Atherogenic risk reduction in patients with dyslipidaemia. comparison between bezafibrate and lovastatin. Comparison of the efficacy of simvastatin and standard fibrate therapy in the treatment of primary hypercholesterolemia and combined hyperlipidemia Efficacy and safety of a combination of fluvastatin and bezafibrate in patients with mixed hyperlipidaemia (FACT study). Statins and Fibrates for Diabetic Retinopathy: Protocol for a Systematic Review Effects of initial BMI and on-treatment weight change on the lipid-lowering efficacy of fibrates 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. A randomized trial of the effect of statin and fibrate therapy on arterial function in CKD. Comparison of bezafibrate and simvastatin in the treatment of dyslipidaemia in patients with NIDDM. Bezafibrate and simvastatin combination therapy for diabetic dyslipidaemia: efficacy and safety. Design and intermediate results of the Lower Extremity Arterial Disease Event Reduction (LEADER)* trial of bezafibrate in men with lower extremity arterial disease [ISRCTN41194621] Effects of simvastatin and ciprofibrate alone and in combination on lipid profile, plasma fibrinogen and low density lipoprotein particle structure and distribution in patients with familial combined hyperlipidaemia and coronary artery disease Combined bezafibrate and simvastatin treatment for mixed hyperlipidaemia. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Modulation of plasma fibrinogen levels by ciprofibrate and gemfibrozil in primary hyperlipidaemia. A Randomized Trial of a Strategy for Increasing High-Density Lipoprotein Cholesterol Levels: Effects on Progression of Coronary Heart Disease and Clinical Events Baseline characteristics of patients participating in the Bezafibrate Infarction Prevention (BIP) Study. Atorvastatin versus Four Statin–Fibrate Combinations in Patients with Familial Combined Hyperlipidaemia
OBJECTIVE To examine the atherogenic risk-reducing effect of bezafibrate and lovastatin . DESIGN , SETTING , PATIENTS , INTERVENTIONS Double-blind , r and omized clinical trial of male and female patients with moderate hypercholesterolaemia with or without hypertriglyceridaemia . Two months dietary treatment followed by 400 mg sustained release bezafibrate every day or 20 mg lovastatin every day for 6 months . Patients recruited ( n = 561 ) and treated ( n = 524 ) by primary care physicians throughout Austria . MAIN OUTCOME MEASURES Multifactorial assessment of atherogenic risk profile . RESULTS Bezafibrate increased high density lipoprotein cholesterol by 16 % , lovastatin by 10 % ( P < 0.05 ) . Bezafibrate decreased low density lipoprotein cholesterol by 20 % , lovastatin by 27 % ( P < 0.001 ) . Bezafibrate decreased total cholesterol by 15 % , lovastatin by 18 % ( P < 0.001 ) . Bezafibrate reduced triglycerides by 29 % , lovastatin by 13 % ( P < 0.001 ) ; and fibrinogen by 9.4 % and 3.0 % , respectively . Fibrinogen reduction as a result of bezafibrate administration was dependent on starting levels . The risk ratio cholesterol : high density lipoprotein cholesterol ( baseline both 6.1 ) reduction was 27 % in both groups . The low : high density lipoprotein ratio ( baseline : 4.1/4.2 ) reduction reached 31 % and 34 % respectively . Coronary events ' probability ( calculated from multifactorial risk functions ) were greatly reduced by both agents ( 41%/33 % ) . Hypertriglyceridaemic patients had a higher initial global coronary risk and profited more from treatment . Bezafibrate was significantly better tolerated ( P < 0.001 ) than lovastatin ; most events were gastrointestinal ( 6 vs 14 , ns ) or as a result of creatine phosphokinase elevations ( 3 vs 12 , P < 0.05 ) . CONCLUSIONS Both treatments significantly reduced the risk parameters for developing coronary heart disease , and calculated multifactorial coronary risk was similarly decreased . When selecting a drug for moderate dyslipidaemia and if haemostatic regulation is disturbed , the additional effect of bezafibrate on elevated fibrinogen levels should be considered Five multicenter , r and omized , double‐blind , placebo‐controlled studies were conducted in France to compare the efficacy and safety of once‐daily simvastatin treatment ( 10–40 mg/day ) with conventional therapy with gemfibrozil 900 mg/day , ciprofibrate 100 mg/day , bezafibrate 400 mg/day , and fenofibrate 300 or 400 mg/day in a total of 800 patients with hypercholesterolemia .  