title: High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Effects of dalcetrapib in patients with a recent acute coronary syndrome. Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease Trial of Clofibrate in the Treatment of Ischaemic Heart Disease: FIVE-YEAR STUDY BY A GROUP OF PHYSICIANS OF THE NEWCASTLE UPON TYNE REGION* Bezafibrate in men with lower extremity arterial disease: randomised controlled trial Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Lipid-altering efficacy and safety of ezetimibe/simvastatin coadministered with extended-release niacin in patients with type IIa or type IIb hyperlipidemia. Cardiovascular Outcomes in Type 2 Diabetes: A double-blind placebo-controlled study of bezafibrate: the St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study The Treatment of Cerebrovascular Disease With Clofibrate: Final Report of the Veterans Administration Cooperative Study of Atherosclerosis, Neurology Section Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. Effects of combination lipid therapy in type 2 diabetes mellitus. Diabetes Intervention Study: Multi-Intervention Trial in Newly Diagnosed NIDDM Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study Effects of extended-release niacin with laropiprant in high-risk patients. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Report from the Committee of Principal Investigators. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. 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. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.
abstract: The British Regional Heart Study ( BRHS ) reported in 1986 that much of the inverse relation of high-density lipoprotein cholesterol ( HDLC ) and incidence of coronary heart disease was eliminated by covariance adjustment . Using the proportional hazards model and adjusting for age , blood pressure , smoking , body mass index , and low-density lipoprotein cholesterol , we analyzed this relation separately in the Framingham Heart Study ( FHS ) , Lipid Research Clinics Prevalence Mortality Follow-up Study ( LRCF ) and Coronary Primary Prevention Trial ( CPPT ) , and Multiple Risk Factor Intervention Trial ( MRFIT ) . In CPPT and MRFIT ( both r and omized trials in middle-age high-risk men ) , only the control groups were analyzed . A 1-mg/dl ( 0.026 mM ) increment in HDLC was associated with a significant coronary heart disease risk decrement of 2 % in men ( FHS , CPPT , and MRFIT ) and 3 % in women ( FHS ) . In LRCF , where only fatal outcomes were documented , a 1-mg/dl increment in HDLC was associated with significant 3.7 % ( men ) and 4.7 % ( women ) decrements in cardiovascular disease mortality rates . The 95 % confidence intervals for these decrements in coronary heart and cardiovascular disease risk in the four studies overlapped considerably , and all contained the range 1.9 - 2.9 % . HDLC levels were essentially unrelated to non-cardiovascular disease mortality . When differences in analytic methodology were eliminated , a consistent inverse relation of HDLC levels and coronary heart disease event rates was apparent in BRHS as well as in the four American studies BACKGROUND In observational analyses , higher levels of high-density lipoprotein ( HDL ) cholesterol have been associated with a lower risk of coronary heart disease events . However , whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain . Inhibition of cholesteryl ester transfer protein ( CETP ) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes . METHODS We r and omly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib  , at a dose of 600 mg daily , or placebo , in addition to the best available evidence -based care . The primary efficacy end point was a composite of death from coronary heart disease , nonfatal myocardial infa rct ion , ischemic stroke , unstable angina , or cardiac arrest with resuscitation . RESULTS At the time of r and omization , the mean HDL cholesterol level was 42 mg per deciliter ( 1.1 mmol per liter ) , and the mean low-density lipoprotein ( LDL ) cholesterol level was 76 mg per deciliter ( 2.0 mmol per liter ) . Over the course of the trial , HDL cholesterol levels increased from baseline by 4 to 11 % in the placebo group and by 31 to 40 % in the dalcetrapib group . Dalcetrapib had a minimal effect on LDL cholesterol levels . Patients were followed for a median of 31 months . At a prespecified interim analysis that included 1135 primary end-point events ( 71 % of the projected total number ) , the independent data and safety monitoring board recommended termination of the trial for futility . As compared with placebo , dalcetrapib did not alter the risk of the primary end point ( cumulative event rate , 8.0 % and 8.3 % , respectively ; hazard ratio with dalcetrapib , 1.04 ; 95 % confidence interval , 0.93 to 1.16 ; P=0.52 ) and did not have a significant effect on any component of the primary end point or total mortality . The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo ( P<0.001 for both comparisons ) . CONCLUSIONS In patients who had had a recent acute coronary syndrome , dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events . ( Funded by F. Hoffmann-La Roche ; dal- OUTCOMES Clinical Trials.gov number , NCT00658515 . ) BACKGROUND Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin‐based treatment of low‐density lipoprotein ( LDL ) cholesterol levels . The inhibition of cholesteryl ester transfer protein ( CETP ) by anacetrapib reduces LDL cholesterol levels and increases high‐density lipoprotein ( HDL ) cholesterol levels . However , trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes . METHODS We conducted a r and omized , double‐blind , placebo‐controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter ( 1.58 mmol per liter ) , a mean non‐HDL cholesterol level of 92 mg per deciliter ( 2.38 mmol per liter ) , and a mean HDL cholesterol level of 40 mg per deciliter ( 1.03 mmol per liter ) . The patients were assigned to receive either 100 mg of anacetrapib once daily ( 15,225 patients ) or matching placebo ( 15,224 patients ) . The primary outcome was the first major coronary event , a composite of coronary death , myocardial infa rct ion , or coronary revascularization . RESULTS During the median follow‐up period of 4.1 years , the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group ( 1640 of 15,225 patients [ 10.8 % ] vs. 1803 of 15,224 patients [ 11.8 % ] ; rate ratio , 0.91 ; 95 % confidence interval , 0.85 to 0.97 ; P=0.004 ) . The relative difference in risk was similar across multiple prespecified subgroups . At the trial midpoint , the mean level of HDL cholesterol was higher by 43 mg per deciliter ( 1.12 mmol per liter ) in the anacetrapib group than in the placebo group ( a relative difference of 104 % ) , and the mean level of non‐HDL cholesterol was lower by 17 mg per deciliter ( 0.44 mmol per liter ) , a relative difference of ‐18 % . There were no significant between‐group differences in the risk of death , cancer , or other serious adverse events . CONCLUSIONS Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy , the use of anacetrapib result ed in a lower incidence of major coronary events than the use of placebo . ( Funded by Merck and others ; Current Controlled Trials number , IS RCT N48678192 ; Clinical Trials.gov number , NCT01252953 ; and EudraCT number , 2010‐023467‐18 . In a double-blind clinical trial of clofibrate versus identical quantity of corn oil 497 patients with ischaemic heart disease were observed over a period of five years . The death rate and the rate of non-fatal infa rcts were significantly less among the clofibrate group , and the difference was greatest in respect of sudden deaths and among patients who had previously suffered from angina rather than infa rct ion . The cholesterol- and triglyceride-reducing properties of clofibrate were maintained throughout the period of the trial and side effects were very few . But the protective action of the drug against new infa rcts and death bore no apparent relation to these properties Objective : To assess the effect of bezafibrate on the risk of coronary heart disease and stroke in men with lower extremity arterial disease . Design : Double blind placebo controlled r and omised trial . Setting : 85 general practice s and nine hospital vascular clinics . Participants : 1568 men , mean age 68.2 years ( range 35 to 92 ) at recruitment . Interventions : Bezafibrate 400 mg daily ( 783 men ) or placebo ( 785 men ) . Main outcome measures : Combination of coronary heart disease and of stroke . All coronary events , fatal and non-fatal coronary events separately , and strokes alone ( secondary end points ) . Results : Bezafibrate did not reduce the incidence of coronary heart disease and stroke . There were 150 and 160 events in the active and placebo groups respectively ( relative risk 0.96 , 95 % confidence interval 0.76 to 1.21 ) . There were 90 and 111 major coronary events in the active and placebo groups respectively ( 0.81 , 0.60 to 1.08 ) , of which 64 and 65 were fatal ( 0.95 , 0.66 to 1.37 ) and 26 and 46 non-fatal ( 0.60 , 0.36 to 0.99 ) . Beneficial effects on non-fatal events were greatest in men aged < 65 years at entry , in whom benefit was also seen for all coronary events ( 0.38 , 0.20 to 0.72 ) . There were no significant effects in older men . There were 60 strokes in those on active treatment and 49 in those on placebo ( 1.34 , 0.80 to 2.01 ) . There were 204 and 195 deaths from all causes in the two groups respectively ( 1.03 , 0.83 to 1.26 ) . Bezafibrate reduced the severity of intermittent claudication for up to three years . Conclusions : Bezafibrate has no effect on the incidence of coronary heart disease and of stroke combined but may reduce the incidence of non-fatal coronary events , particularly in those aged < 65 years at entry , in whom all coronary events may also be reduced AIMS High-density lipoprotein cholesterol ( HDL-C ) is inversely associated with cardiovascular ( CV ) events and thus an attractive therapeutic target . However , in spite of marked elevations in HDL-C , the first cholesterol transport protein ( CETP ) inhibitor torcetrapib raised blood pressure ( BP ) , impaired endothelial function , and increased CV mortality and morbidity . Dalcetrapib is a novel molecule acting on CETP with a different chemical structure to torcetrapib . As HDL stimulates nitric oxide ( NO ) , suppresses inflammation , and exerts protective CV effects , we investigated the effects of dalcetrapib on endothelial function , blood pressure , inflammatory markers , and lipids in patients with , or at risk of , coronary heart disease ( CHD ) in a double-blind r and omized placebo-controlled trial ( clinical trials.gov number NCT00655538 ) . METHODS AND RESULTS Patients with target low-density lipoprotein cholesterol ( LDL-C ) levels received dalcetrapib 600 mg/day or placebo for 36 weeks on top of st and ard therapy ( including statins ) . The primary outcome measures were the change from baseline of flow-mediated dilatation ( % FMD ) of the right brachial artery after 5 min of cuff occlusion at 12 weeks and the 24 h ambulatory blood pressure monitoring ( ABPM ) at week 4 . Secondary outcomes included change from baseline in FMD after 36 weeks and the change in ABPM at 12 and 36 weeks , changes in HDL-C , LDL-C , triglycerides , CETP activity , as well as st and ard safety parameters . Four hundred seventy-six patients were r and omized . Baseline FMD was 4.1 ± 2.2 and 4.0 ± 2.4 % with placebo or dalcetrapib , respectively and did not change significantly from placebo after 12 and 36 weeks ( P = 0.1764 and 0.9515 , respectively ) . After 4 , 24 , and 36 weeks of treatment with dalcetrapib , CETP activity decreased by 51 , 53 , and 56 % ( placebo corrected , all P < 0.0001 ) , while at weeks 4 , 12 , and 36 HDL-C increased by 25 , 27 , and 31 % ( placebo corrected , all P < 0.0001 ) . Low-density lipoprotein cholesterol levels did not change . At baseline , ABPM was 125 ± 12/74 ± 8mmHg in the placebo and 128 ± 11/75 ± 7mmHg in the dalcetrapib group ( P = 0.3372 and 0.1248 , respectively , placebo-corrected change from baseline ) and did not change for up to 36 weeks . Biomarkers of inflammation , oxidative stress , and coagulation did not change during follow-up except for Lp-PLA(2 ) mass levels which increased by 17 % ( placebo corrected ) . Overall 7 patients given dalcetrapib and 8 patients given placebo experienced at least one pre-specified adjudicated event ( 11 events with dalcetrapib and 12 events with placebo ) . CONCLUSION The dal-VESSEL trial has established the tolerability and safety of CETP-inhibition with dalcetrapib in patients with or at risk of CHD . Dalcetrapib reduced CETP activity and increased HDL-C levels without affecting NO-dependent endothelial function , blood pressure , or markers of inflammation and oxidative stress . The dal- OUTCOMES trial ( NCT00658515 ) will show whether dalcetrapib improves outcomes in spite of a lack of effect on endothelial function Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more OBJECTIVES This study evaluated the safety and lipid-altering efficacy of ezetimibe/simvastatin ( E/S ) coadministered with extended-release niacin ( N ) in patients with type IIa or IIb hyperlipidemia . BACKGROUND Current guidelines recommend consideration of combination drug therapy to achieve optimal low-density lipoprotein cholesterol ( LDL-C ) lowering and broader lipid-altering effects when treating hypercholesterolemic patients at high risk for atherosclerotic cardiovascular events . METHODS In this 24-week multicenter , r and omized , double-blind study , 1,220 type IIa or IIb hyperlipidemic patients were r and omized to treatment with E/S ( 10/20 mg/day ) + N ( titrated to 2 g/day ) , or N ( titrated to 2 g/day ) , or E/S ( 10/20 mg/day ) . Changes from baseline in LDL-C ( primary ) and other secondary variables were assessed in the completers and modified intent-to-treat population s. RESULTS Coadministered E/S with N result ed in significantly greater reductions in LDL-C , non-high-density lipoprotein cholesterol , triglycerides , apolipoprotein B , and lipid/lipoprotein ratios , compared with either agent alone ( p < 0.001 ) . The combination increased levels of apolipoprotein A-I and high-density lipoprotein cholesterol significantly more than E/S ( p < 0.001 ) , and reduced high-sensitivity C-reactive protein levels significantly more than N ( p = 0.005 ) . A significantly greater percentage of patients discontinued the study in the N ( 25.0 % ) and N + E/S ( 23.3 % ) groups , compared with E/S ( 9.6 % , p < 0.001 ) because of clinical adverse experiences ( primarily flushing ) . Incidences of other clinical and laboratory adverse experiences ( liver- , muscle- , and gastrointestinal-related ) were similar for all groups . CONCLUSIONS Combination treatment with E/S plus N showed superior lipid-altering efficacy compared with N or E/S in type IIa or IIb hyperlipidemia patients and was generally well tolerated aside from N-associated flushing . This combination offers an effective , broad , lipid-altering therapy with improvements in lipid effects beyond LDL-C in these patients . ( To Evaluate Ezetimibe/Simvastatin and Niacin [ Extended Release Tablet ] in Patients With High Cholesterol OBJECTIVE To determine whether serum lipid intervention , in addition to conventional diabetes treatment , could alter cardiovascular outcomes in type 2 diabetes . RESEARCH DESIGN AND METHODS There were 164 type 2 diabetic subjects ( 117 men , 47 women ) without a history of clinical cardiovascular disease r and omized to receive either bezafibrate or placebo daily on a double-blind basis in addition to routine diabetes treatment and followed prospect ively for a minimum of 3 years . Serial biochemical and noninvasive vascular assessment s , carotid and femoral artery B-mode ultrasound measurements , and those pertaining to coronary heart disease (CHD)— clinical history , the World Health Organization ( WHO ) cardiovascular question naire , and resting and exercise electrocardiogram (ECG)—were recorded . RESULTS Bezafibrate treatment was associated with significantly greater reductions over 3 years in median serum triglyceride ( −32 vs. 4 % , P = 0.001 ) , total cholesterol ( −7 vs. −0.3 % , P = 0.004 ) , and total−to-HDL cholesterol ratio ( −12 vs. −0.0 % , P = 0.001 ) , and an increase in HDL cholesterol ( 6 vs. −2 % , P = 0.02 ) as compared with placebo . There was a trend toward a greater reduction of fibrinogen ( −18 vs. −6 % , P = 0.08 ) at 3 years . No significant differences between the two groups were found in the progress of ultrasonically measured arterial disease . In those treated with bezafibrate , there was a significant reduction ( P = 0.01 , log-rank test ) in the combined incidence of Minnesota-coded probable ischemic change on the resting ECG and of documented myocardial infa rct ion . CONCLUSIONS Improving dyslipidemia in type 2 diabetic subjects had no effect on the progress of ultrasonically measured arterial disease , although the lower rate of “ definite CHD events ” in the treated group suggests that this might result in a reduction in the incidence of coronary heart disease A cooperative study in 20 Veterans Administration hospitals investigated the effect of clofibrate on morbidity and mortality due to atherosclerotic vascular disease in men with either an established cerebral infa rct ion or transient cerebrovascular ischemic attacks ( TIA ) . Follow-up observations were made for up to 4.5 years in 532 patients assigned on a r and om basis to placebo medication or to treatment with 2 gm of clofibrate daily . Baseline and follow-up cholesterol and triglyceride levels were measured . Recurrence of cerebral infa rct ion was increased in patients receiving clofibrate as compared to controls . The incidence of new myocardial infa rct ion and new TIA was similar in both groups . Despite the more frequent strokes in treated patients , they had a decrease in mortality , partially explained by a lower death rate from these recurrences . There was no correlation between pretreatment lipid ( cholesterol and triglyceride ) values and the result of therapy . Use of clofibrate , however , was associated with a slight reduction of cholesterol and a sustained fall in triglyceride . These findings do not support recently published reports that clofibrate reduces the occurrence of myocardial ischemia ; however , the investigative design and type of data collected in these various studies are different and make it difficult to compare results BACKGROUND In patients with established cardiovascular disease , residual cardiovascular risk persists despite the achievement of target low-density lipoprotein ( LDL ) cholesterol levels with statin therapy . It is unclear whether extended-release niacin added to simvastatin to raise low levels of high-density lipoprotein ( HDL ) cholesterol is superior to simvastatin alone in reducing such residual risk . METHODS We r and omly assigned eligible patients to receive extended-release niacin , 1500 to 2000 mg per day , or matching placebo . All patients received simvastatin , 40 to 80 mg per day , plus ezetimibe , 10 mg per day , if needed , to maintain an LDL cholesterol level of 40 to 80 mg per deciliter ( 1.03 to 2.07 mmol per liter ) . The primary end point was the first event of the composite of death from coronary heart disease , nonfatal myocardial infa rct ion , ischemic stroke , hospitalization for an acute coronary syndrome , or symptom-driven coronary or cerebral revascularization . RESULTS A total of 3414 patients were r and omly assigned to receive niacin ( 1718 ) or placebo ( 1696 ) . The trial was stopped after a mean follow-up period of 3 years owing to a lack of efficacy . At 2 years , niacin therapy had significantly increased the median HDL cholesterol level from 35 mg per deciliter ( 0.91 mmol per liter ) to 42 mg per deciliter ( 1.08 mmol per liter ) , lowered the triglyceride level from 164 mg per deciliter ( 1.85 mmol per liter ) to 122 mg per deciliter ( 1.38 mmol per liter ) , and lowered the LDL cholesterol level from 74 mg per deciliter ( 1.91 mmol per liter ) to 62 mg per deciliter ( 1.60 mmol per liter ) . The primary end point occurred in 282 patients in the niacin group ( 16.4 % ) and in 274 patients in the placebo group ( 16.2 % ) ( hazard ratio , 1.02 ; 95 % confidence interval , 0.87 to 1.21 ; P=0.79 by the log-rank test ) . CONCLUSIONS Among patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of less than 70 mg per deciliter ( 1.81 mmol per liter ) , there was no incremental clinical benefit from the addition of niacin to statin therapy during a 36-month follow-up period , despite significant improvements in HDL cholesterol and triglyceride levels . ( Funded by the National Heart , Lung , and Blood Institute and Abbott Laboratories ; AIM -HIGH Clinical Trials.gov number , NCT00120289 . ) BACKGROUND We investigated whether combination therapy with a statin plus a fibrate , as compared with statin monotherapy , would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease . METHODS We r and omly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo .  The primary outcome was the first occurrence of nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes . The mean follow-up was 4.7 years . RESULTS The annual rate of the primary outcome was 2.2 % in the fenofibrate group and 2.4 % in the placebo group ( hazard ratio in the fenofibrate group , 0.92 ; 95 % confidence interval [ CI ] , 0.79 to 1.08 ; P=0.32 ) . There were also no significant differences between the two study groups with respect to any secondary outcome . Annual rates of death were 1.5 % in the fenofibrate group and 1.6 % in the placebo group ( hazard ratio , 0.91 ; 95 % CI , 0.75 to 1.10 ; P=0.33 ) . Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex , with a benefit for men and possible harm for women ( P=0.01 for interaction ) , and a possible interaction according to lipid subgroup , with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol ( P=0.057 for interaction ) . CONCLUSIONS The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events , nonfatal myocardial infa rct ion , or nonfatal stroke , as compared with simvastatin alone . These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes . ( Clinical Trials.gov number , NCT00000620 . Objective In a r and omized 5-yr multi-intervention trial , we tested the efficacy of intensified health education ( IHE ) in improving metabolic control and reducing the level of coronary risk factors and incidence of ischemic heart disease ( IHD ) . Research Design and Methods Within the intervention group , the benefit of clofibric acid was evaluated in a double-blind study . One thous and one hundred thirty-nine newly diagnosed middle-aged ( 30- to 55-yr-old ) patients with non-insulindependent diabetes mellitus ( NIDDM ) entered the study . They were classified as diet controlled after a 6- wk screening phase with conventional dietary treatment . During the follow-up , the control group ( n = 378 ) was cared for at different diabetes outpatient clinics with a st and ardized surveillance . The intervention group ( n = 761 ) had a structured IHE that included dietary advice , antismoking and antialcohol education , and ways to enhance physical activity . Results R and omly , 379 of the IHE patients received 1.6 g clofibric acid/day , and the others received placebo . IHE result ed in improved glucose control ( adjusted fasting blood glucose ) levels after 5 yr ( control subjects 9.27 mM , IHE group 8.71 mM , and IHE plus clofibric acid group 8.60 mM , P < 0.01 ) . The better glycemic control was achieved with fewer antidiabetic drugs . After 5 yr , antidiabetic drugs were prescribed to 47 % of the control subjects , 28 % of the IHE group , and 34 % of the IHE plus clofibric acid group ( cutoff limit for drug application was postpr and ial blood glucose of ≥13.87 mM ) . The ratio of polyunsaturated to saturated fatty acids ( 0.26 vs. 0.40 , P < 0.01 ) and physical activity ( 174 vs. 327 scores , P < 0.01 ) were increased , and blood pressure , tobacco , and alcohol consumption were significantly reduced by IHE . However , IHE had no effect on calorie intake , percentage of fat in the diet ( 45 % ) , and body weight . The most important finding was the significant increase of blood cholesterol in all three groups ( + 0.47 , + 0.36 , and + 0.34 mM , respectively ) . Clofibric acid only prevented the increase of triglyceride levels ( + 0.56 , + 0.24 , and + 0.05 mM , respectively ) . The incidence rate per 1000 for myocardial infa rct ion was 30.3 for control subjects , 53.6 for the IHE group , and 55.6 for the IHE plus clofibric acid group . The corresponding rates for IHD incidence were 90.9 , 97.8 , and 98.8 , respectively . Men suffered more frequently from myocardial infa rct ion , whereas women developed ECG criteria for IHD more frequently . Among the 35 cases of death , besides cardiovascular diseases , liver cirrhosis and neoplasia were the predominant causes . The death rate per 1000 in control subjects was 46.2 , 30.6 in the IHE group , and 27 among patients with IHE plus clofibric acid . Conclusions IHE was of substantial benefit for the control of glycemia , significantly diminished the need for antidiabetic drugs , and reduced a cluster of risk factors but had no effect on the control of blood lipids . This could be one major reason for the failure of IHE , effective lowering of blood pressure , and clofibric acid to prevent cardiovascular complications .  Clofibric acid was only effective in reducing triglycerides Consecutive survivors of a myocardial infa rct ion from the Southern Hospital , below 70 years of age , were r and omized into a  Control group ( n = 276 ) and a Treatment group ( n = 279 ) . The latter was openly prescribed the combination of clofibrate and nicotinic acid for serum lipid lowering . Each patient should remain in the study for 5 years and be seen regularly every 4 months at a special IHD outpatient clinic within the hospital . The concentration of serum cholesterol and triglyceride was lowered by 13 % and 19 % , respectively , in the Treatment group compared to the Control group . Total mortality was 82 cases in the Control group and 61 in the Treatment group , a 26 % reduction ( p less than 0.05 ) . For patients above 60 years of age in the Treatment group the reduction in mortality was 28 % ( p less than 0.05 ) . IHD mortality was reduced by 36 % ( p less than 0.01 ) in the Treatment group compared to the Control group . The beneficial effect of the serum lipid lowering treatment was related to the serum triglyceride concentration in two ways . First , it only occurred in patients with a triglyceride level greater than 1.5 mmol/l ( n = 216 ) . Secondly , it was most pronounced in the 44 % of the treated patients who had a lowering of the serum triglyceride by 30 % or more , and in this subgroup the reduction of IHD mortality was 60 % ( p less than 0.01 ) . For serum cholesterol there were no such relations . The difference between serum triglycerides and cholesterol concerning these relations to the treatment outcome may be due to the fact that hypertriglyceridaemia was the most common hyperlipidaemia among our patients , occurring in 50 % , while hypercholesterolaemia only occurred in 13 % . Caution should be exercised in the interpretation of the results as the trial was not blind . However , the fact that the decrease in IHD deaths was directly related to the degree of serum triglyceride lowering indicates that it was the drug effect on serum lipids that was responsible for the beneficial effect of the treatment The Cholesterol-Lowering Atherosclerosis Study ( CLAS ) was a r and omized , placebo-controlled , angiographic trial testing combined colestipol hydrochloride and niacin therapy in 162 nonsmoking men aged 40 to 59 years with previous