Cost-effectiveness of gemfibrozil for coronary heart disease patients with low levels of high-density lipoprotein cholesterol: the Department of Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial. CETP inhibitors boost 'good' cholesterol to no avail Should both HDL-C and LDL-C be targets for lipid therapy? A review of current evidence. 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. Phase 3 trials suggest ways to improve current hematologic cancer therapies. Comprehensive cardiac rehabilitation improves the control of dyslipidemia in secondary prevention. Comparison of effects of simvastatin alone versus fenofibrate alone versus simvastatin plus fenofibrate on lipoprotein subparticle profiles in diabetic patients with mixed dyslipidemia (from the Diabetes and Combined Lipid Therapy Regimen study). Effects of atorvastatin versus fenofibrate on lipoprotein profiles, low-density lipoprotein subfraction distribution, and hemorheologic parameters in type 2 diabetes mellitus with mixed hyperlipoproteinemia. Evacetrapib and Cardiovascular Outcomes in High‐Risk Vascular Disease Canadian Cardiovascular Society position statement--recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease. Randomized Evaluation of the Effects of Anacetrapib through Lipid-modification (REVEAL)—A large-scale, randomized, placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease: Trial design, recruitment, and baseline characteristics Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Rationale and design of the Department of Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (HIT) for secondary prevention of coronary artery disease in men with low high-density lipoprotein cholesterol and desirable low-density lipoprotein cholesterol. Influence of Low High-Density Lipoprotein Cholesterol and Elevated Triglyceride on Coronary Heart Disease Events and Response to Simvastatin Therapy in 4S Baseline characteristics of patients participating in the Bezafibrate Infarction Prevention (BIP) Study. A Randomized Trial of a Strategy for Increasing High-Density Lipoprotein Cholesterol Levels: Effects on Progression of Coronary Heart Disease and Clinical Events Effects of initial BMI and on-treatment weight change on the lipid-lowering efficacy of fibrates 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. Joint Effects of Serum Triglyceride and LDL Cholesterol and HDL Cholesterol Concentrations on Coronary Heart Disease Risk in the Helsinki Heart Study: Implications for Treatment Lipids, Apolipoproteins, and Their Ratios in Relation to Cardiovascular Events With Statin Treatment Safety and efficacy of ezetimibe added to atorvastatin versus up titration of atorvastatin to 40 mg in Patients > or = 65 years of age (from the ZETia in the ELDerly [ZETELD] study). Gemfibrozil for secondary prevention of cardiovascular events in mild to moderate chronic renal insufficiency. Comparative effects of cerivastatin and fenofibrate on the atherogenic lipoprotein phenotype in proteinuric renal disease.
BACKGROUND Although numerous clinical trials and economic analyses have established the efficacy and cost-effectiveness of lowering cholesterol for the prevention of coronary heart disease , there are few data on the role of raising high-density lipoprotein cholesterol ( HDL-C ) levels and lowering triglyceride levels . The US Department of Veterans Affairs ( VA ) Cooperative Studies Program HDL-C Intervention Trial ( VA-HIT ) was a multicenter , r and omized trial of gemfibrozil , an agent that raised HDL-C levels and lowered triglyceride levels , yet had no effect on low-density lipoprotein cholesterol ( LDL-C ) levels . The study showed that gemfibrozil therapy significantly reduced major cardiovascular events ( cardiovascular death , myocardial infa rct ion , and stroke ) in patients with coronary heart disease , low HDL-C levels , and low LDL-C levels . OBJECTIVE To report the results of a cost-effectiveness study based on the results of the VA-HIT . METHODS The cost per year of life gained with gemfibrozil therapy was calculated . Hazard functions were estimated , and the result ing probabilities were used in a Markov model simulation to estimate the effect of gemfibrozil on life expectancy and costs over a simulated lifetime . Sensitivity analyses were used to account for uncertainty . RESULTS Using the prices of gemfibrozil that were negotiated by the VA , gemfibrozil was cost