Simvastatin was associated with statistically significantly greater ( p ≪ 0.01 ) mean percent reductions in plasma low‐density lipoprotein ( LDL ) cholesterol compared with each of the five fibrate regimens , even when administered at its recommended starting dose of 10 mg/day . Furthermore , approximately 90 % of patients treated once daily with simvastatin experienced an at least 20 % decrease in plasma LDL cholesterol compared with only 36 to 68 % of patients treated with the individual fibrate agents ( p ≪ 0.05 ) . The effectiveness of simvastatin in reducing LDL cholesterol did not differ as a function of the baseline plasma concentrations of total cholesterol or triglycerides . In contrast , the effectiveness of fibrate therapy in lowering plasma LDL cholesterol levels was significantly diminished ( p ≪ 0.05 ) among patients with triglyceride concentrations  >  1.7 mmol/1 . Plasma highdensity lipoprotein ( HDL ) cholesterol levels were increased by approximately 10 % after treatment with simvastatin or the fibrates . Although fibrate therapy was more effective overall in lowering plasma triglyceride levels , the effectiveness of simvastatin in reducing plasma triglyceride levels was generally 2‐ to 4‐fold greater in patients with hypercholesterolemia associated with triglyceride levels ≫ 2.3 mmol/1 than in those with hypercholesterolemia associated with triglyceride levels < 2.3 mmol/1 . The results of these studies confirm the superiority of simvastatin to st and ard fibrate therapy in reducing plasma levels of total and LDL cholesterol . They further indicate that once‐daily treatment with simvastatin is effective in patients with isolated hypercholesterolemia or hypercholesterolemia associated with elevated triglyceride levels Preliminary data suggest that fluvastatin may be safely combined with fibrates . The Fluvastatin Alone and in Combination Treatment Study examined the effects on plasma lipids and safety of a combination of fluvastatin and bezafibrate in patients with coronary artery disease and mixed hyperlipidaemia . A total of 333 patients were r and omly allocated in this multicentre double-blind trial to receive 40 mg fluvastatin alone ( n=80 ) , 400 mg bezafibrate ( n=86 ) , 20 mg fluvastatin+400 mg bezafibrate ( n=85 ) or 40 mg fluvastatin+400 mg bezafibrate ( n=82 ) for 24 weeks . Low-density lipoprotein (LDL)-cholesterol decreased > 20 % in all fluvastatin-containing regimens , with significantly greater decreases compared with bezafibrate alone ( P<0.001 ) . Bezafibrate alone and fluvastatin+bezafibrate combinations result ed in greater increases in high-density lipoprotein (HDL)-cholesterol and decreases in triglycerides compared with fluvastatin alone ( P<0.001 ) . Fluvastatin ( 40 mg)+bezafibrate was the most effective for all lipid parameters with a decrease from baseline at endpoint in LDL-cholesterol of 24 % , a decrease in triglycerides of 38 % and an increase in HDL-cholesterol of 22 % . All treatments were well tolerated with no increase in adverse events for combination therapy versus monotherapy , or between combination regimens . No clinical ly relevant liver ( aspartate aminotransferase [ ASAT ] or alanine aminotransferase [ ALAT ] ) greater than three times the upper limit of normal ) or muscular ( creatine phosphokinase ( CPK ) greater than four times the upper limit of normal ) laboratory abnormalities were reported . This large study shows 40 mg fluvastatin in combination with 400 mg bezafibrate to be highly effective and superior to either drug given as monotherapy in mixed hyperlipidaemia , and to be safe and well tolerated Background Diabetic retinopathy ( DR ) is a common microvascular complication of diabetes mellitus , and more than 75 % of patients who have had diabetes for more than 20 years will have some degree of DR . This disease is highly destructive to self-esteem and puts a high burden on public health and pension systems due to the effects that it has on people of working age . The current mainstay of treatment is laser photocoagulation , which causes impairment of vision and discomfort to patients . Thus , finding a systemic drug that could act on all microcirculation and prevent direct manipulation of the eyes would be highly desirable . Objective To assess the efficacy and safety of the drugs in the statin and /or fibrate groups for the prevention and treatment of DR . Methods In this systematic review , we will select r and omized controlled trials of fibrates or statins used for the treatment or prevention of DR . Our search strategy will include free text terms and controlled vocabulary ( eg , MeSH , Emtree ) for , “ diabetic retinopathy ” , “ statins ” , “ fibrates ” , “ hypolipidemic agents ” , and for drugs from both groups . Data bases that will be used include Medical Literature Analysis and Retrieval System/ PubMed , Embase , Cochrane Central Register of Controlled Trials , Latin American and Caribbean Center on