coronary bypass surgery . During two years of treatment there was a 26 % reduction in total plasma cholesterol , a 43 % reduction in low-density lipoprotein cholesterol , plus a simultaneous 37 % elevation of high-density lipoprotein cholesterol . This result ed in a significant reduction in the average number of lesions per subject that progressed ( P less than .03 ) and the percentage of subjects with new atheroma formation ( P less than .03 ) in native coronary arteries . Also , the percentage of subjects with new lesions ( P less than .04 ) or any adverse change in bypass grafts ( P less than .03 ) was significantly reduced . Deterioration in overall coronary status was significantly less in drug-treated subjects than placebo-treated subjects ( P less than .001 ) . Atherosclerosis regression , as indicated by perceptible improvement in overall coronary status , occurred in 16.2 % of colestipol-niacin treated vs 2.4 % placebo treated ( P = .002 ) BACKGROUND Atherosclerosis is the most common complication of diabetes . Correction of hyperglycaemia helps to prevent microvascular complications but has little effect on macrovascular disease . Post-hoc analyses of diabetic sub population s in lipid intervention trials suggest that correction of lipoprotein abnormalities will lead to a decrease in coronary-artery disease . The Diabetes Atherosclerosis Intervention Study ( DAIS ) was specifically design ed to assess the effects of correcting lipoprotein abnormalities on coronary atherosclerosis in type 2 diabetes . METHODS 731 men and women with type 2 diabetes were screened by metabolic and angiographic criteria . 418 were r and omly assigned micronised fenofibrate ( 200 mg/day ) or placebo for at least 3 years . They were in good glycaemic control ( mean haemoglobin A1c 7.5 % ) , had mild lipoprotein abnormalities , typical of type 2 diabetes , and at least one visible coronary lesion . Half had no previous clinical coronary disease . Initial and final angiograms followed a st and ard protocol and were analysed by a computer-assisted quantitative approach . Missing data for the primary endpoints ( minimum lumen diameter , mean segment diameter , and mean percentage stenosis ) were imputed . Analyses were by intention to treat . FINDINGS Total plasma cholesterol , HDL-cholesterol , LDL-cholesterol , and triglyceride concentrations all changed significantly more from baseline in the fenofibrate group ( n=207 ) than in the placebo group ( n=211 ) . The fenofibrate group showed a significantly smaller increase in percentage diameter stenosis than the placebo group ( mean 2.11 [ SE 0.594 ] vs 3.65 [0.608]% , p=0.02 ) , a significantly smaller decrease in minimum lumen diameter ( -0.06 [ 0.016 ] vs -0.10 [ 0.016 ] mm , p=0.029 ) , and a non-significantly smaller decrease in mean segment diameter ( -0.06 [ 0.017 ] vs -0.08 [ 0.018 ] mm , p=0.171 ) . The trial was not powered to examine clinical endpoints , but there were fewer in the fenofibrate group than the placebo group ( 38 vs 50 ) . INTERPRETATION DAIS suggests that treatment with fenofibrate reduces the angiographic progression of coronary-artery disease in type 2 diabetes . This effect is related , at least partly , to the correction of lipoprotein abnormalities , even those previously judged not to need treatment BACKGROUND Patients with evidence of vascular disease are at increased risk for subsequent vascular events despite effective use of statins to lower the low-density lipoprotein ( LDL ) cholesterol level . Niacin lowers the LDL cholesterol level and raises the high-density lipoprotein ( HDL ) cholesterol level , but its clinical efficacy and safety are uncertain . METHODS After a prer and omization run-in phase to st and ardize the background statin-based LDL cholesterol-lowering therapy and to establish participants ' ability to take extended-release niacin without clinical ly significant adverse effects , we r and omly assigned 25,673 adults with vascular disease to receive 2 g of extended-release niacin and 40 mg of laropiprant or a matching placebo daily . The primary outcome was the first major vascular event ( nonfatal myocardial infa rct ion , death from coronary causes , stroke , or arterial revascularization ) . RESULTS During a median follow-up period of 3.9 years , participants who were assigned to extended-release niacin-laropiprant had an LDL cholesterol level that was an average of 10 mg per deciliter ( 0.25 mmol per liter as measured in the central laboratory ) lower and an HDL cholesterol level that was an average of 6 mg per deciliter ( 0.16 mmol per liter ) higher than the levels in those assigned to placebo . Assignment to niacin-laropiprant , as compared with assignment to placebo , had no significant effect on the incidence of major vascular events ( 13.2 % and 13.7 % of participants with an event , respectively ; rate ratio , 0.96 ; 95 % confidence interval [ CI ] , 0.90 to 1.03 ; P=0.29 ) . Niacin-laropiprant was associated with an increased incidence of disturbances in diabetes control that were considered to be serious ( absolute excess as compared with placebo , 3.7 percentage points ; P<0.001 ) and with an increased incidence of diabetes diagnoses ( absolute excess , 1.3 percentage points ; P<0.001 ) , as well as increases in serious adverse events associated with the gastrointestinal system ( absolute excess , 1.0 percentage point ; P<0.001 ) , musculoskeletal system ( absolute excess , 0.7 percentage points ; P<0.001 ) , skin ( absolute excess , 0.3 percentage points ; P=0.003 ) , and unexpectedly , infection ( absolute excess , 1.4 