title: Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2 l-Carnitine/Simvastatin Reduces Lipoprotein (a) Levels Compared with Simvastatin Monotherapy: A Randomized Double-Blind Placebo-Controlled Study Long term statin treatment reduces lipoprotein(a) concentrations in heterozygous familial hypercholesterolaemia Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia. 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). [Gemfibrozil reduces elevated lipoprotein (a) levels in hypercholesterolemic patients]. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor. Effects of combination lipid therapy in type 2 diabetes mellitus. Effect of a new HMG-CoA reductase inhibitor, atorvastatin, on lipids, apolipoproteins and lipoprotein particles in patients with elevated serum cholesterol and triglyceride levels. Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). Comparison of the effects of atorvastatin or fenofibrate on nonlipid biochemical risk factors and the LDL particle size in subjects with combined hyperlipidemia. Comparison of lovastatin and bezafibrate on lipoprotein(a) plasma levels in cardiac transplant recipients. Effect of gemfibrozil versus lovastatin on increased serum lipoprotein(a) levels of patients with hypercholesterolemia. Comparison of the Efficacy of Atorvastatin and Micronized Fenofibrate in the Treatment of Mixed Hyperlipidemia Treatment of primary hypercholesterolemia: fluvastatin versus bezafibrate. Effects of gemfibrozil or simvastatin on apolipoprotein-B-containing lipoproteins, apolipoprotein-CIII and lipoprotein(a) in familial combined hyperlipidaemia. Treatment of patients with familial defective apolipoprotein B-100 with pravastatin and gemfibrozil: a two-period cross-over study Effects of lipid-lowering drugs on left ventricular function and exercise tolerance in dyslipidemic coronary patients. Atorvastatin lowers lipoprotein(a) but not apolipoprotein(a) fragment levels in hypercholesterolemic subjects at high cardiovascular risk. A comparison between the effects of gemfibrozil and simvastatin on insulin sensitivity in patients with non-insulin-dependent diabetes mellitus and hyperlipoproteinemia. Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women. Combined bezafibrate and simvastatin treatment for mixed hyperlipidaemia. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. 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. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data. Post-prandial effects of gemfibrozil vs simvastatin in hypercholesterolemic subjects with borderline hypertriglyceridemia. Lipoprotein(a) Concentrations, Rosuvastatin Therapy, and Residual Vascular Risk: An Analysis From the JUPITER Trial (Justification for the Use of Statins in Prevention An Intervention Trial Evaluating Rosuvastatin)
abstract: CONTEXT High levels of lipoprotein(a ) are associated with increased risk of myocardial infa rct ion ( MI ) . OBJECTIVE To assess whether genetic data are consistent with this association being causal . DESIGN , SETTING , AND PARTICIPANTS Three studies of white individuals from Copenhagen , Denmark , were used : the Copenhagen City Heart Study ( CCHS ) , a prospect i ve general population study with 16 years of follow-up ( 1991 - 2007 , n = 8637 , 599 MI events ) ; the Copenhagen General Population Study ( CGPS ) , a cross-sectional general population study ( 2003 - 2006 , n = 29 388 , 994 MI events ) ; and the Copenhagen Ischemic Heart Disease Study ( CIHDS ) , a case-control study ( 1991 - 2004 , n = 2461 , 1231 MI events ) . MAIN OUTCOME MEASURES Plasma lipoprotein(a ) levels , lipoprotein(a ) kringle IV type 2 ( KIV-2 ) size polymorphism genotype , and MIs recorded from 1976 through July 2007 for all participants . RESULTS In the CCHS , multivariable-adjusted hazard ratios ( HRs ) for MI for elevated lipoprotein(a ) levels were 1.2 ( 95 % confidence interval [ CI ] , 0.9 - 1.6 ; events/10,000 person-years , 59 ) for levels between the 22nd and 66th percentile , 1.6 ( 95 % CI , 1.1 - 2.2 ; events/10,000 person-years , 75 ) for the 67th to 89th percentile , 1.9 ( 95 % CI , 1.2 - 3.0 ; events/10,000 person-years , 84 ) for the 90th to 95th percentile , and 2.6 ( 95 % CI , 1.6 - 4.1 ; events/10,000 person-years , 108 ) for levels greater than the 95th percentile , respectively , vs levels less than the 22nd percentile ( events/10,000 person-years , 55 ) ( trend P < .001 ) . Numbers of KIV-2 repeats ( sum of repeats on both alleles ) ranged from 6 to 99 and on analysis of variance explained 21 % and 27 % of all variation in plasma lipoprotein(a ) levels in the CCHS and CGPS , respectively . Mean lipoprotein(a ) levels were 56 , 31 , 20 , and 15 mg/dL for the first , second , third , and fourth quartiles of KIV-2 repeats in the CCHS , respectively ( trend P < .001 ) ; corresponding values in the CGPS were 60 , 34 , 22 , and 19 mg/dL ( trend P < .001 ) . In the CCHS , multivariable-adjusted HRs for MI were 1.5 ( 95 % CI , 1.2 - 1.9 ; events/10,000 person-years , 75 ) , 1.3 ( 95 % CI , 1.0 - 1.6 ; events/10,000 person-years , 66 ) , and 1.1 ( 95 % CI , 0.9 - 1.4 ; events/10,000 person-years , 57 ) for individuals in the first , second , and third quartiles , respectively , as compared with individuals in the fourth quartile of KIV-2 repeats ( events/10,000 person-years , 51 ) ( trend P < .001 ) . Corresponding odds ratios were 1.3 ( 95 % CI , 1.1 - 1.5 ) , 1.1 ( 95 % CI , 0.9 - 1.3 ) , and 0.9 ( 95 % CI , 0.8 - 1.1 ) in the CGPS ( trend P = .005 ) , and 1.4 ( 95 % CI , 1.1 - 1.7 ) , 1.2 ( 95 % CI , 1.0 - 1.6 ) , and 1.3 ( 95 % CI , 1.0 - 1.6 ) in the CIHDS ( trend P = .01 ) . Genetically elevated lipoprotein(a ) was associated with an HR of 1.22 ( 95 % CI , 1.09 - 1.37 ) per doubling of lipoprotein(a ) level on instrumental variable analysis , while the corresponding value for plasma lipoprotein(a ) levels on Cox regression was 1.08 ( 95 % CI , 1.03 - 1.12 ) . CONCLUSION These data are consistent with a causal association between elevated lipoprotein(a ) levels and increased risk of MI Objective — Lipoprotein-associated phospholipase A2 ( Lp-PLA2 ) is a predictor for incident atherosclerotic disease . We