Health Sciences Information , Clinical trials.gov , World Health Organization International Clinical Trials Registry Platform , and OpenGrey , and we will not have language or date limits . Two review authors will independently select eligible studies and assess the risk of bias using the Cochrane Collaboration ’s tool . We will report structured summaries of the included studies and , if possible , conduct meta-analyses . Results This is a protocol for a systematic review , therefore results are not available . We registered a short version of this protocol before progressing in the review and we are currently in the process of selecting the studies for inclusion . Conclusions Intensive glucose control and lowering blood pressure and lipids are mechanisms that protect macrocirculation in diabetic patients . Both macrovascular and microvascular events in diabetic patients appear to have a common pathway , starting with endothelial injury . Thus , prevention and treatment of microvascular events may benefit from the same interventions . In the review for which we have written this protocol , we will assess whether the use of lipid-lowering oral drugs of the statin and /or fibrate groups may prevent and /or retard progression of DR , with the added benefit of preserving visual acuity . Trial Registration PROSPERO OBJECTIVE : To assess the effects of BMI at baseline and on-treatment weight change on the lipid-lowering efficacy of diet plus fibric acid derivatives ( fibrates ) in hypercholesterolemic adults . SUBJECTS : 6003 participants in a Belgian General Practitioners Trial , an open-label , prospect i ve study conducted in a primary care setting . MEASURES : Effect of initial BMI , on-treatment weight change , or lipid values at baseline on percentage changes in low-density lipoprotein cholesterol ( LDL-C ) , high-density lipoprotein cholesterol ( HDL-C ) , and triglycerides ( TG ) . Multiple linear regression models , including initial BMI , on-treatment weight change , age , gender , and baseline lipid values , were fitted to control the influences exerted by these variables on each other . RESULTS : Reductions in LDL-C after diet plus fibrate treatment for 12 weeks were inversely related to initial BMI and to TG levels at baseline , and were positively associated with baseline LDL-C concentrations and with on-treatment weight change ( P<0.001 for all analyses ) . Decreases in TG related negatively with initial BMI ( P=0.012 ) , and positively with weight loss ( P=0.011 ) and TG at baseline ( P<0.001 ) . Increases in HDL-C were negatively associated with initial BMI ( P=0.012 ) and with baseline TG ( P<0.001 ) . CONCLUSIONS : The LDL-C lowering efficacy of fibrates is inversely related to initial BMI , and is positively associated with on-treatment weight loss 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 Although patients with chronic kidney disease ( CKD ) are at increased risk of cardiovascular disease ( CVD ) , the roles of lipid-modifying therapies in decreasing CVD risk are unclear . Our aim is to compare the effects of statin and fibrate therapy on arterial function as a risk marker of CVD . STUDY DESIGN Double-blind , r and omized , placebo-controlled , parallel-group study . SETTING & PARTICIPANTS Ambulatory patients with stages 3 to 5 CKD . INTERVENTION 6 weeks of atorvastatin , 40 mg/d , or gemfibrozil , 600 mg twice daily , with placebo . OUTCOMES & MEASUREMENTS Primary outcome was arterial function assessed by means of endothelial-dependent flow-mediated dilatation ( FMD ) and small-artery compliance ( C2 ) . Secondary outcomes included endothelial-independent glyceryl trinitrate-mediated dilatation ( GTNMD ) , large-artery compliance ( C1 ) , and levels of lipids , lipoproteins , and oxidized low-density lipoprotein , as well as markers of insulin resistance and inflammation . RESULTS Compared with placebo , atorvastatin significantly decreased low-density lipoprotein ( -52 % ) , triglyceride ( -30 % ) , and oxidized low-density lipoprotein levels ( -41 % ; P < 0.0001 ) . Gemfibrozil significantly decreased triglyceride levels ( -40 % ) and increased high-density lipoprotein levels ( + 20 % ; P < 0.0001 ) . Neither atorvastatin nor gemfibrozil had a significant effect on markers of insulin resistance or inflammation . There was no significant change in FMD , GTNMD , or C1 with either atorvastatin or gemfibrozil . There was improvement in C2 with atorvastatin ( + 1.1 mL/mm Hg x 100 ) compared with placebo ( P = 0.024 ) , but not with gemfibrozil compared with placebo . LIMITATIONS Small sample size leading to inadequate power , short duration of therapy , and use of a heterogeneous group of patients with CKD and dialysis patients . CONCLUSION In patients with advanced CKD , atorvastatin is associated with improvement in dyslipidemia and small-artery stiffness , but not endothelial function .  