saving . Using drug prices found outside the VA , a quality -adjusted life-year saved by gemfibrozil therapy cost between $ 6300 and $ 17 100 . CONCLUSIONS Gemfibrozil reduces major cardiovascular events in male coronary heart disease patients with low levels of HDL-C and low levels of LDL-C and would result in cost saving at annual drug costs of $ 100 or less in 1998 dollars . Even at the higher drug prices represented by the average wholesale price in the United States , the cost of a life-year saved is well below the threshold that would be deemed cost-effective . To our knowledge , this is the first economic analysis based on clinical trial data to assess the cost-effectiveness of raising HDL-C levels and lowering triglyceride levels in a setting in which LDL-C levels were not lowered 5 ( Arteriosclerosis 8 , 737–741 , 1988 ) . Animal data appeared to support the concept as well — mice and rats are naturally deficient in CETP and do not develop atherosclerosis , whereas rabbits , which have high levels of CETP , appeared to benefit from inhibition . But , following failures in large-scale outcomes trials , drug developers have lost faith in the idea that raising HDL-c is beneficial . “ The goal posts have moved now , ” says Sekar Kathiresan , director of preventive cardiology at Massachusetts General Hospital , in Boston . “ I think there is some suggestive evidence , at least , from human genetics that the LDL-lowering properties of CETP might be protective , ” he says . “ That part of the hypothesis is still in play . ” Merck , of Kenilworth , New Jersey , is banking on this aspect of the mechanism in a mammoth outcomes trial , dubbed REVEAL ( R and omized Evaluation of the Effects of Anacetrapib Through Lipid-modification ) , which is recruiting 30,000 patients . “ They ’ve powered their study entirely for the LDLlowering effect , ” says Kathiresan . The scale of the trial is huge — in contrast , Lilly ’s trial of evacetrapib , called ACCELERATE ( Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes ) , recruited 12,000 patients . Not only will it improve Eli Lilly ’s decision to stop phase 3 studies of its cholesteryl ester transfer protein ( CETP ) inhibitor evacetrapib in patients with atherosclerotic cardiovascular disease adds another expensive , late-stage failure to a drug class that has confounded the pharma industry ’s expectations for a decade . This drug class was once bullishly pursued by big pharma originally because its effects on raising high-density lipoprotein cholesterol ( HDL-c ) were considered to be complementary to the effect of statins on lowering low density-lipoprotein cholesterol ( LDL-c ) . But Lilly ’s trial failure — the third major disappointment for this drug class — raises wider questions surrounding the utility of the CETP inhibitor class as a whole . If the CETP inhibitor class is to be ab and oned due to lack of efficacy , it will necessitate a revision of the LDL hypothesis , which holds that lowering LDL-c by any means is beneficial . CETP inhibitors raise cholesterol levels in high-density lipoprotein ( HDL ) and at the same time lower cholesterol in low-density lipoprotein ( LDL ) , by preventing the net transfer of cholesterol esters from HDL to LDL and other lipoprotein fractions . So far , at least , no CETP inhibitor has demonstrated in a largescale outcomes trial that these effects reduce the risk of death or major coronary events , such as heart attack or stroke . With Lilly ’s drug out of the running , Merck ’s drug anacetrapib , currently undergoing a large-scale outcomes trial , is now the lead molecule in the class ( Table 1 ) . Differences between the two study protocol s and between the two drug molecules may be sufficient to explain differing outcomes , but why Merck ’s drug may yet succeed where evacetrapib failed remains moot for now . CETP inhibition first emerged as a therapeutic concept on the back of observations in the Framingham heart study — and in other population -based studies —of an apparent inverse association between high levels of HDL-c and risk of death from cardiovascular disease CETP inhibitors boost ‘ good ’ cholesterol to no The current guidelines for treatment of high-risk of lipid disorders do not specify a therapeutic target level of high-density lipoprotein cholesterol ( HDL-C ) for prevention of vascular disease in high-risk population s. However , there is a