percentage points ; P<0.001 ) and bleeding ( absolute excess , 0.7 percentage points ; P<0.001 ) . CONCLUSIONS Among participants with atherosclerotic vascular disease , the addition of extended-release niacin-laropiprant to statin-based LDL cholesterol-lowering therapy did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events . ( Funded by Merck and others ; HPS2-THRIVE Clinical Trials.gov number , NCT00461630 . ) 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 A double-blind intervention trial was started in 1965 to test the hypothesis that the incidence of ischaemic heart disease in middle-aged men can be reduced by lowering raised serum cholesterol levels . It was carried out in 3 European centres-Edinburgh , Budapest , and Prague . Serum cholesterol was to be lowered by the drug clofibrate ( ethyl chlorophenoxyisobutyrate ) which was considered to be free from serious side effects . Studies were carried out on 15 745 males , aged 30 to 59 at entry , for an average of 5 - 3 years , accumulating 83 534 years of experience . The treatment group , of about 5000 , Group I , was a r and omly chosen half of the men in the upper third of the serum cholesterol distribution in some 30 000 volunteers . The comparable control group , Group II , comprised the other 5000 men of the upper third of the cholesterol distribution , and these were given a placebo . A further control group , Group III , of 5000 men , was selected r and omly from the lower third of the cholesterol distribution . These numbers were chosen in order to be 90 per cent certain of detecting a 30 per cent reduction in the incidence of ischaemic heart disease should this occur . Subjects with manifest heart or other major disease were excluded from the trial . No attempt was made to correct other ' risk factors ' for IHD , but their presence was monitored and considered in the analysis . Investigators and participants in the trial were unaware of the groups to which individual men belonged . A mean reduction of approximately 9 per cent of the initial serum cholesterol levels was achieved in the treatment group ( ranging from 7 to 11 % in the 3 centres ) ; this was less than the 15 per cent fall expected . In Edinburgh , during treatment , serum triglyceride concentrations in Group I resembled those naturally occurring in Group III . The incidence ofIHO was lower by 20 per cent in the clofibrate group compared with the high cholesterol controls ( P < 0.05 ) ; this fall was confined to non-fatal myocardial infa rcts which were reduced by 25 per cent . The incidence offatal heart attacks was similar in the 2 high cholesterol groups and there was no significant difference in the incidence of angina . Group III showed substantially lower rates of ischaemic heart disease . The reduction of myocardial infa rct ion in the clofibrate-treated group was greatest in men with the highest levels , and greatest reduction in serum cholesterol . Men with a substantial reduction of cholesterol concentration , who smoked , and also had above average blood pressure levels showed the most benefit . The numbers of deaths , and crude mortality rates from all causes in the clofibrate-treated group significantly exceeded those in the high cholesterol control group ( P < 0.05 ) , though the age-st and ardised mortality rates did not differ significantly between the 3 groups . The numbers of deaths from ' In a r and omized , double-blind five-year trial , we tested the efficacy of simultaneously elevating serum levels of high-density lipoprotein ( HDL ) cholesterol and lowering levels of non-HDL cholesterol with gemfibrozil in reducing the risk of coronary heart disease in 4081 asymptomatic middle-aged men ( 40 to 55 years of age ) with primary dyslipidemia ( non-HDL cholesterol greater than or equal to 200 mg per deciliter [ 5.2 mmol per liter ] in two consecutive pretreatment measurements ) . One group ( 2051 men ) received 600 mg of gemfibrozil twice daily , and the other ( 2030 men ) received placebo . Gemfibrozil caused a marked increase in HDL cholesterol and persistent reductions in serum levels of total , low-density lipoprotein ( LDL ) , and non-HDL cholesterol and triglycerides . There were minimal changes in serum lipid levels in the placebo group . The cumulative rate of cardiac end points at five years was 27.3 per 1,000 in the gemfibrozil group and 41.4 per 1,000 in the placebo group -- a reduction of 34.0 percent in the incidence of coronary heart disease ( 95 percent confidence interval , 8.2 to 52.6 ; P less than 0.02 ; two-tailed test ) . The decline in incidence in the gemfibrozil group became evident in the second year and continued throughout the study . There was no difference between the groups in the total death rate , nor did the treatment influence the cancer rates . The results are in accord with two previous trials with different pharmacologic agents and indicate that modification of lipoprotein levels with gemfibrozil reduces the incidence of coronary heart disease in men with dyslipidemia BACKGROUND Although it is generally accepted that lowering elevated serum levels of low-density lipoprotein ( LDL ) cholesterol in patients with coronary heart disease is beneficial , there are few data to guide decisions about therapy for patients whose primary lipid abnormality is a low level of high-density lipoprotein ( HDL ) cholesterol . METHODS We conducted a double-blind trial comparing gemfibrozil ( 1200 mg per day ) with placebo in 2531 men with coronary heart disease , an HDL cholesterol level of 40 mg per deciliter ( 1.0 mmol per liter ) or less , and