investigated the effect of 3 hypolipidemic drugs that exert their action through different mechanisms on plasma and lipoprotein-associated Lp-PLA2 activity and mass . Methods and Results — In 50 patients with Type IIA dyslipidemia were administered rosuvastatin ( 10 mg daily ) , whereas in 50 Type IIA dyslipidemic patients exhibiting intolerance to previous statin therapy were administered ezetimibe as monotherapy ( 10 mg daily ) . Fifty patients with Type IV dyslipidemia were given micronised fenofibrate ( 200 mg daily ) . Low- and high-density lipoprotein ( LDL and HDL , respectively ) subclass analysis was performed electrophoretically , whereas lipoprotein subfractions were isolated by ultracentrifugation . Ezetimibe reduced plasma Lp-PLA2 activity and mass attributable to the reduction in plasma levels of all LDL subfractions . Rosuvastatin reduced enzyme activity and mass because of the decrease in plasma levels of all LDL subfractions and especially the Lp-PLA2 on dense LDL subfraction ( LDL-5 ) . Fenofibrate preferentially reduced the Lp-PLA2 activity and mass associated with the VLDL+IDL and LDL-5 subfractions . Among studied drugs only fenofibrate increased HDL-associated Lp-PLA2 ( HDL-Lp-PLA2 ) activity and mass attributable to a preferential increase in Lp-PLA2 associated with the HDL-3c subfraction . Conclusion — Ezetimibe , rosuvastatin , and fenofibrate reduce Lp-PLA2 activity and mass associated with the atherogenic apoB-lipoproteins . Furthermore , fenofibrate improves the enzyme specific activity on apoB-lipoproteins and induces the HDL-Lp-PLA2 . The clinical implication s of these effects remain to be established Lipoprotein ( a ) [ Lp(a ) ] is an independent risk factor for cardiovascular disease . There are currently limited therapeutic options to lower Lp(a ) levels . l-Carnitine has been reported to reduce Lp(a ) levels . The aim of this study was to compare the effect of l-carnitine/simvastatin co-administration with that of simvastatin monotherapy on Lp(a ) levels in subjects with mixed hyperlipidemia and elevated Lp(a ) concentration . Subjects with levels of low-density lipoprotein cholesterol ( LDL-C ) > 160 mg/dL , triacylglycerol ( TAG ) > 150 mg/dL and Lp(a ) > 20 mg/dL were included in this study . Subjects were r and omly allocated to receive l-carnitine 2 g/day plus simvastatin 20 mg/day ( N = 29 ) or placebo plus simvastatin 20 mg/day ( N = 29 ) for a total of 12 weeks . Lp(a ) was significantly reduced in the l-carnitine/simvastatin group [ −19.4 % , from 52 ( 20–171 ) to 42 ( 15–102 ) mg/dL ; p = 0.01 ] , but not in the placebo/simvastatin group [ −6.7 % , from 56 ( 26–108 ) to 52 ( 27–93 ) mg/dL , p = NS versus baseline and p = 0.016 for the comparison between groups ] . Similar significant reductions in total cholesterol , LDL-C , apolipoprotein ( apo ) B and TAG were observed in both groups . Co-administration of l-carnitine with simvastatin was associated with a significant , albeit modest , reduction in Lp(a )  compared with simvastatin monotherapy in subjects with mixed hyperlipidemia and elevated baseline Lp(a ) levels Background : Raised plasma lipoprotein(a ) ( Lp(a ) ) is associated with increased risk of cardiovascular disease . It is unknown whether increased Lp(a ) is an additional risk factor for coronary artery disease in familial hypercholesterolaemia ( FH ) or whether statin treatment can reduce Lp(a ) concentrations in the long term . Objective : To investigate Lp(a ) concentrations in relation to statin treatment and the progression of atherosclerosis in a large cohort of FH patients . Design : A two year , r and omised , double blind trial ( the ASAP trial ) . Patients : 325 heterozygous FH patients . Intervention : Treatment with 80 mg atorvastatin or 40 mg simvastatin . Main outcome measure : Change in Lp(a ) concentrations and intima – media thickness of carotid artery segments at one year and two years . Results : At baseline , median Lp(a ) concentrations were 327 mg/l and 531 mg/l in the atorvastatin and simvastatin arms , respectively ( p = 0.03 ) . In the atorvastatin arm , Lp(a ) concentrations decreased to 243 mg/l after one year ( p < 0.001 ) and to 263 mg/l after two years ( p < 0.001 ) . In the simvastatin arm , Lp(a ) concentrations decreased to 437 mg/l after one year ( p < 0.001 ) and to 417 mg/l after two years ( p < 0.001 ) . The difference in Lp(a ) reduction between the two treatment arms was significant after one year ( p = 0.004 ) , but not after two years ( p = 0.086 ) . Lp(a ) concentrations at baseline were not related to cardiovascular events at baseline . There was no correlation between baseline Lp(a ) concentrations and low density lipoprotein cholesterol concentrations or intima – media thickness at baseline . Change in Lp(a ) concentrations was not correlated with change in intima – media thickness after one or two years . Conclusions : Long term statin treatment significantly lowers Lp(a ) in FH patients . However , this reduction was unrelated to changes in intima – media thickness and casts doubt on the importance of Lp(a ) in the progression of atherosclerotic disease in these patients OBJECTIVE This study evaluated the effect of a atorvastatin-fenofibrate combination on lipid profile , in comparison to each drug alone , in patients with type 2 diabetes and combined hyperlipidemia ( CHL ) . RESEARCH DESIGN AND METHODS A total of 120 consecutive patients , who were free of coronary artery disease ( CAD ) at entry , were studied for a period of 24 weeks . These patients were r and omly assigned to atorvastatin ( 20 mg/day , n = 40 ) , micronized fenofibrate ( 200 mg/day , n = 40 ) , or a combination of both ( atorvastatin 20 mg/day plus fenofibrate 200 mg/day , n = 40 ) . The effect of treatment on LDL cholesterol , triglycerides ( TGs ) , HDL cholesterol , apolipoprotein A-I and B , lipoprotein(a ) , and plasma fibrinogen ( PF ) was recorded . Moreover , the percentage of patients that reached the American Diabetes Association treatment goals and the estimated CAD risk status were calculated . RESULTS No patient was withdrawn from the study because of side effects . The