substantial body of evidence from basic science and epidemiologic studies and from clinical trials , providing the strong , consistent message that raising HDL-C by therapeutic means will effectively and independently reduce cardiovascular risk . This review summarizes epidemiologic evidence and the results of a meta- analysis of 23 published , prospect i ve , r and omized , placebo-controlled clinical trials . It focuses on the effects of lipid therapies on coronary stenosis progression , as measured by quantitative arteriography and /or , on clinical cardiovascular endpoints . Among the seven drug/treatment classes into which individual study results were categorized and averaged , reduction in stenosis progression and reduction in clinical events are both very highly correlated with the composite lipid variable ( % ΔHDL-C - % Δ low-density lipoprotein cholesterol [ LDL-C ] ; where % Δ is percent change relative to the placebo group response ) . This holds true for all lipid drug classes or combinations of lipid drug therapy , with the exception of the unexpectedly anomalous effects of the torcetrapib-atorvastatin combination . There is a strong and consistent body of evidence that therapeutic HDL-C-raising is at least as effective as comparable percentages of LDL-C-lowering for reduction of atherosclerosis progression or clinical cardiovascular events over a broad range of risk levels . Adoption of this strategy into guidelines probably awaits results of at least one large controlled HDL-C-raising clinical trial , of which two are ongoing and one other is planned 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 be determined . That may change by early in the next decade , when results are expected from 3 large trials of combination therapies . Brown is leading the Niacin Plus Statin to Prevent Vascular Events ( AIM HIGH ) trial , r and omizing 6600 patients with established vascular disease and atherogenic dyslipidemia to either simvastatin or an extendedrelease combination therapy of niacin and simvastatin . These patients will be followed up for a median of 4 years to see if the combination therapy delays the time to a first major cardiovascular disease event . Another trial is the HPS2-THRIVE ( Treatment of HDL to Reduce the Incidence of Vascular Events ) study of 20 000 patients in the United Kingdom , China , and Sc and inavia to determine if combining niacin with a new drug ( MK-0524A ) that minimizes flushing can reduce cardiovascular disease risk in patients already effectively treating their low-density lipoprotein cholesterol ( LDL-C ) levels . The study is sponsored by Merck & Co Inc ( Whitehouse Station , NJ ) . The third study is an arm of the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial . A portion of the 10 251 study participants with type 2 diabetes mellitus are being followed up to determine if , in the context of good glycemic control , raising HDL-C and lowering triglyceride and LDL-C levels with a combination of a fibrate and a statin reduces the rate of cardiovascular events compared with statin therapy only for treatment of BACKGROUND Secondary prevention is an important goal of cardiac rehabilitation in patients with coronary heart disease ( CHD ) . Dyslipidemia is one of the major risk factors that is important to control to reduce the incidence of future ischemic coronary events . The aim of the present study was to assess whether control of dyslipidemia , in secondary prevention , could be improved by a comprehensive cardiac rehabilitation program . METHODS Fifty-two newly diagnosed hyperlipidemic men , who had experienced a recent CHD event , were separated in two equal groups of 26 patients : group CR+ , in which patients were included in a 2-month cardiac rehabilitation program including an extensive educational program on cardiovascular risk factors , lipids , and diet , and group CR-without any cardiac rehabilitation . Mean age , body mass index , initial levels of total cholesterol , triglycerides , high-density lipoprotein ( HDL ) cholesterol , low-density lipoprotein ( LDL ) cholesterol , and LDL/HDL ratio were not significantly different between the 2 groups . In both groups , each patient was referred to a dietitian and to the same lipidologist to start an appropriate hypolipidemic treatment . Treatment of coronary event , type of hyperlipidemia , and hypolipidemic treatment were not different