison study from 10 Finnish centers . After a 4-week placebo run-in period , they were r and omly assigned to simvastatin or gemfibrozil . The simvastatin group ( n = 47 ) received 10 mg once nightly for 8 weeks , 20 mg for the next 8 weeks , and 40 mg for the third 8-week period . The gemfibrozil group ( n = 49 ) received 600 mg twice daily throughout the 24 weeks . The lipid-lowering efficacies of both drugs were compared in all patients as well as separately in patients with CHL and IHC . RESULTS In all patients , simvastatin reduced LDL and total cholesterol and the LDL-to-HDL cholesterol ratio more effectively , whereas gemfibrozil was more effective in elevating HDL cholesterol and decreasing triglyceride levels . The drug effects differed according to lipid phenotype at baseline . Simvastatin decreased LDL cholesterol levels by 30–40 % in both phenotypes . Gemfibrozil caused a 15 % reduction in LDL cholesterol in IHC but no change in CHL patients . Simvastatin produced 15–30 % reductions in triglyceride levels in CHL but no change in IHC patients . Gemfibrozil caused reductions in triglycerides in CHL ( 50 % and more ) and in IHC ( 40 % ) patients , with 12–18 % increases in HDL cholesterol in these groups . CONCLUSIONS Simvastatin is useful in both CHL and IHC patients , whereas gemfibrozil can be used in patients with high triglyceride and low or normal LDL cholesterol levels 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 During screening in the Helsinki Heart Study ( HHS ) , a 5-year coronary primary prevention trial with gemfibrozil , some 600 dyslipidaemic individuals were detected who exhibited symptoms and signs of possible coronary heart disease ( CHD ) . These subjects were excluded from the primary study . To secure successful conduct in the HSS , an ancillary protocol was developed for the treatment of these individuals . Three-hundred and eleven subjects were r and omized to receive gemfibrozil 600 mg twice daily and 317 subjects to receive a matching placebo over 5 years in a double-blind fashion . The end-point rate , consisting of fatal and non-fatal myocardial infa rct ion and cardiac death , did not differ significantly between the placebo and gemfibrozil groups . The same was true for total mortality . Missing key prognostic factors , e.g. true prevalence of CHD , extent of coronary artery obstructions , degree of left ventricular dysfunction , and their distribution in the groups render the results less reliable and hence the data can not be used to refute the thesis that treatment of dyslipidaemia in manifest CHD in successful Abstract A controlled trial of Clofibrate in 95 patients with established cerebral vascular disease is described . The level of serum cholesterol is significantly lowered in patients on treatment compared with control patients . There is no evidence to indicate that lowering the level of serum cholesterol in patients with established cerebral vascular disease has affected either the incidence of further episodes of cerebral ischaemia or the mortality rate BACKGROUND Although it is generally accepted that lowering elevated serum levels of low-density lipoprotein ( LDL ) cholesterol in patients with coronary heart disease is beneficial , there are few data to guide decisions about therapy for patients whose primary lipid abnormality is a low level of high-density lipoprotein ( HDL ) cholesterol . METHODS We conducted a double-blind trial comparing gemfibrozil ( 1200 mg per day ) with placebo in 2531 men with coronary heart disease , an HDL cholesterol level of 40 mg per deciliter ( 1.0 mmol per liter ) or less , and an LDL cholesterol level of 140 mg per deciliter ( 3.6 mmol per liter ) or less . The primary study outcome was nonfatal myocardial infa rct ion or death from coronary causes . RESULTS The median follow-up was 5.1 years . At one year , the mean HDL cholesterol level was 6 percent higher , the mean triglyceride level was 31 percent lower , and the mean total cholesterol level was 4 percent lower in the gemfibrozil group than in the placebo group . LDL cholesterol levels did not differ significantly between the groups . A primary event occurred in 275 of the 1267 patients assigned to placebo ( 21.7 percent ) and in 219 of the 1264 patients assigned to gemfibrozil ( 17.3 percent ) . The overall reduction in the risk of an event was 4.4 percentage points , and the reduction in relative risk was 22 percent ( 95 percent confidence interval , 7 to 35 