atorvastatin-fenofibrate combination reduced total cholesterol by 37 % , LDL cholesterol by 46 % , TGs by 50 % , and PF by 20 % , whereas it increased HDL cholesterol by 22 % ( P < 0.0001 for all ) . These changes were significantly better than those of both monotherapies . Of the patients on drug combination , 97.5 % reached the LDL cholesterol treatment goal of < 100 mg/dl , 100 % reached the desirable TG levels of < 200 mg/dl , and 60 % reached the optimal HDL cholesterol levels of > 45 mg/dl . These rates were significantly higher than those of both monotherapies . Combined treatment reduced the 10-year probability for myocardial infa rct ion from 21.6 to 4.2 % . CONCLUSIONS The atorvastatin-fenofibrate combination has a highly beneficial effect on all lipid parameters and PF in patients with type 2 diabetes and CHL . It improved patients ' CAD risk status significantly more than each drug alone 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 PURPOSE To compare the effects of gemfibrozil and lovastatin in patients with hypercholesterolemia and increased lipoprotein(a ) [ Lp(a ) ] levels .  METHODS Twenty-seven subjects with total cholesterol ( TC ) > 240 mg/dL , LDL-C > 160 mg/dL and Lp(a ) > 25 mg/dL were studied . Patients were r and omized to receive gemfibrozil 1200 mg/day , ( n = 14 , 54 + /- 7 years ) or lovastatin 40 - 80 mg at night ( n = 13 , 55 + /- 9 years ) for 12 weeks . Lipid profile and Lp(a ) were determined at 4 and 12 weeks of treatment . RESULTS Gemfibrozil reduced TC ( -21 % ) , LDL-C ( -26 % ) , triglycerides (TG)(-48 % ) and Lp(a ) ( -25 % ) , increased HDL-C (+48%)(p < 0.001 ) . Lovastatin reduced TC ( -29 % ) , LDL-C ( -37 % ) and TG ( -25 % ) ( p < 0.001 ) however , it did not affect Lp(a ) . CONCLUSION Besides reducing plasma LDL-C , TG and increasing HDL-C , gemfibrozil effectively lowers Lp(a ) levels .  Lovastatin did not affect Lp(a ) levels Patients with combined hyperlipidemia ( elevated triglyceride [ TG ] levels , elevated low-density lipoprotein [ LDL ] cholesterol , and multiple lipoprotein abnormalities ) are at increased risk for coronary heart disease . We conducted a multicenter ( in the United States ) , r and omized , double-blind , active-controlled , 18-week study to determine if combination therapy with simvastatin plus fenofibrate is more effective in reducing elevated TG levels , thus improving the lipoprotein pattern in patients with combined hyperlipidemia compared with simvastatin monotherapy , and to evaluate safety and tolerability . Patients ( aged 21 to 68 years ) with a diagnosis of combined hyperlipidemia ( fasting TG levels > /=150 and < /=500 mg/dl , and LDL cholesterol > 130 mg/dl ) received simvastatin monotherapy  ( 20 mg/day , n = 207 ) or simvastatin 20 mg plus fenofibrate ( 160 mg/day ) combination therapy ( n = 411 ) for 12 weeks following a 6-week diet and placebo run-in period . From baseline to week 12 , median TG levels decreased 43.0 % ( combination therapy ) and 20.1 % ( simvastatin monotherapy [ treatment difference -23.6 % , p < 0.001 ] ) . Mean LDL cholesterol levels decreased 31.2 % and 25.8 % ( treatment difference -5.4 % , p < 0.001 ) , and high-density lipoprotein cholesterol levels increased 18.6 % and 9.7 % ( treatment difference 8.8 % , p < 0.001 ) in the combination therapy versus monotherapy groups , respectively . No drug-related serious adverse experiences were observed . No patient experienced clinical myopathy or severe abnormalities in liver function . Combination therapy with simvastatin 20 mg and fenofibrate 160 mg in patients with combined hyperlipidemia result ed in additional improvement in all lipoprotein parameters measured compared with simvastatin 20 mg monotherapy and was well tolerated . Thus , this combination therapy is a beneficial therapeutic option for managing combined hyperlipidemia In view of the evidence linking plasma high density lipoprotein (HDL)-cholesterol levels to a protective effect against coronary artery disease and the widespread use of fibrates in the treatment of hyperlipidemia , the goal of this study was to analyze the influence of fibrates on the expression of apolipoprotein ( apo ) A-II , a major protein constituent of HDL . Administration of fenofibrate ( 300 mg/d ) to 16 patients with coronary artery disease result ed in a marked increase in plasma apo A-II concentrations ( 0.34 + /- 0.11 to 0.45 + /- 0.17 grams/liter ; P < 0.01 ) . This increase in plasma apo A-II was due to a direct effect on hepatic apo A-II production , since fenofibric acid induced apo A-II mRNA levels to 450 and 250 % of control levels in primary cultures of human hepatocytes and in human hepatoblastoma HepG2 cells respectively . The induction in apo A-II mRNA levels was followed by an increase in apo A-II secretion in both cell culture systems . Transient transfection experiments of a reporter construct driven by the human apo A-II gene promoter indicated that fenofibrate induced apo A-II gene expression at the transcriptional level . Furthermore , several other peroxisome proliferators , such as the fibrate , Wy-14643 , and the fatty acid , eicosatetraynoic acid ( ETYA ) , also induced apo A-II gene transcription . Unilateral deletions and site-directed mutagenesis identified a sequence element located in the J-site of the apo A-II promoter mediating the responsiveness to fibrates and fatty acids . This element contains two imperfect half sites spaced by 1 oligonucleotide similar to a peroxisome proliferator responsive element ( PPRE ) . Cotransfection assays showed that the peroxisome proliferator activated receptor ( PPAR ) transactivates the apo A-II promoter through this AII-PPRE . Gel retardation assays demonstrated that PPAR binds to the AII-PPRE with an affinity comparable to its binding affinity to the acyl coA oxidase (ACO)-PPRE . In conclusion , in humans fibrates increase plasma apo A-II concentrations by inducing hepatic apo A-II production . Apo A-II expression is regulated at the transcriptional level by fibrates and fatty acids via the interaction of PPAR with the AII-PPRE , thereby demonstrating the pivotal role of PPAR in controlling human