Gemfibrozil improves dyslipidemia , but has no effect on arterial function Fibrates and HMG CoA reductase inhibitors are commonly used in the treatment of diabetic dyslipidaemia . However , these two groups of drugs have not been compared in diabetic patients in a r and omized controlled trial . Therefore , a multicentre study was performed in 73 subjects with non-insulin-dependent ( Type 2 ) diabetes mellitus ( NIDDM ) and combined hyperlipidaemia ( serum cholesterol 6.2 - 10.0 mmol l(-1 ) , serum triglycerides 2.3 - 10.0 mmol l(-1 ) ) , comparing the efficacy of 400 mg bezafibrate with 10 mg simvastatin in a double-blind fashion . Treatment with bezafibrate during 12 weeks reduced serum triglycerides significantly more than simvastatin ( -41 % vs -22 % , p < 0.001 ) and increased HDL cholesterol more ( bezafibrate : + 17 % vs simvastatin : + 9 % , p < 0.05 ) . LDL cholesterol levels decreased by 14 % ( p < 0.001 ) during simvastatin and increased by 21 % ( p < 0.01 ) during bezafibrate . This increase in LDL cholesterol was positively correlated with fasting serum triglycerides ( p < 0.001 ) and was associated with a reduction of the serum apolipoprotein B concentration , suggesting an increase in LDL particle size . Metabolic control of diabetes ( fasting glycaemia ; HbA1c ) and insulin secretion ( C-peptide levels ) were unaffected by both treatments . The incidence of side-effects during treatment was similar for both drugs . Thus , 400 mg bezafibrate mainly increases HDL cholesterol and lowers serum triglycerides but at the expense of an increase in LDL cholesterol ; 10 mg simvastatin lowers LDL cholesterin more effectively but has a smaller effect on HDL cholesterol and triglycerides OBJECTIVE To determine the efficacy and safety of a statin-fibrate combination in diabetes patients . DESIGN . : An open 21-month trial in which each patient first received the single drug for 6 months and then a combination of the two for 1 year . SETTING Three lipid clinics in university-based tertiary care hospitals . PATIENTS One hundred and forty-eight patients with type 2 ( non-insulin-dependent , NIDDM ) diabetes mellitus under stable control for 3 months by means of diet and oral hypoglycaemic medication . INTERVENTION Patients from one clinic ( n = 48 ) received bezafibrate slow release ( 400 mg day-1 ) , and patients from the other two clinics ( n = 100 ) received simvastatin 20 mg day-1 . Six months later , all patients were switched to a daily combination of 400 mg bezafibrate slow release and 20 mg simvastatin for 1 year . RESULTS The combination of statin and fibrate led to a 23 % reduction in total cholesterol , 42 % reduction in triglycerides , 29 % reduction in LDL-c , 25 % increase in HDL-c , 10 % decrease in fibrinogen and 19 % reduction of Lp(a ) levels , and a decrease in the cholesterol/HDL-c ratio ( from 8.9 to 5.4 ) in all 148 patients . Cardiovascular ( CV ) event rate was significantly reduced from 9.5 % during the first 6 months of the study to less than 2 % during the last year of the study ( whilst on combination Rx ) . Side-effects with all treatments included only two patients who developed myopathy when on the combined regimen and one on the single statin regimen . However , plasma creatinine phosphokinase ( CPK ) levels doubled ( but remained within the normal range ) in most of the patients on combination therapy , compared with only a mild increase in patients receiving a single medication . CONCLUSIONS The statin and fibrate combination was found to be more efficacious than a single medication for treatment of diabetic dyslipidaemia , as evidence d by improvement in the lipoprotein profile , reductions in Lp(a ) , fibrinogen and CV event rate , and almost no clinical ly significant side-effects 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 Background Hypolipidaemic agents do not usually normalize all of the multiple lipoprotein abnormalities in patients with familial combined hyperlipidaemia ( FCHL ) . The effect of the simvastatin-ciprofibrate combination in comparison with each drug alone on the lipoprotein abnormality patterns was studied in patients with FCHL and coronary artery disease ( CAD ) . Methods Sixty patients ( 53 men and seven women ) , mean age 52 years ( range 36–60 years ) , were studied . After a 4-week placebo period , patients were r and omly assigned to three groups . The first group ( n = 20 ) received simvastatin ( 20 mg daily ) , the second group ( n = 20 ) ciprofibrate ( 100 mg daily ) and the third