percent ; P=0.006 ) . We observed a 24 percent reduction in the combined outcome of death from coronary heart disease , nonfatal myocardial infa rct ion , and stroke ( P < 0.001 ) . There were no significant differences in the rates of coronary revascularization , hospitalization for unstable angina , death from any cause , and cancer . CONCLUSIONS Gemfibrozil therapy result ed in a significant reduction in the risk of major cardiovascular events in patients with coronary disease whose primary lipid abnormality was a low HDL cholesterol level . The findings suggest that the rate of coronary events is reduced by raising HDL cholesterol levels and lowering levels of triglycerides without lowering LDL cholesterol levels BACKGROUND Diabetes risk is often complicated by a mixed hyperlipoproteinemia not sufficiently controlled by a single antihyperlipidemic drug ; however , there are some concerns about the safety of combined statin and fibrate treatments . OBJECTIVE The aim of this study was to compare the efficacy and safety profile of fluvastatin + fenofibrate combination therapy and those of fluvastatin monotherapy in the treatment of combined hyperlipidemia , type 2 diabetes mellitus ( DM ) , and coronary heart disease ( CHD ) ( ie , high risk for cardiovascular disease [ CVD ] ) . METHODS This 12-month , r and omized , double-blind , controlled trial was conducted at the University of Pavia , Pavia , Italy . Patients aged 18 to 80 years with combined hyperlipidemia , type 2 DM , and CHD were r and omly assigned to receive combination therapy with extended-release fluvastatin 80 mg + micronized fenofibrate 200 mg or monotherapy with extended-release fluvastatin 80 mg . All treatments were given in tablet form , once daily with the evening meal , for 12 months . Lipid variables ( low-density lipoprotein cholesterol [ LDL-C ] , high-density lipoprotein cholesterol [ HDL-C ] , total cholesterol [ TC ] , and triglycerides [ TG ] ) at 6 and 12 months were the primary efficacy variables , and glycemic status ( glycosylated hemoglobin [ HbA(1c ) ] , fasting plasma glucose , and postpr and ial plasma glucose levels ) at 6 and 12 months was the secondary efficacy variable . Tolerability was assessed using physical examination , including vital-sign assessment , body-weight measurement , electrocardiography , adverse events , and laboratory tests . A pharmacoeconomic analysis of both treatment regimens was also carried out using the incremental cost-effectiveness ratio ( ICER ) . RESULTS A total of 48 patients ( 24 men , 24 women ; mean [ SD ] age , 60 [ 5 ] years ) were enrolled . After 6 months , all primary efficacy variables , except for TG level , showed significant improvements from baseline only in the combination-therapy group ( changes : LDL-C , -25 % ; HDL-C , + 12 % ; and TC , -19 % ; all , P < 0.05 vs baseline ) . After 12 months , lipid variables showed significant improvements over baseline in both groups ( all , P < 0.05 ) , except for TG in the monotherapy group . Significant changes in LDL-C , HDL-C , and TG were found in the combination-therapy group ( -35 % , + 34 % , -32 % , respectively ) versus the monotherapy group ( -25 % , + 14 % , -17 % , respectively ; all , P < 0.05 between groups ) . The change from baseline in HbA(1c ) level was significant with combination therapy ( -12 % vs -7 % ; P < 0.05 ) . Both treatments were well tolerated , with no significant differences in the incidences of adverse events between the 2 groups . The ICER showed that each 1 % decrease in LDL-C level achieved with the fenofibrate + fluvastatin combination added a cost of 14.97 Euros/y ( US 12.25 US dollars/y ) , and each 1 % increase in HDL-C level added a cost of 7.48 Euros/y ( 6.12/y US dollars ) , over the cost of monotherapy . CONCLUSIONS In this selected sample of patients with combined hyperlipidemia , type 2 DM , and CHD , the combination of extended-release fluvastatin + micronized fenofibrate was associated with a more improved lipid profile  than fluvastatin monotherapy , and was a well-tolerated and cost-effective therapeutic choice to treat these patients at high risk for CVD 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 The independent contributions of subfractions of high-density lipoprotein ( HDL ) cholesterol ( HDL2 and HDL3 ) and apolipoproteins in predicting the risk of myocardial infa rct ion are unclear . Prospect i ve data are sparse , but HDL2 is widely believed to be a more important