lipoprotein metabolism 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 . The effects of atorvastatin ( lipitor ) on cholesterol-rich and triglyceride-rich lipoproteins were evaluated in this multicenter trial . Following a 6-week baseline period , 47 patients with elevated cholesterol and triglyceride levels were treated with atorvastatin 10 mg once daily ( QD ) for the initial 12 weeks ( Period 1 ) increasing to 20 mg QD for the following 12 weeks ( Period 2 ) . At both the 10 and 20 mg doses , atorvastatin treatment result ed in significant reductions compared to pretreatment levels in low-density lipoprotein cholesterol ( LDL-C ) , total cholesterol ( TC ) , very low-density lipoprotein cholesterol ( VLDL-C ) , apolipoprotein ( apo ) B , apoB in LDL ( LDL-apo B ) , apo B in VLDL ( VLDL-apo B ) , lipoprotein (Lp)B , lipoprotein B-complex ( LpBc ) , triglycerides ( TG ) , low-density lipoprotein triglycerides ( LDL-TG ) , very low-density lipoprotein triglyceride ( VLDL-TG ) , high-density lipoprotein triglycerides ( HDL-TG ) , and apo C-III .  Atorvastatin 10 and 20 mg QD also result ed in significant increases in high-density lipoprotein cholesterol ( HDL-C ) , apo AI , and LpAII : B : C : D : E. Due to its unique ability to normalize both cholesterol-rich and triglyceride-rich particles , atorvastatin is a promising c and i date for monotherapy in a broad range of patients including those with varying degrees of hypercholesterolemia and hypertriglyceridemia International guidelines recommend lower target cholesterol levels and treatment of low high-density lipoprotein cholesterol ( HDL-C ) and elevated triglycerides for patients at moderately high to high coronary heart disease ( CHD ) risk . Combination therapy is often required to achieve multiple lipid treatment goals , and > or = 50 % reduction in low-density lipoprotein cholesterol ( LDL-C ) is needed in some patients to achieve aggressive LDL-C targets . In this context , we evaluated comparative effects on lipid levels of combination therapy at low to moderate doses with a statin plus extended-release niacin ( niacin ER ) , a statin plus ezetimibe , and a highly potent statin alone . This was an open-label , multicenter , 12-week study in 292 patients ( 50 % women ) who qualified for drug therapy based on number of CHD risk factors . Patients were r and omized to four parallel arms , titrated from low to moderate or high doses : atorvastatin/niacin ER , rosuvastatin/niacin ER , simvastatin/ezetimibe , or rosuvastatin alone . Baseline mean values were , for LDL-C 197 mg/dL ( 5.1 mmol/L ) , HDL-C 49 mg/dL ( 1.3 mmol/L ) , triglycerides 168 mg/dL ( 1.9 mmol/L ) . There were no significant differences among treatment groups in the change from baseline in LDL-C at pre-specified timepoints during treatment . All groups lowered LDL-C by approximately 50 % or more ( range -49 to -57 % ) , achieving mean levels of 82 - 98 mg/dL ( 2.1 - 2.5 mmol/L ) . Changes in non-HDL-C ( range -46 to -55 % ) mirrored those for LDL-C and did not differ among treatment groups . Statin/niacin ER combination regimens also increased HDL-C and large HDL ( HDL2 ) and lowered triglycerides and lipoprotein ( a ) significantly more than other regimens . No drug-related myopathy or hepatotoxicity was observed . In this study , low to moderate dose combination therapy with a statin and niacin ER provided broad control of lipids and lipoproteins independently associated with CHD BACKGROUND Combined hyperlipidemia ( CH ) is an increasingly prevalent risk factor for premature heart disease , and its treatment is troublesome . The aim of this study was to compare the effects of atorvastatin and fenofibrate on nonlipid biochemical risk factors and the low-density lipoprotein ( LDL ) particle size in subjects with CH . METHODS Twenty-nine middle-aged men with CH were r and omly assigned to open-label therapy with atorvastatin ( 10 mg daily ) or micronized fenofibrate ( 200 mg daily ) ; they were sequentially treated with both drugs , with crossover of medication after 10 weeks . RESULTS Atorvastatin was more efficient in the reduction of total cholesterol , whereas fenofibrate was more efficient in the reduction of triglycerides . Only atorvastatin led to a significant reduction of LDL cholesterol and apolipoprotein B. Only fenofibrate increased high-density lipoprotein cholesterol . Neither drug influenced lipoprotein(a ) . Mean LDL particle size increased both after fenofibrate ( 3.08 % ) and atorvastatin ( 1.77 % ) . Fenofibrate increased serum homocysteine ( HCY ) by 36.5 % . Atorvastatin had no effect on HCY . Only atorvastatin increased fibrinogen by 17.4 % . Only fenofibrate reduced C-reactive protein by 51.7 % . Neither drug influenced HOMA ( homeostasis model assessment ) index of insulin resistance . The plasma level of thiobarbituric acid reactive substances , an index of oxidative stress , decreased after both treatments . CONCLUSIONS Both atorvastatin and fenofibrate had similar beneficial effects on LDL particle size and on oxidative stress . The effects of both drugs on other parameters such as triglycerides , total and high-density lipoprotein cholesterol , fibrinogen , or HCY differed significantly . These differences , together with the risk profile of a patient , should be considered during selection of a particular lipid-lowering modality Our results suggest that bezafibrate may be useful in the treatment of high Lp(a ) levels in heart transplant patients The aim of this study was to determine the effect of gemfibrozil , compared with lovastatin , in patients with high levels of lipoprotein(a ) and on plasma lipid profile . Twenty-seven nondiabetic patients with high levels of plasma lipids and lipoprotein(a ) , 19 male and eight female , aged 37 - 68 ( mean + /- S.D. 54.2 + /- 7.5 ) years , were r and omly assigned to 2 weeks of treatment with gemfibrozil 600 mg twice daily ( 14 pts . ) or lovastatin 40 - 80 mg once daily ( 13 pts . ) . Patients had fasting plasma total cholesterol levels > or = 6.2 mmol/l , low-density lipoprotein > 4.14 mmol/l and lipoprotein(a ) > 0.62 mmol/l . All patients but one had triglycerides > 2.82 mmol/l . There were no statistical differences between both groups in terms of age , sex , clinical diagnosis and previous medication . After 3 months of treatment , gemfibrozil reduced triglycerides ( 47.9 % vs. 24.5 % ; P < 0.001 ) , very low density lipoprotein ( 43.9 % vs. 24.6 % ; P < 0.05 ) , lipoprotein(a ) ( 25.3 % vs. 4.9 % ; P < 0.05 ) and increased high-density lipoprotein ( 34.4 % vs. 11 % ; P < 0.01 ) more than lovastatin . Gemfibrozil and lovastatin reduced comparably total cholesterol ( 21.4 % vs. 29.0 % ; P = NS ) and low-density lipoprotein ( 26.5 % vs. 37.3 % ; P = NS ) . The plasma levels of high-density lipoprotein and lipoprotein(a ) were unchanged significantly by lovastatin . In conclusion , besides well-known efficacy in hyperlipidemia treatment , gemfibrozil also increased high-density lipoprotein and reduced lipoprotein(a ) , which may have important epidemiologic implication Objective To evaluate and compare the influences of micronized fenofibrate and atorvastatin on serum lipid profile , including lipoprotein(a ) levels , and on fibrinogen levels in a large group of patients with primary mixed hyperlipidemia ( serum total and low-density lipoprotein cholesterol levels > 240 and 160 mg/dl , respectively , and serum triglyceride level > 200 mg/dl ) . Methods This was a 16-week , open-label , parallel- design study conducted in our lipid clinic . After a 6-week dietary baseline phase , we implemented a treatment phase , during which patients received 10 mg/day atorvastatin ( n=45 ) or 200 mg/day micronized fenofibrate ( n = 46 ) for 16 weeks . Patients were assigned to one of the drugs in sequential orders . Serum lipid profiles , including levels of lipoprotein(a ) and fibrinogen , as well as muscle and liver enzymes , were measured during screening , and during weeks −4 , −2 , 0 , 8 , and 16 of the treatment period . Results Atorvastatin was more effective than was micronized fenofibrate at lowering levels of total and low-density lipoprotein cholesterol , whereas fenofibrate was more effective at lowering levels of triglycerides , and raising levels of high-density lipoprotein cholesterol and apolipoprotein A1 . However , micronized fenofibrate could significantly decrease plasma fibrinogen levels , whereas atorvastatin evoked a small increase . Conclusion Both atorvastatin in small doses and micronized fenofibrate are effective for improving serum lipid profiles of patients with mixed hyperlipidemia . However , there are considerable differences between the two drugs concerning their influences on plasma fibrinogen levels The effects of fluvastatin and bezafibrate on lipids , lipoproteins , and apoproteins ( apo ) were investigated in a multicenter r and omized , double-blind , parallel-group study . After 8 weeks of strictly controlled ( computer-based assessment ) dietary stabilization , patients with primary hypercholesterolemia ( low-density lipoprotein cholesterol [ LDL-C ] > or = 160 mg/dL ; triglycerides < or = 300 mg/dL ) were enrolled into a 6-week placebo phase . Altogether , 131 patients were r and omized to receive either  fluvastatin at 40 mg once daily ( n = 64 ; mean age 53 years ) or  bezafibrate at 400 mg once daily ( n = 67 ; mean age 52 years ) for 12 weeks . Compliance with the diet was monitored ( 3-day food records ) after 6 and 12 weeks . Fluvastatin led to significant reductions in LDL-C ( -23 % ) , total cholesterol ( -17 % ) , LDL-C/high-density lipoprotein cholesterol ( HDL-C ) ( -24 % ) and apo B ( -19 % ) . Fluvastatin significantly increased LpA-I ( + 8 % ) and apo E ( + 20 % ) . Bezafibrate produced significant reductions in LDL-C ( -17 % ) , total cholesterol ( -13 % ) , LDL-C/HDL-C ( -24 % ) , triglycerides ( -28 % ) , apo B ( -15 % ) , and LpA-I ( -10 % ) and significantly increased HDL-C ( + 12 % ) , apo A-I ( + 9 % ) , apo A-II ( + 30 % ) , apo E ( + 14 % ) , and Lp(a ) ( + 3 % ) . No clinical ly notable increases in levels of liver enzymes or creatine phosphokinase were observed with either treatment . Both treatments were well tolerated . There was a low incidence of adverse events that tended to be mild and included headache , muscular pain , angina , and dyspepsia . The frequency of adverse events was similar in both treatment groups , and no significant differences in dietary behavior were observed . In conclusion , fluvastatin is a well tolerated 3-hydroxy-3-methylglutaryl-coenzyme A ( HMG-CoA ) reductase inhibitor for the treatment of primary hypercholesterolemia . Effects of fluvastatin on LpA-I occur irrespective of changes in BACKGROUND Familial combined hyperlipidaemia ( FCH ) , characterized by elevated very-low-density lipoprotein ( VLDL ) and /or low-density lipoprotein ( LDL ) , is associated with an increased prevalence of premature cardiovascular disease . Therefore , lipid-lowering is frequently indicated . METHODS We evaluated in a parallel , double-blind r and omized fashion the effect of gemfibrozil ( 1200 mg/day ) ( n = 40 ) or simvastatin ( 20 mg/day ) ( n = 41 ) on lipids , apolipoprotein-B (apo-B)-containing lipoproteins , apo-CIII and lipoprotein(a ) [ Lp(a ) ] , in 81 well-defined FCH patients . RESULTS While both drugs lowered plasma cholesterol and triglyceride levels , gemfibrozil lowered plasma triglycerides more effectively by reduction of triglycerides in VLDL and LDL , whereas simvastatin was more effective in its reduction of total plasma cholesterol by exclusively decreasing LDL cholesterol . High-density lipoprotein ( HDL ) increased to an equal extent on both therapies . Total serum apo-B levels were reduced with both drugs ; however , gemfibrozil decreased apo-B only in VLDL + IDL , whereas simvastatin decreased apo-B in both VLDL + IDL and LDL . In keeping with a more effective reduction of VLDL particles , a more pronounced reduction of apo-CIII also was observed after gemfibrozil , which correlated with the reduction in plasma triglycerides . Baseline concentrations of Lp(a ) showed a wide range in both treatment groups . Median Lp(a ) levels increased after simvastatin , but were not affected by gemfibrozil . CONCLUSION Both therapies exhibited their specific effects , although none of the drugs alone completely normalized the lipid profiles of these patients with FCH . Therefore , the choice of treatment should be based on the most elevated lipoprotein fraction , and in some cases a combination of the two drugs may be indicated Thirty patients with familial defective apolipoprotein B-100 were treated in a two-period ( 8 weeks each ) cross-over study with pravastatin and gemfibrozil .  