between the two groups . RESULTS Lipid measurements , performed 3 months after the beginning of the hypolipidemic treatment , showed that patients from the CR+ group , compared with those from the CR-group , had a significantly greater reduction of total cholesterol ( 23 % versus 13 % ; P < 0.001 ) , of LDL cholesterol ( 28 % versus 12 % ; P < 0.001 ) , of LDL/HDL ratio ( 34 % versus 13 % ; P < 0.01 ) and of triglycerides ( 33 % versus 21 % ; P = 0.05 ) . CONCLUSIONS Patients with CHD included in a comprehensive cardiac rehabilitation program showed a significantly better response to the hypolipidemic treatment than patients without cardiac rehabilitation . These results could be attributable to the extensive educational program on secondary prevention performed during cardiac rehabilitation , leading to optimized knowledge on lipid-lowering diet and to improved diet and drug adherence . A secondary prevention educational program must be an important part of any comprehensive cardiac rehabilitation program in patients with CHD Diabetes mellitus is a strong risk factor for atherosclerosis and is often characterized by dyslipidemia . Besides acting on traditional lipids , statins and fibrates may also exert beneficial effects on various pro- and antiatherogenic lipid subparticles . This analysis was undertaken to evaluate combination therapy on lipid subparticles in the Diabetes and Combined Lipid Therapy Regimen ( DIACOR ) study . Patients with type 2 diabetes mellitus and no histories of coronary heart disease were evaluated ( n = 498 ) . Eligible patients underwent a 6- to 8-week washout period of all lipid-lowering medications  and were enrolled if they demonstrated mixed dyslipidemia ( having > or=2 of the following 3 lipid parameters : low-density lipoprotein [ LDL ] cholesterol > or=100 mg/dl , triglycerides > or=200 mg/dl , and high-density lipoprotein cholesterol < 40 mg/dl ) . Patients were r and omized to simvastatin 20 mg , fenofibrate 160 mg , or combined simvastatin 20 mg and fenofibrate 160 mg . Lipid subparticles were assessed 12 weeks after r and omization by the Vertical Auto Profile II method . A total of 300 patients ( mean age 61.6 + /- 11.5 years , 55 % men ) were r and omized . Combination therapy was superior in lowering LDL cholesterol pattern B ( -33.9 mg/dl ) and dense very low-density lipoprotein cholesterol ( -10.0 mg/dl ) and increasing high-density lipoprotein3 ( + 2.3 mg/dl ) and exerted the greatest change in altering the LDL cholesterol size profile . A potential effect on lipoprotein(a ) ( -0.5 mg/dl ) was also found . For those with triglycerides > 170 mg/dl , combination therapy was superior in lowering dense very low density lipoprotein cholesterol ( -10.7 mg/dl ) and LDL cholesterol pattern B ( -35.8 mg/dl ) , the lipids that tend to be formed in the presence of elevated triglycerides . In conclusion , in this trial of mixed dyslipidemic patients with diabetes , combination therapy was more effective in changing a variety of other cardiovascular risk markers Diabetic dyslipoproteinemia characterized by hypertriglyceridemia , low high-density lipoprotein ( HDL ) cholesterol , and often elevated low-density lipoprotein ( LDL ) cholesterol with predominance of small , dense LDL is a strong risk factor for atherosclerosis . It is unclear whether fibrate or statin therapy is more effective in these patients . We compared atorvastatin ( 10 mg/day ) with fenofibrate ( 200 mg/day ) , each for 6 weeks separated by a 6-week washout period in 13 patients ( 5 men and 8 women ; mean age 60.0+/-6.8 years ; body mass index 30.0+/-3.0 kg/m2 ) with type 2 diabetes mellitus ( hemoglobin A1c 7.3+/-1.1 % ) and mixed hyperlipoproteinemia ( LDL cholesterol 164.0+/-37.8 mg/dl , triglycerides 259.7+/-107 mg/dl , HDL cholesterol 48.7+/-11.0 mg/dl ) using a r and omized , crossover design . Lipid profiles , LDL subfraction distribution , fasting plasma viscosity , red cell aggregation , and fibrinogen concentrations were determined before and after each drug . Atorvastatin decreased all LDL subfractions ( LDL cholesterol , -29 % ; p < 0.01 ) including small , dense LDL .  