predictor than HDL3 . METHODS Blood sample s were collected at base line from 14,916 men ( ages , 40 to 84 years ) who were participants in the Physicians ' Health Study . After five years of follow-up , plasma sample s from 246 men with new myocardial infa rct ion ( case subjects ) were analyzed together with specimens from 246 men matched to them for age and smoking status who had not had a myocardial infa rct ion . RESULTS The levels of total cholesterol and apolipoprotein B-100 were significantly associated with an increased risk of myocardial infa rct ion ( data on levels of low-density lipoprotein cholesterol were unavailable ) . Both HDL cholesterol and HDL2 levels were associated with a substantially decreased risk of myocardial infa rct ion , but the HDL3 level was the strongest predictor ; the relative risk was 0.3 ( 95 percent confidence interval , 0.2 to 0.6 ) for those in the fifth of the group with the highest HDL3 levels , as compared with the fifth with the lowest levels . The benefit of a higher HDL cholesterol level was most pronounced among those with lower total cholesterol levels . Levels of apolipoprotein A-I and apolipoprotein A-II were also associated with decreased risk . However , the levels of HDL subfractions and apolipoproteins did not add significantly to the value of a multivariate model that included the ratio of total to HDL cholesterol in predicting myocardial infa rct ion , whereas that ratio remained a significant independent predictor of risk . After adjustment for other risk factors , a change of one unit in the ratio of total to HDL cholesterol was associated with a 53 percent change in risk ( 95 percent confidence interval , 26 percent to 85 percent ) . CONCLUSIONS This study underscores the importance of HDL cholesterol in predicting the risk of myocardial infa rct ion and demonstrates protective effects of both the HDL3 and HDL2 subfractions of HDL cholesterol . We found little or no predictive value for the levels of apolipoproteins A-I , A-II , and B or HDL subfractions after conventional risk factors and the ratio of total to HDL cholesterol were considered The relationship of future clinical coronary heart-disease ( C.H.D. ) to the plasma-high-density-lipoprotein (H.D.L.)-cholesterol concentration has been examined in a 2-year case-control follow-up study of 6595 men aged 20 - 49 years living in the municipality of Tromsø , Norway . Measurements were also made of the  cholesterol concentration in lower-density ( i.e. , density less than 1 - 603 g/ml ) lipoproteins , plasma-triglycerides , systolic and diastolic blood-pressures , relative body-weight , and cigarette consumption . Discriminant-function analysis showed that coronary risk was inversely related to  H.D.L.-cholesterol concentration and directly related to density less than 1 - 063 cholesterol . These relationships were independent of each other and of the other measured variables , which showed no significant differences between the cases and controls .  H.D.L. cholesterol made a three-fold greater contribution to the prediction of future C.H.D. than did density less than 1 - 063 cholesterol in this cohort of young men . These findings support the proposal that a low  H.D.L. concentration is a common antecedent of clinical C.H.D. and is important in accelerating the progression of coronary atherosclerosis
target: Subgroup analyses showed the benefit of fibrates on the primary composite outcome to be consistent irrespective of age , gender , and diabetes mellitus .
  Moderate evidence showed that the fibrate class can be effective in the secondary prevention of composite outcome of non-fatal stroke , non-fatal MI , and vascular death .
  However , this beneficial effect relies on the inclusion of clofibrate data , a drug that was discontinued in 2002 due to its unacceptably large adverse effects .
background: BACKGROUND Fibrates are a class of drugs characterised by mainly lowering high triglyceride , raising high-density lipoprotein ( HDL ) cholesterol , and lowering the small dense fraction of low-density lipoprotein ( LDL ) cholesterol .
  Their efficacy for secondary prevention of serious vascular events is unclear , and to date no systematic review focusing on secondary prevention has been undertaken .
  OBJECTIVES To assess the efficacy and safety of fibrates for the prevention of serious vascular events in people with previous cardiovascular disease ( CVD ) , including coronary heart disease and stroke .