Cholesterol , LDL cholesterol , and apo B were reduced by 20–25 % ( P < 10−4 ) by pravastatin and by 4–6 % by gemfibrozil ( pravastatin vs. gemfibrozil : P < 10−4 ) . Response to pravastatin was variable and not correlated to gender , age , or apo E genotype . Gemfibrozil  lowered triglycerides by 25 % ( P < 10−4 ) and raised HDL cholesterol by 11 % . The effects of pravastatin on these two interrelated variables were significantly smaller . Both drugs increased Lp(a ) significantly by about 10 % . The LDL cholesterol lowering effect of pravastatin in patients with FDB is similar to that observed in patients with familial hypercholesterolemia Previous studies suggested that certain lipid-lowering drugs such as statins suppress ubiquinone , affect mitochondrial function , and may have deleterious effect on skeletal or cardiac muscles with potentially serious clinical consequences , especially in patients with established coronary heart disease and left ventricular dysfunction . In this double-blind study , we assessed the effects of 20 mg simvastatin ( S , n = 32 ) or 200 mg micronized fenofibrate ( F  , n = 32 ,  control group ) on rest and exercise left ventricular function in hypercholesterolemic survivors of a previous Q-wave acute myocardial infa rct ion . Left ventricular radionuclide imaging was performed at rest and during submaximal exercise and global and segmental ( nine segment regional wall-motion score ) ejection fractions were measured before treatment and 12 weeks later . Serum ubiquinone was reduced after treatment ( p = 0.03 ) in the S but not the F group , whereas total and low-density lipoprotein ( LDL ) cholesterol were significantly reduced in both groups . Before treatment , mean global ejection fraction was 52.1+/-12.2 % and 49.3+/-11.8 % at rest in F and S patients , respectively , and increased ( 56.0+/-13.7 % in F and 52.1+/-12.9 % in S ) at peak exercise ( no difference between groups ) . After treatment , the increase in ejection fraction tended to be lower in S ( 0 ) than in F ( + 3.8 % ) but not significantly . However , ejection fraction at rest increased after treatment in S ( p = 0.009 ) but not in F. Subgroup analyses indicated that the improvement in rest ejection fraction in S was essentially observed in patients with ejection fraction < 40 % ( n = 8 , + 6 % ) , whereas it was stable in patients with ejection fraction > 40 % ( + 1.8 % ) . Finally , the numbers of akinetic or hypokinetic segments at rest and during exercise were not different in the two groups before and after treatment . Mean maximal exercise load ( 113+/-23 watts in F vs. 104+/-27 W in S before treatment ) was not modified by the treatment ( 111+/-21 and 104+/-27 W ) . Thus a 12-week lipid-lowering treatment with either S or F did not negatively alter left ventricular function during exercise in dyslipidemic patients with established coronary heart disease and did not affect their ability to exercise . The improvement in left ventricular function at rest after simvastatin in patients with left ventricular dysfunction warrants confirmation in further studies with large sample size The effect of statins on Lp(a ) levels is controversial ; furthermore , the potential action of statins on apo(a ) fragmentation is indeterminate . We therefore determined the circulating levels of Lp(a ) and of apo(a ) fragments in hypercholesterolemic patients before and after treatment ( 6 weeks ) with Atorvastatin 10 mg/day ( A10 ) or Simvastatin 20 mg/day ( S20 ) . In a double blind study , hypercholesterolemic patients ( n=391 ) at high cardiovascular risk ( LDL-C>=4.13 mmol/l ; TG<2.24 mmol/l ; 34 % with documented CHD ; 45 % hypertensive ; and 29 % current smokers ) were assigned to treatment with A10 ( n=199 ) or S20 ( n=192 ) . Plasma Lp(a ) and apo(a ) fragment levels ( n=206 ) were measured prior to and after treatment . At baseline , A10 and S20 groups did not differ in plasma levels of lipids , Lp(a ) ( A10 : 0.45+/-0.48 mg/ml , S20 : 0.46+/-0.5 ) , and apo(a ) fragments ( A10 : 3.88+/-5.22 microg/ml ; S20 : 3.25+/-3 ) , and equally in apo(a ) isoform size ( A10 : 26+/-5 kr , S20 : 25.5+/-5.3 ) . After treatment , both statins significantly reduced Lp(a ) levels ( A10 : 0.42+/-0.47 mg/ml , 6 % variation , P<0.001 ; S20 : 0.45+/-0.53 mg/ml , 0.02 % variation , P=0.046 ) . A10 and S20 did not significantly differ in their efficacy to lower Lp(a ) levels . In a multivariate logistic regression analysis , the reduction of Lp(a ) levels was independently associated with Lp(a ) baseline concentration , but not to other variables , including LDL-C reduction . Plasma levels of apo(a ) fragments were not modified by either statin . In conclusion , both A10 and S20 significantly lowered Lp(a ) , although this effect was of greater magnitude in atorvastatin-treated patients In a double-blind , r and omized crossover study , 29 patients with non-insulin-dependent diabetes mellitus ( NIDDM ) and hyperlipoproteinemia were treated with gemfibrozil ( 1,200 mg/d ) or simvastatin ( 10 mg/d ) for 4 months . After gemfibrozil treatment , the insulin concentration was increased during the major part of the intravenous glucose tolerance test ( IVGTT ) and during the hyperinsulinemic euglycemic clamp . Similar but less pronounced elevations were caused by simvastatin .  