Fenofibrate predominantly decreased triglyceride concentrations ( triglycerides , -39 % ; p < 0.005 ) and induced a shift in LDL subtype distribution from small , dense LDL ( -31 % ) to intermediate-dense LDL ( + 36 % ) . The concentration of small , dense LDL was comparable during therapy to both drugs ( atorvastatin 62.8+/-19.5 mg/dl , fenofibrate 63.0+/-18.1 mg/dl ) . Both drugs induced an increase in HDL cholesterol  ( atorvastatin + 10 % , p < 0.05 ; fenofibrate + 11 % , p = 0.06 ) . In addition , fenofibrate decreased fibrinogen concentration ( -15 % , p < 0.01 ) associated with a decrease in plasma viscosity by 3 % ( p < 0.01 ) and improved red cell aggregation by 15 % ( p < 0.05 ) , whereas atorvastatin did not affect any hemorheologic parameter . We conclude that atorvastatin and fenofibrate can improve lipoprotein metabolism in type 2 diabetes . However , the medications affect different aspects of lipoprotein metabolism BACKGROUND The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high‐density lipoprotein ( HDL ) cholesterol level , reduces the low‐density lipoprotein ( LDL ) cholesterol level , and enhances cellular cholesterol efflux capacity . We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high‐risk vascular disease . METHODS In a multicenter , r and omized , double‐blind , placebo‐controlled phase 3 trial , we enrolled 12,092 patients who had at least one of the following conditions : an acute coronary syndrome within the previous 30 to 365 days , cerebrovascular atherosclerotic disease , peripheral vascular arterial disease , or diabetes mellitus with coronary artery disease . Patients were r and omly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo , administered daily , in addition to st and ard medical therapy . The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes , myocardial infa rct ion , stroke , coronary revascularization , or hospitalization for unstable angina . RESULTS At 3 months , a 31.1 % decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0 % increase with placebo , and a 133.2 % increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6 % increase with placebo . After 1363 of the planned 1670 primary end‐point events had occurred , the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy . After a median of 26 months of evacetrapib or placebo , a primary end‐point event occurred in 12.9 % of the patients in the evacetrapib group and in 12.8 % of those in the placebo group ( hazard ratio , 1.01 ; 95 % confidence interval , 0.91 to 1.11 ; P=0.91 ) . CONCLUSIONS Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers , treatment with evacetrapib did not result in a lower rate of cardiovascular events  than placebo among patients with high‐risk vascular disease . ( Funded by Eli Lilly ; ACCELERATE Clinical Trials.gov number , NCT01687998 . Since the last publication of the recommendations for the management and treatment of dyslipidemia , new clinical trial data have emerged that support a more vigorous approach to lipid lowering in specific patient groups . The decision was made to up date the lipid guidelines in collaboration with the Canadian Cardiovascular Society . A systematic electronic search of medical literature for original research consisting of blinded , r and omized controlled trials was performed . Meta-analyses of studies of the efficacy and safety of lipid-lowering therapies , and of the predictive value of established and emerging risk factors were also review ed . All recommendations are evidence -based , and have been review ed in detail by primary and secondary review panels . Major changes include a lower low-density lipoprotein cholesterol ( LDL-C ) treatment target ( lower than 2.0 mmol/L ) for high-risk patients , a slightly higher intervention point for the initiation of drug therapy in most low-risk individuals ( LDL-C of 5.0 mmol/L or a total cholesterol to high-density lipoprotein cholesterol ratio of 6.0 ) and recommendations regarding additional investigations of potential use in the further evaluation of coronary artery disease risk in subjects in the moderate-risk category Background Patients with prior vascular disease remain at high risk for cardiovascular events despite intensive statin – based treatment . Inhibition of cholesteryl ester transfer protein by anacetrapib reduces low‐density lipoprotein ( LDL ) cholesterol by around 25 % to 40 % and more than doubles high‐density lipoprotein ( HDL ) cholesterol . However , it is not known if these apparently favorable lipid changes translate into reductions in cardiovascular events . Methods The REVEAL study is a r and omized , double‐blind , placebo‐controlled clinical trial