group ( n = 20 ) the combination of both drugs for a 1 2-week period . Parameters measured were as follows : plasma fibrinogen , total cholesterol , triglycerides , low density lipoprotein ( LDL ) , very low density lipoprotein , intermediate density lipoprotein , and high density lipoprotein cholesterol , as well as LDL subfraction distribution and structure by density gradient ultracentrifugation . Apoproteins ( apo ) B and Al were assessed by immunoturbidometry . Results At baseline , apoB , LDL cholesterol and triglycerides were increased , whereas LDL particles were small and dense . ApoB was significantly reduced by all three interventions . Drug combination and ciprofibrate significantly reduced plasma fibrinogen ( -24 and −25 % , respectively ; P < 0.001 ) and triglycerides ( -51 and −49 % , respectively ; P < 0.001 ) . Drug combination and simvastatin significantly reduced LDL cholesterol ( -25 and −22 % , respectively ; P < 0.001 ) compared with ciprofibrate ( -10 % ; P<0.01 ) . Ciprofibrate and drug combination  increased LDL particle size ( parameter K −0.24 versus −0.61 and −0.30 versus −0.62 , respectively ; P < 0.001 ) , whereas simvastatin had no significant effect on LDL particle size . The cholesterol content of LDL particles was reduced with ciprofibrate and the drug combination only in the dense LDL particles ( LDL3–5 ) and increased in the light ( LDL1–2 ) subfractions , whereas simvastatin reduced the cholesterol content of all LDL subfractions except LDL2 . Ciprofibrate and drug combination reduced the triglyceride content of al ! LDL subfractions . Conclusion Combined treatment with simvastatin and ciprofibrate  effectively reduced plasma fibrinogen , triglycerides , total and LDL cholesterol and increased LDL particle size in patients with FCHL and CAD . These effects might induce a clinical benefit for these patients The safety and efficacy of combined bezafibrate-simvastatin therapy was evaluated in 49 patients with diet-resistant mixed hyperlipidaemia ( type IIb ) . After a two-month placebo phase , patients were r and omized to receive either Bezafibrate Slow Release ( SR ) 400 mg mane or simvastatin 20 mg nocte followed by three months combination therapy . Total cholesterol , triglycerides and high-density lipoprotein ( HDL ) cholesterol were measured at monthly intervals . Apolipoproteins ( apo ) A1 and B , lipoprotein ( a ) [ Lp(a ) ] and fibrinogen were measured before and after each treatment . Simvastatin was more effective than Bezafibrate SR in reducing total cholesterol ( 2.0 vs. 1.1 mmol/l , p = 0.003 ) and lowering LDL cholesterol ( 1.7 vs. 0.4 mmol/l , p = 0.0001 ) whereas Bezafibrate SR was more effective in reducing triglycerides ( by 41 % vs. 17 % , p = 0.001 ) and fibrinogen ( by 23 % vs. 3 % , p = 0.004 ) . Compared with simvastatin monotherapy , combined drug therapy induced further reductions in triglycerides ( by 26 % , p = 0.0003 ) and apoB ( by 11 mg/dl , p = 0.03 ) and an increase in apoA1 ( by 21 mg/dl , p = 0.0008 ) . Symptomatic and biochemical adverse events did not occur more frequently on combined drug therapy than on monotherapy . The combination of bezafibrate and simvastatin was more effective in controlling mixed hyperlipidaemia than either drug alone and did not provoke more adverse events 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 An elevated plasma fibrinogen level is increasingly accepted as an independent risk indicator of cardiovascular disease . This has enhanced the interest in identifying agents that can normalize elevated plasma fibrinogen levels . One group of agents with this capacity are the fibric acid derivatives , e.g. ciprofibrate and gemfibrozil . We studied fibrinogen levels after 12 weeks of treatment with ciprofibrate  ( n = 48 ) and gemfibrozil  ( n = 51 ) in hypercholesterolenic patients . The correlation of the decrease in fibrinogen with lipid lowering and the contribution of the acute phase and genetic polymorphisms to this decrease were also evaluated . After 12 weeks of treatment , the fibrinogen levels were significantly decreased ( p < 0.0005 ) with both drugs , although the decrease in the ciprofibrate group ( mean 3.4 g/l pre-treatment to 2.4 g/l after 12 weeks ) was larger than in the gemfibrozil group ( mean 3.4 g/l to 3.0 g/l ) . The lipid lowering effect was comparable for the two drugs but there was no correlation for either ciprofibrate or gemfibrozil between the lipid lowering and the magnitude or the velocity of the fibrinogen lowering effect . An attenuation of the major regulatory mechanism of plasma fibrinogen levels , the acute phase reaction , was invoked as the underlying mechanism . However , pre-treatment C-reactive