Insulin sensitivity decreased by 27 % and 28 % during gemfibrozil and simvastatin treatment , respectively . Low-density lipoprotein ( LDL ) cholesterol was decreased with simvastatin treatment by 24 % . The LDL cholesterol level was not changed by gemfibrozil , but very-low-density lipoprotein ( VLDL ) cholesterol was reduced by 40 % . The VLDL triglyceride concentration was reduced to a significantly greater extent by gemfibrozil . After gemfibrozil treatment , lipoprotein(a ) [ Lp(a ) ] was decreased by 24 % , and the plasma free fatty acid ( FFA ) concentration was increased by 20 % and skeletal muscle lipoprotein lipase activity ( LPLA ) by 37 % . Although simvastatin more effectively decreased LDL cholesterol levels and the LDL to high-density lipoprotein ( HDL ) ratio , it can not be cl aim ed unreservedly that this drug is necessarily preferable in NIDDM patients . Gemfibrozil improved triglyceride removal and decreased VLDL concentrations , with qualitative changes in LDL . The apparent effects on insulin sensitivity are difficult to evaluate and need further study CONTEXT Controversy exists as to whether lipoprotein(a ) , a lipoprotein with homology to plasminogen , is a clinical ly meaningful cardiovascular risk marker in women . There is also poor agreement among lipoprotein(a ) levels obtained by different assays . OBJECTIVE To determine the association of  lipoprotein(a ) levels , measured with an assay independent of apolipoprotein(a ) isoform size , with the incidence of future cardiovascular events . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve study of 27,791 initially healthy women in the Women 's Health Study , enrolled between November 1992 and July 1995 and followed up for 10 years .  Lipoprotein(a ) level  was measured in blood sample s obtained at baseline with an assay independent of apolipoprotein(a ) isoform size . MAIN OUTCOME MEASURE Hazard ratios ( HRs ) for first-ever major cardiovascular events ( nonfatal myocardial infa rct ion , nonfatal cerebrovascular event , coronary revascularization , or cardiovascular deaths ) . RESULTS During follow-up , there were 899 incident cardiovascular events . After adjusting for age , smoking , blood pressure , body mass index , total cholesterol , high-density lipoprotein cholesterol , diabetes , hormone use , C-reactive protein , and r and omization treatment groups , women in the highest quintile of lipoprotein(a ) ( > or = 44.0 mg/dL ) were 1.47 times more likely ( 95 % CI , 1.21 - 1.79 ; P for trend < .001 ) to develop cardiovascular events than women in the lowest quintile ( < or = 3.4 mg/dL ) . This association , however , was due almost entirely to a threshold effect among those with the highest lipoprotein(a ) levels . After adjusting for all of the variables listed above , the HR associated with lipoprotein(a ) levels exceeding the 90th percentile ( > or = 65.5 mg/dL ) was 1.66 ( 95 % CI , 1.38 - 1.99 ) ; 95th percentile ( > or = 83 mg/dL ) , 1.87 ( 95 % CI , 1.50 - 2.34 ) ; and 99th percentile ( > or = 130.7 mg/dL ) , 1.99 ( 95 % CI , 1.32 - 3.00 ) , with almost no risk gradient at lower levels . Associations were strongest among women with low-density lipoprotein cholesterol ( LDL-C ) above the median level . In this subgroup , the adjusted HR associated with lipoprotein(a ) levels exceeding the 90th percentile was 1.81 ( 95 % CI , 1.48 - 2.23 ) ; 95th percentile , 1.93 ( 95 % CI , 1.51 - 2.48 ) ; and 99th percentile , 1.93 ( 95 % CI , 1.21 - 3.05 ) ( P value for interaction with LDL-C = .001 ) . CONCLUSIONS In this cohort of initially healthy women , extremely high levels of lipoprotein(a ) ( > or = 90th percentile ) , measured with an assay independent of apolipoprotein(a ) isoform size , were associated with increased cardiovascular risk , particularly in women with high levels of LDL-C. However , the threshold and interaction effects observed do not support routine measurement of lipoprotein(a ) for cardiovascular stratification in women The safety and efficacy of combined bezafibrate-simvastatin therapy was evaluated in 49 patients with diet-resistant mixed hyperlipidaemia ( type IIb ) . After a two-month placebo phase , patients were r and omized to receive either Bezafibrate Slow Release ( SR ) 400 mg mane or simvastatin 20 mg nocte followed by three months combination therapy . Total cholesterol , triglycerides and high-density lipoprotein ( HDL ) cholesterol were measured at monthly intervals . Apolipoproteins ( apo ) A1 and B , lipoprotein ( a ) [ Lp(a ) ] and fibrinogen were measured before and after each treatment . Simvastatin was more effective than Bezafibrate SR in reducing total cholesterol ( 2.0 vs. 1.1 mmol/l , p = 0.003 ) and lowering LDL cholesterol ( 1.7 vs. 0.4 mmol/l , p = 0.0001 ) whereas Bezafibrate SR was more effective in reducing triglycerides ( by 41 % vs. 17 % , p = 0.001 ) and fibrinogen ( by 23 % vs. 3 % , p = 0.004 ) . Compared with simvastatin monotherapy , combined drug therapy induced further reductions in triglycerides ( by 26 % , p = 0.0003 ) and apoB ( by 11 mg/dl , p = 0.03 ) and an increase in apoA1 ( by 21 mg/dl , p = 0.0008 ) . Symptomatic and biochemical adverse events did not occur more frequently on combined drug therapy than on monotherapy . The combination of bezafibrate and simvastatin was more effective in controlling mixed hyperlipidaemia than either drug alone and did not provoke more adverse events OBJECTIVES The primary objective of this study was to evaluate the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of 5 SAR236553/REGN727 ( SAR236553 ) dosing regimens versus placebo at week 12 in patients with LDL-C ≥100 mg/dl on stable atorvastatin therapy . Secondary objectives included evaluation of effects on other lipid parameters and the attainment of LDL-C treatment goals of < 100 mg/dl ( 2.59 mmol/l ) and < 70 mg/dl ( 1.81 mmol/l ) . BACKGROUND Serum proprotein convertase subtilisin kexin 9 ( PCSK9 ) binds to low-density lipoprotein receptors , increasing serum LDL-C. SAR236553 is a fully human monoclonal antibody to PCSK9 . METHODS This double-blind , parallel-group , placebo-controlled trial r and omized 183 patients with LDL-C ≥100 mg/dl ( 2.59 mmol/l ) on stable-dose atorvastatin 10 , 20 , or 40 mg for ≥6 weeks to : subcutaneous placebo every 2 weeks ( Q2W ) ; SAR236553 50 , 100 , or 150 mg Q2W ; or SAR236553 200 or 300 mg every 4 weeks ( Q4W ) , alternating with placebo for a total treatment period of 12 weeks . RESULTS SAR236553 demonstrated a clear dose-response relationship with respect to