that is assessing the efficacy and safety of adding anacetrapib to effective LDL‐lowering treatment with atorvastatin for an average of at least 4 years among patients with preexisting atherosclerotic vascular disease . The primary assessment is an intention‐to‐treat comparison among all r and omized participants of the effects of allocation to anacetrapib on major coronary events ( defined as the occurrence of coronary death , myocardial infa rct ion , or coronary revascularization ) . Results Between August 2011 and October 2013 , 30,449 individuals in Europe , North America , and China were r and omized to receive anacetrapib 100 mg daily or matching placebo .  Mean ( SD ) age was 67 ( 8) years , 84 % were male , 88 % had a history of coronary heart disease , 22 % had cerebrovascular disease , and 37 % had diabetes mellitus . At the r and omization visit ( after at least 8 weeks on a protocol ‐defined atorvastatin regimen ) , mean plasma LDL cholesterol was 61 ( 15 ) mg/dL and HDL cholesterol was 40 ( 10 ) mg/dL. Interpretation The REVEAL trial will provide a robust evaluation of the clinical efficacy and safety of adding anacetrapib to an effective statin regimen . Results are anticipated in 2017 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 Although a large body of epidemiologic evidence suggests that low levels of high-density lipoprotein ( HDL ) cholesterol are strongly associated with an increased risk of coronary artery disease ( CAD ) , no large-scale clinical trials focusing on this association have been reported . This report describes the rationale and design of the Department of Veterans Affairs HDL Intervention Trial ( HIT ) , a multicenter , r and omized , controlled clinical trial design ed to determine whether lipid therapy reduces the combined incidence of CAD death and nonfatal myocardial infa rct ion in men with established CAD who have low levels of HDL cholesterol with " desirable " levels of low-density lipoprotein ( LDL ) cholesterol . Twenty-five hundred men with CAD and HDL cholesterol < or = 40 mg/dl , LDL cholesterol < or = 140 mg/dl , and triglycerides < or = 300 mg/dl are being recruited at 20 Department of Veterans Affairs medical centers , r and omized to either gemfibrozil or placebo  , and followed in a double-blind manner for an average of 6 years . In this population , gemfibrozil is expected to increase HDL cholesterol by 10 to 15 % , have a negligible effect on LDL cholesterol , and lower triglycerides by 30 to 40 % . Because an estimated 20 to 30 % of patients with CAD have a low HDL cholesterol as their primary lipid abnormality , the results of this trial are expected to have far-reaching clinical implication Background — Patients with low HDL cholesterol ( HDL-C ) and elevated triglyceride had an increased  risk for coronary heart disease ( CHD ) events and received the greatest benefit with fibrate therapy in sub study analyses of the Helsinki Heart Study and the Bezafibrate Infa rct ion Prevention Study . Methods and Results —In this post hoc analysis of the Sc and inavian Simvastatin Survival Study , which enrolled patients with elevated LDL cholesterol ( LDL-C ) and CHD , subgroups defined by HDL-C and triglyceride quartiles were compared to examine the influence of HDL-C and triglyceride on CHD events and response to therapy . Patients in the lowest HDL-C ( < 1.00 mmol/L [ 39 mg/dL ] ) and highest triglyceride ( > 1.80 mmol/L [ 159 mg/dL ] ) quartiles ( lipid triad ; n=458 ) had increased proportions of other features of the metabolic syndrome ( increased body mass index , hypertension , diabetes ) , men , prior myocardial infa rct ion , prior revascularization , and & bgr;-blocker use than patients in the highest HDL-C ( > 1.34 mmol/L [ 52 mg/dL ] ) and lowest triglyceride ( < 1.11 mmol/L [ 98 mg/dL ] ) quartiles ( isolated LDL-C elevation ; n=545 ) . The major coronary event rate was highest in lipid triad patients on placebo ( 35.9 % ) , and this subgroup had the greatest event reduction ( relative risk 0.48 , 95 % CI 0.33 to 0.69 ) ; a significant treatment-by-subgroup interaction ( P = 0.03 ) indicated a greater treatment effect in the lipid triad subgroup than the isolated LDL-C elevation subgroup . Conclusions — Patients with elevated LDL-C , low HDL-C , and elevated triglycerides  were more likely than patients with isolated LDL-C elevation to have other characteristics of the metabolic