protein levels were not increased and did not change after treatment . Moreover , no effects of the polymorphisms of the fibrinogen beta-gene on the decrease of the plasma fibrinogen levels were observed . This suggests that a new , as yet unknown , mechanism is involved in fibrinogen lowering by fibrates Context Most trials that address lipid management focus on reducing low-density lipoprotein ( LDL ) cholesterol levels rather than increasing high-density lipoprotein ( HDL ) cholesterol levels . Contribution In this double-blind trial , 143 military retirees with low HDL cholesterol levels and coronary artery disease were r and omly assigned to placebo or aggressive HDL cholesterolincreasing therapy with gemfibrozil , niacin , and cholestyramine for 30 months . All participants received diet and exercise counseling . Compared with the placebo group , the treated group had a 20 % decrease in total cholesterol level ; a 36 % increase in HDL cholesterol level ; less focal coronary stenosis ; fewer total cardiovascular events ; and more flushing , skin rashes , and abdominal symptoms . Caution s The small trial had limited ability to assess clinical outcomes . The Editors Large epidemiologic studies have repeatedly demonstrated that cardiovascular risk increases proportionally with increasing total cholesterol and low-density lipoprotein ( LDL ) cholesterol levels and decreasing high-density lipoprotein ( HDL ) cholesterol levels ( 1 , 2 ) . Although many studies have documented that statins , drugs that primarily reduce LDL cholesterol levels , significantly reduce the risk for cardiovascular events ( 3 - 7 ) , prospect i ve studies that examine the clinical effects of increasing HDL cholesterol levels have been more limited . The Coronary Drug Project first reported evidence of a mortality benefit in patients treated with niacin ; however , the difference was seen long after withdrawal of the study drug , making the mechanism of benefit less clear ( 8) . The Helsinki Heart Study ( 9 ) examined the use of gemfibrozil in primary prevention . Coronary events were reduced by 34 % , but the increase in HDL cholesterol level was modest ( only 11 % ) . The Bezafibrate Infa rct ion Prevention Trial failed to show a reduction in cardiovascular events in the composite population , although a recent re analysis of the data suggests an improved outcome in patients experiencing a greater increase in HDL cholesterol level ( 10 ) . The Veterans Affairs HDL Intervention Trial ( VA-HIT ) ( 11 ) demonstrated a modest reduction in coronary events when gemfibrozil was used in patients with normal levels of LDL cholesterol and low levels of HDL cholesterol . The authors ascribed most of the reduction in clinical events to the improvement in HDL cholesterol , although the overall improvement was only approximately 6 % with drug therapy . More recently , a combination of a statin ( simvastatin ) with niacin was found to favorably modify both HDL cholesterol and LDL cholesterol levels and reduce cardiovascular events compared with both placebo therapy and underlying treatment with antioxidants in a cohort of 160 patients with coronary disease ( 12 ) . Despite a significant increase in mean HDL cholesterol levels , the overwhelming treatment effect in this study was the reduction in LDL cholesterol level ( 42 % in the treatment group ) . The most suggestive evidence of benefit from an increase in HDL cholesterol level has come from trials assessing the effect on coronary stenosis . Trials of quantitative angiography after monotherapy with fibrates ( 13 ) , as well as combinations of medications that both reduce LDL cholesterol levels and increase HDL cholesterol levels ( 14 - 18 ) , have shown an attenuation in angiographic progression . Nissen and colleagues ( 19 ) recently took this theory a step further by demonstrating that an infusion of a recombinant form of HDL , apolipoprotein A-I Milano , can lead to regression of angiographic stenosis as assessed by intravascular ultrasonography . We undertook the Armed Forces Regression Study ( AFREGS ) in 1993 to determine whether coronary atherosclerosis , assessed by quantitative coronary angiography and clinical coronary events , would improve when combination drug therapy focused on increasing HDL cholesterol levels in a sample of patients with fairly normal LDL cholesterol levels and low HDL cholesterol levels . A pilot study by Whitney and colleagues ( 20 ) showed the feasibility of this trial design , and the safety of using these drugs in combination has been previously established ( 21 ) . Methods Patients Participants living within a 150-mile radius of Wilford Hall Medical Center in San Antonio , Texas , who could provide written informed consent were eligible for enrollment . We recruited men and women younger than 76 years of age who had established or suspected coronary artery disease ( positive results on an exercise treadmill test or classic angina ) and did not have unstable symptoms . We allowed LDL cholesterol levels up to 4.1 mmol/L ( 160 mg/dL ) with HDL cholesterol levels less than 1.0 mmol/L ( 40 mg/dL ) after adherence to the American Heart Association ( AHA ) step II diet for at least 6 months . We set no lower limit to either HDL cholesterol or LDL cholesterol level . Each patient was required to have measurable stenosis between 30 % and 80 % of the luminal diameter within the coronary tree by caliper inspection . Patients with stenosis greater than 80 % were eligible if they had a favorable prognosis based on functional testing ( ability to exercise for > 9 minutes on a full Bruce protocol exercise treadmill test ) . Exclusions included a major vascular event ( myocardial infa rct ion , cerebrovascular accident , coronary artery bypass grafting , or other coronary catheterbased intervention ) within 6 months , a history of congestive heart failure ( other than in the setting of myocardial infa rct ion ) , or a left ventricular ejection fraction less than 0.4 on ventriculography . Other exclusion criteria included alcohol or substance abuse within the past year , uncontrolled arrhythmias , resistant hypertension , diabetes , uncontrolled gout , uncontrolled thyroid disease , liver or gall bladder disease , renal dysfunction ( creatinine concentration > 176.8 mol/L [ > 2.0 mg/dL ] or proteinuria greater than 2 + by dipstick or 500 mg/24 h ) , uncontrolled peptic ulcer disease , or pancreatic disorders . In addition , we excluded patients taking any lipid-modifying medications within 4 weeks of r and omization , heparin or coumarin-type anticoagulants , long-term oral corticosteroid therapy , or other immunosuppressive agents . We also excluded patients if they had hypersensitivity to or history of intolerance that required cessation of therapy for any component of gemfibrozil , nicotinic acid , cholestyramine , aspirin , or nitrates . Other exclusion criteria were the potential for childbearing , technically inadequate coronary arteriography for stenosis quantification , or any serious condition that we thought would compromise participation in the study or preclude survival for the duration of the study . We thoroughly informed participants of the details of the study . Each patient voluntarily enrolled and signed an informed consent statement that the Wilford Hall Medical Center Institutional Review Board review ed and approved . From screening laboratory records , we identified 1290 participant c and i date s and invited them to participate ( Figure 1 ) . Of the 847 patients who attended the introductory briefing , 671 met LDL cholesterol and HDL cholesterol entry criteria on fasting lipid analysis . Of the 269 participants who eventually provided informed consent , 55 subsequently withdrew for personal reasons , most commonly citing a fear of cardiac catheterization , and an additional 27 met an exclusion criterion . Of the 187 participants who completed the 6-month lifestyle modification phase and underwent coronary angiography  , 44 were excluded after initial coronary arteriography ; 27 had extensive coronary disease necessitating revascularization ( percutaneous coronary intervention in 3 patients and coronary artery bypass grafting in 24 patients ) , and 17 had insignificant coronary disease on angiography . Thus , we eventually r and omly assigned 143 patients ( 11 % of those initially contacted ) to either pharmacologic therapy or placebo . Figure 1 . Flow of patients through the study . Protocol After inclusion and exclusion criteria were met , a 6- to 8-month run-in period was performed to ensure that patients could adhere to the prescribed diet . During this phase , all patients received diet counseling from a study dietitian , exercise guidance from an exercise specialist , and smoking cessation advice . All study participants committed to attending a bimonthly food show for training in the AHA step II diet , with reinforcing presentations from the dietitian , exercise specialist , and cardiologist that discussed cardiac risk factor modification . We r and omly assigned each participant by using a computer-generated r and omization schedule . The central pharmacy held the code , and the information was not shared with physicians or patients until the completion of the protocol . Patients were r and omly assigned to 1 of 2 treatment groups : pharmacologic therapy with gemfibrozil , niacin , and