an LDL cholesterol level of 140 mg per deciliter ( 3.6 mmol per liter ) or less . The primary study outcome was nonfatal myocardial infa rct ion or death from coronary causes . RESULTS The median follow-up was 5.1 years . At one year , the mean HDL cholesterol level was 6 percent higher , the mean triglyceride level was 31 percent lower , and the mean total cholesterol level was 4 percent lower in the gemfibrozil group than in the placebo group . LDL cholesterol levels did not differ significantly between the groups . A primary event occurred in 275 of the 1267 patients assigned to placebo ( 21.7 percent ) and in 219 of the 1264 patients assigned to gemfibrozil ( 17.3 percent ) . The overall reduction in the risk of an event was 4.4 percentage points , and the reduction in relative risk was 22 percent ( 95 percent confidence interval , 7 to 35 percent ; P=0.006 ) . We observed a 24 percent reduction in the combined outcome of death from coronary heart disease , nonfatal myocardial infa rct ion , and stroke ( P < 0.001 ) . There were no significant differences in the rates of coronary revascularization , hospitalization for unstable angina , death from any cause , and cancer . CONCLUSIONS Gemfibrozil therapy result ed in a significant reduction in the risk of major cardiovascular events in patients with coronary disease whose primary lipid abnormality was a low HDL cholesterol level . The findings suggest that the rate of coronary events is reduced by raising HDL cholesterol levels and lowering levels of triglycerides without lowering LDL cholesterol levels BACKGROUND Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease , partly owing to dyslipidaemia , which can be amenable to fibrate therapy . We design ed the Fenofibrate Intervention and Event Lowering in Diabetes ( FIELD ) study to assess the effect of fenofibrate on cardiovascular disease events in these patients . METHODS We did a multinational , r and omised controlled trial with 9795 participants aged 50 - 75 years , with type 2 diabetes mellitus , and not taking statin therapy at study entry . After a placebo and a fenofibrate run-in phase , we r and omly assigned patients ( 2131 with previous cardiovascular disease and 7664 without ) with a total-cholesterol concentration of 3.0 - 6.5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4.0 or more or plasma triglyceride of 1.0 - 5.0 mmol/L to micronised fenofibrate 200 mg daily ( n=4895 ) or matching placebo ( n=4900 ) . Our primary outcome was coronary events ( coronary heart disease death or non-fatal myocardial infa rct ion ) ; the outcome for prespecified subgroup analyses was total cardiovascular events ( the composite of cardiovascular death , myocardial infa rct ion , stroke , and coronary and carotid revascularisation ) . Analysis was by intention to treat . The study was prospect ively registered ( number IS RCT N 64783481 ) . FINDINGS Vital status was confirmed on all but 22 patients . Averaged over the 5 years ' study duration , similar proportions in each group discontinued study medication ( 10 % placebo vs 11 % fenofibrate ) and more patients allocated placebo ( 17 % ) than fenofibrate ( 8 % ; p<0.0001 ) commenced other lipid treatments , predominantly statins . 5.9 % ( n=288 ) of patients on placebo and 5.2 % ( n=256 ) of those on fenofibrate had a coronary event ( relative reduction of 11 % ; hazard ratio [ HR ] 0.89 , 95 % CI 0.75 - 1.05 ; p=0.16 ) . This finding corresponds to a significant 24 % reduction in non-fatal myocardial infa rct ion ( 0.76 , 0.62 - 0.94 ; p=0.010 ) and a non-significant increase in coronary heart disease mortality ( 1.19 , 0.90 - 1.57 ; p=0.22 ) . Total cardiovascular disease events were significantly reduced from 13.9 % to 12.5 % ( 0.89 , 0.80 - 0.99 ; p=0.035 ) . This finding included a 21 % reduction in coronary revascularisation ( 0.79 , 0.68 - 0.93 ; p=0.003 ) . Total mortality was 6.6 % in the placebo group and 7.3 % in the fenofibrate group ( p=0.18 ) . Fenofibrate was associated with less albuminuria progression ( p=0.002 ) , and less retinopathy needing laser treatment ( 5.2%vs 3.6 % , p=0.0003 ) . There was a slight increase in pancreatitis ( 0.5%vs 0.8 % , p=0.031 ) and pulmonary embolism ( 0.7%vs 1.1 % , p=0.022 ) , but no other significant adverse effects . INTERPRETATION Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events . It did reduce total cardiovascular events , mainly due to fewer non-fatal myocardial infa rct ions and revascularisations . The higher rate of starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit
target: This significant effect was derived by the use of fibrates ( RR 0.80 , 95 % CI 0.73–0.87 , P < 0.001 , I2 = 22 % ) and meta-regression analysis showed that this benefit was consistent with an absolute reduction in low-density lipoprotein cholesterol .
  Meta-regression analyses failed to demonstrate a significant association of pharmacologically increased high-density lipoprotein cholesterol with key endpoints .
  Conclusion The use of high-density lipoprotein cholesterol modifying treatments had no significant effect on cardiovascular mortality , stroke or all-cause mortality .
  The beneficial effect on myocardial infa rct ion was lost when drugs were used with statin therapy
background: Background The effects of increasing high-density lipoprotein cholesterol on cardiovascular outcomes remain uncertain .
  Design We conducted a meta- analysis to investigate the effects of high-density lipoprotein cholesterol modifiers ( niacin , fibrates and cholesteryl ester transfer protein inhibitors ) on cardiovascular outcomes .