syndrome , had increased risk for CHD events on placebo , and received greater benefit with simvastatin therapy 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 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 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 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 We studied the joint effect of baseline triglyceride and lipoprotein cholesterol levels on the incidence of cardiac end points in the trial group ( n = 4,081 ) of the Helsinki Heart Study , a 5-year r and omized coronary primary prevention trial among dyslipidemic middle-aged men . The relative risks ( RR ) were calculated using Cox proportional hazards models with a dummy variable technique that allows simultaneous study of subgroup combinations from the placebo and treatment groups . Methods and Results In the  placebo group ( n = 2,045 ) , the low density lipoprotein cholesterol (LDL-C)/high density lipoprotein cholesterol ( HDL-C ) ratio was the best single predictor of cardiac events . This ratio in combination with the serum triglyceride level revealed a high-risk subgroup : subjects with LDL-C/HDL-C ratio > 5 and triglycerides > 2.3 mmol/1 had a RR of 3.8 ( 95 % CI , 2.2 - 6.6 ) compared with those with LDL-C/HI)L-C ratio ≤5 and triglyceride concentration ≤2.3 mmol/1 . In subjects with triglyceride concentration > 2.3 mmol/l and LDL-C/H1)L-C ratio ≤5 , RR was close to unity ( 1.1 ) , whereas in those with triglyceride level ≤2.3 mmoVIl and LDL-C/HDL-C ratio > 5 , RR was 1.2 . The high-risk group with LDL-C/HDL-C ratio > 5 and triglyceride level > 2.3 mmol/1 profited most from treatment with gemfibrozil , with a 71 % lower incidence of coronary heart disease events than the corresponding placebo subgroup . In all other subgroups , the reduction in CHD incidence was substantially smaller Conclusions Serum triglyceride concentration has prognostic value , both for assessing coronary heart disease risk and in predicting the effect of gemfibrozil treatment , especially when used in combination with HDL-C and Background — Low-density lipoprotein ( LDL ) cholesterol is the principal target of lipid-lowering therapy , but recent evidence has suggested more appropriate targets . We compared the relationships of on-treatment levels of LDL cholesterol , non – high-density lipoprotein ( HDL ) cholesterol , and apolipoprotein B , as well as ratios of total/HDL cholesterol , LDL/HDL cholesterol , and apolipoprotein B/A-I , with the occurrence of cardiovascular events in patients receiving statin therapy .  Methods and Results — A post hoc analysis was performed that combined data from 2 prospect i ve , r and omized clinical trials in which 10 001 ( “ Treating to New Targets ” ) and 8888 ( “ Incremental Decrease in End Points through Aggressive Lipid Lowering ” ) patients with established coronary heart disease were assigned to usual-dose or high-dose statin treatment . In models with LDL cholesterol , non-HDL cholesterol and apolipoprotein B were positively associated with cardiovascular outcome , whereas a positive relationship with LDL cholesterol was lost . In a model that contained non-HDL cholesterol and apolipoprotein B , neither was significant owing to collinearity . Total/HDL cholesterol ratio and the apolipoprotein B/A-I ratio in particular were each more closely associated with outcome than any of the individual proatherogenic lipoprotein parameters . Conclusions — In patients receiving statin therapy  , on-treatment levels of non-HDL cholesterol and apolipoprotein B were more closely associated with cardiovascular outcome than levels of LDL cholesterol . Inclusion of measurements of the antiatherogenic lipoprotein fraction further strengthened the relationships . These data support the use of non-HDL cholesterol or apolipoprotein B as novel treatment targets for statin therapy . Given the absence of interventions that have been proven to consistently reduce cardiovascular disease risk through raising plasma levels of HDL cholesterol or apolipoprotein A-I , it seems premature to consider the ratio variables as clinical ly useful Few clinical studies have focused on the efficacy of lipid-lowering therapies  in patients > or = 65 years of age . The percentage of change from baseline in low-density lipoprotein ( LDL ) cholesterol and the percentage of patients achieving prespecified LDL cholesterol levels after 12 weeks of