cholestyramine or conventional therapy . The goal of therapy was to increase HDL cholesterol level by at least 25 % . The study was double-blind and placebo-controlled . The pharmaceutical company prepared all medications and placebos , and the central pharmacy dispensed them at 30-day intervals . The pharmacologic therapy group began receiving gemfibrozil , 600 mg twice per day . Short-acting niacin was added in the third month at a dosage of 250 mg/d and was titrated to 3000 mg/d as tolerated . Cholestyramine was added in the sixth month , and the dosage was titrated to 16 g/d as tolerated . The conventional therapy group was maintained on the AHA step II diet and applicable matching placebos for the duration of the investigation . If LDL cholesterol levels exceeded 4.14 mmol/L ( 160 mg/dL ) during the trial , cholestyramine was administered in an open-label fashion . Participants visited 1 clinic on a monthly basis for the duration of the study . At each monthly visit , clinicians measured vital signs and weight , counted unused study drugs , review ed changes in medications or medical status , provided Low high density lipoprotein ( HDL ) cholesterol , elevated triglycerides , or a combination of both , carries an increased risk of coronary heart disease ( CHD ) . The benefit of therapy that increases serum HDL cholesterol concentrations and lowers triglyceride concentrations on the reduced incidence of myocardial infa rct ions and mortality has not been unequivocally demonstrated in healthy persons or patients with CHD . The Bezafibrate Infa rct ion Prevention ( BIP ) study r and omized men and women , with CHD and with total serum cholesterol 180 - 250 mg . dl-1 , low density lipoprotein ( LDL ) cholesterol < or = 180 mg . dl-1 ( < or = 160 mg . dl-1 below age 50 years ) , HDL cholesterol < or = 45 mg . dl-1 and triglycerides < or = 300 mg . dl-1 , to bezafibrate retard ( 400 mg once daily ) or placebo . In addition to its effect on the lipids , this drug significantly lower plasma fibrinogen . The demographic , clinical and biochemical characteristics and existing cardiovascular therapy at baseline of 3122 patients r and omized onto the study are presented here . A comparison is made with other on-going or recently published secondary prevention studies of lipid modification in CHD patients Background Statin – fibrate combinations are very effective in the treatment of familial combined hyperlipidaemia ( FCHL ) . Nonetheless , they have not been extensively used because of the fear of side effects . Thus , a therapeutic alternative is required for this lipid disorder . Objective To compare the long-term ( one-year ) efficacy of atorvastatin monotherapy with those of four statin – fibrate combinations in 675 FCHL patients . Methods Patients were r and omly assigned to atorvastatin monotherapy ( A 20 mg/day ) n=134 , or pravastatin ( P 20 mg/day)+gemfibrozil ( G 1200 mg/day ) n=135 , simvastatin ( S 20 mg/day)+G ( 1200 mg/day ) n=137 , P ( 20 mg/day)+ciciprofibrate ( C 100 mg/day ) n=135 , and S ( 20 mg/day)+C ( 100 mg/day ) n=134 . Results Twelve patients on statin – fibrate combinations were withdrawn from the study because of side effects : Three because of CK elevation , two because of myalgia and seven due to increase in serum transaminase levels . One patient on A was withdrawn because of persistent epigastric discomfort .  Atorvastatin  reduced low density lipoprotein cholesterol and apoprotein B more than all four combinations ( −45 % vs. maximum −40 % of S+C , and −39 % vs. maximum −32 % of the same combination , respectively , P < 0.001 for both ) , but had a lesser effect on triglycerides ( −38 % vs. maximum −53 % of S+C , P=0.0002 ) and high density lipoprotein cholesterol ( 6 % vs. maximum 21 % of S+G , P=0.0003 ) . The effect of A on plasma fibrinogen was analogous to that of G combinations ( −8 % vs. −9 % of P+G and −11 % of S+G , P = NS vs. baseline and among each other ) and inferior to that of the ciprofibrate combinations ( −8 % vs. −24 % of P+C , P=0.0002 and −26 % S+C , P=0.0001 ) . A had a lower treatment cost and better patient compliance , P=0.04 vs. C combinations and P=0.02 vs. G combinations . Conclusions The data suggest that statin – fibrate combinations have a beneficial effect on all lipid parameters . Atorvastatin monotherapy has a better effect on LDL-C and apoprotein B than statin – fibrate combinations , but a lesser effect on HDL-C , TG and in the case of ciprofibrate combinations , fibrinogen . The clinical significance of these findings should be tested in a large , long-term survival study
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 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 .