ezetimibe 10 mg plus atorvastatin versus up titration of atorvastatin were assessed in subjects > or = 65 years old with hyperlipidemia and at high risk of coronary heart disease . After stabilization of atorvastatin 10-mg therapy , 1,053 patients , > or = 65 years old , at high risk of coronary heart disease , with and without atherosclerotic vascular disease and a LDL cholesterol level that was not < 70 or < 100 mg/dl , respectively , were r and omized to receive ezetimibe added to atorvastatin 10 mg for 12 weeks versus up titration to atorvastatin 20 mg for 6 weeks followed by up titration to atorvastatin 40 mg for an additional 6 weeks . Ezetimibe added to atorvastatin 10 mg result ed in significantly greater changes at week 6 in LDL cholesterol ( p < 0.001 ) , significantly more patients with atherosclerotic vascular disease achieving a LDL cholesterol level of < 70 mg/dl ( p < 0.001 ) , and significantly more patients without atherosclerotic vascular disease achieving a LDL cholesterol level of < 100 mg/dl ( p < 0.001 ) at weeks 6 and 12 compared to atorvastatin 20 mg or atorvastatin 40 mg . In addition , ezetimibe plus atorvastatin 10 mg result ed in significantly greater changes at week 6 in total cholesterol , triglycerides , non-high-density lipoprotein ( HDL ) cholesterol , apolipoprotein B ( all p < 0.001 ) , and HDL cholesterol ( p = 0.021 ) compared with atorvastatin 20 mg and significantly greater changes at week 12 in LDL cholesterol , non-HDL cholesterol , apolipoprotein A-I ( p = 0.001 ) , total cholesterol , apolipoprotein B ( p < 0.030 ) , and HDL cholesterol ( p < 0.001 ) compared with atorvastatin 40 mg . Both treatments were generally well tolerated , with comparable safety profiles . In conclusion , adding ezetimibe to atorvastatin 10 mg produced significantly greater favorable changes in most lipids at 6 and 12 weeks and significantly greater attainment of prespecified LDL cholesterol levels than doubling or quadrupling the atorvastatin dose in patients > or = 65 years old at high risk for coronary heart disease 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 Patients with nephrotic-range proteinuria have impaired clearance of triglyceride-rich lipoproteins . This results in the atherogenic lipoprotein phenotype ( mild hypertriglyceridemia , low high-density lipoproteins [ HDL ] , and excess small , dense low-density lipoproteins [ LDLIII ] ) . Excess remnant lipoproteins ( RLP ) are linked to hypertriglyceridemia and may contribute to the atherogenicity of nephrotic dyslipidemia . A r and omized crossover study compared the effects of a statin ( cerivastatin ) and a fibrate ( fenofibrate ) on LDLIII and RLP in 12 patients with nephrotic-range proteinuria .  Cerivastatin reduced cholesterol ( 21 % , P : < 0.01 ) , triglyceride ( 14 % , P : < 0.05 ) , LDL cholesterol ( LDL-C ; 23 % , P : < 0.01 ) , total LDL ( 18 % , P : < 0.01 ) , and LDLIII concentration ( 27 % P : < 0.01 ) . % LDLIII , RLP-C , and RLP triglyceride ( RLP-TG ) were unchanged . Plasma LDLIII reduction with cerivastatin treatment correlated with LDL-C reduction ( r(2 ) = 34 % , P : < 0.05 ) . Fenofibrate lowered cholesterol ( 19 % ) , triglyceride ( 41 % ) , very low-density lipoprotein cholesterol ( 52 % ) , LDLIII concentration ( 49 % ) , RLP-C ( 35 % ) , and RLP-TG ( 44 % ; all P : < 0.01 ) . Fenofibrate also reduced % LDLIII from 60 to 33 % ( P : < 0.01 ) . HDL-C ( 19 % , P : < 0.01 ) increased with fenofibrate treatment ; LDL-C and total LDL were unchanged . The reduction in LDLIII concentration and RLP-C with fenofibrate treatment correlated with plasma triglyceride reduction ( LDLIII r(2 ) = 67 % , P : < 0.001 ; RLP cholesterol r(2 ) = 58 % , P : < 0.005 ) . Serum creatinine increased with fenofibrate treatment ( 14 % , P : < 0.01 ) ; however , creatinine clearance was unchanged . LDLIII concentration was 187 + /- 85 mg/dl after cerivastatin treatment and 133 + /- 95 mg/dl after fenofibrate treatment . Cerivastatin and fenofibrate reduce LDLIII concentration in nephrotic-range proteinuria . However , atherogenic concentrations of LDLIII remain prevalent after either treatment . Fenofibrate but not cerivastatin reduces remnant lipoproteins . The two treatments seem to reduce LDLIII by different mechanisms , suggesting a potential role for combination therapy to optimize lowering of LDLIII and RLP
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 .