percentage LDL-C lowering for both Q2W and Q4W administration : 40 % , 64 % , and 72 % with 50 , 100 , and 150 mg Q2W , respectively , and 43 % and 48 % with 200 and 300 mg Q4W . LDL-C reduction with placebo at week 12 was 5 % . SAR236553 also substantially reduced non-high-density lipoprotein cholesterol , apolipoprotein B , and lipoprotein(a ) . SAR236553 was generally well tolerated . One patient on SAR236553 experienced a serious adverse event of leukocytoclastic vasculitis . CONCLUSIONS When added to atorvastatin , PCSK9 inhibition with SAR236553  further reduces LDL-C by 40 % to 72 % . These additional reductions are both dose- and dosing frequency-dependent . ( Efficacy and Safety Evaluation of SAR236553 [ REGN727 ] in Patients With Primary Hypercholesterolemia and LDL-cholesterol on Stable Atorvastatin Therapy ; NCT01288443 ) 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 OBJECTIVES The purpose of this study was assess the effect of  evolocumab  (  AMG 145 ) on lipoprotein (Lp)(a ) from a pooled analysis of 4 phase II trials . BACKGROUND Lp(a ) , a low-density lipoprotein ( LDL ) particle linked to the plasminogen-like glycoprotein apolipoprotein(a ) , shows a consistent and independent positive association with cardiovascular disease risk in epidemiological studies . Current therapeutic options to reduce Lp(a ) are limited . METHODS A pooled analysis of data from 1,359 patients in 4 phase II trials assessed the effects of  evolocumab  , a fully human monoclonal antibody to PCSK9 , on Lp(a ) , the relationship between Lp(a ) and lowering of low-density lipoprotein cholesterol ( LDL-C ) and apolipoprotein B , and the influence of background statin therapy . Lp(a ) was measured using a st and ardized isoform-independent method . RESULTS Evolocumab treatment for 12 weeks result ed in significant ( p < 0.001 ) mean ( 95 % confidence interval ) dose-related reductions in Lp(a ) compared to control : 29.5 % ( 23.3 % to 35.7 % ) and 24.5 % ( 20.4 % to 28.7 % ) with 140 mg and 420 mg , dosed every 2 and 4 weeks , respectively , with no plateau of effect . Lp(a ) reductions were significantly correlated with percentages of reductions in LDL-C ( Spearman correlation coefficient , 0.5134 ; p < 0.001 ) and apolipoprotein B ( Spearman correlation coefficient , 0.5203 ; p < 0 . 001 ) . Mean percentage reductions did not differ based on age or sex but the trend was greater in those patients taking statins . CONCLUSIONS Inhibition of PCSK9 with evolocumab result ed in significant dose-related reductions in Lp(a ) . While the mean percentage of reduction was significantly greater in those patients with baseline Lp(a ) of ≤125 nmol/l , the absolute reduction was substantially larger in those with levels > 125 nmol/l BACKGROUND Large-scale prospect i ve data are needed to determine whether associations between lipoprotein(a ) ( Lp[a ] ) and coronary heart disease ( CHD ) risk are independent of established risk factors , to characterize the shape of this relationship , and to quantify associations in relevant subgroups . METHODS Levels of Lp(a )  were measured in sample s obtained at baseline from 2047 patients who had first-ever nonfatal myocardial infa rct ion or who died of CHD during the study and from 3921 control participants in the Reykjavik Study ( n=18 569 ) , as well as in paired sample s obtained 12 years apart from 372 participants to quantify within-person fluctuations . RESULTS Baseline Lp(a ) levels had little or no correlation with known cardiovascular risk factors , such as age , sex , total cholesterol level , and blood pressure . The Lp(a ) values were highly consistent from decade to decade , with a regression dilution ratio ( calculated on the log scale ) of 0.92 ( 95 % confidence interval , 0.85 - 0.99 ) . The odds ratio for CHD , unaltered after adjustment for several established risk factors ( age , sex , smoking status , blood pressure , total cholesterol , triglycerides level , diabetes mellitus , and body mass index ) , was 1.60 ( 95 % confidence interval , 1.38 - 1.85 ) in a comparison of extreme thirds of baseline Lp(a ) levels . Odds ratios were progressively higher with increasing Lp(a ) levels and did not vary material ly by several individual- or study -level characteristics . CONCLUSIONS There are independent , continuous associations between Lp(a ) levels and risk of future CHD in a broad range of individuals . Levels of Lp(a ) are highly stable within individuals across many years and are only weakly correlated with known risk factors . Further assessment of their possible role in CHD prevention is warranted BACKGROUND AND AIM Impaired triglyceride-rich lipoprotein metabolism is most probably related to an enhanced cardiovascular risk , and may be associated with a pro-coagulant state . A double-blind , r and omized study was undertaken to evaluate two widely utilized hypolipidemic drugs in the post-pr and ial phase and their impact on lipid , coagulation and fibrinolytic parameters . METHODS AND RESULTS Thirty middle-aged men selected according to their low density lipoprotein-cholesterol ( LDL-C ) > or = 160 and < or = 240 mg/dl and borderline hypertriglyceridemia ( 110 - 220 mg/dl ) after at least one month of a lipid-lowering diet received gemfibrozil ( 600 mg bid ) or simvastatin ( 20 mg qd ) and the corresponding placebo . On enrollment and after 2 months of drug treatment , they were tested with a st and ard oral fat load ( OFL ) ( 35 g fat/m2 body surface ) . On both occasions plasma total-cholesterol , LDL-C , HDL-C , triglycerides , lipoprotein[a ] ( Lp[a ] ) , tissue plasminogen activator ( tPA ) , plasminogen activator inhibitor-1 ( PAI-1 ) , antithrombin-III ( AT-III ) , plasminogen and fibrinogen were determined just before the meal ( t0 ) and at times 2 hours , 4 h , 6 h , 8 h after it ( t2-t8 ) . A two-factor ( time and visit ) multivariate analysis for repeated measurements was performed to evaluate the data . Total cholesterol , and LDL-C were significantly diminished 2 months after both gemfibrozil and simvastatin , the latter being more active . Plasma triglycerides showed a marked reduction with gemfibrozil at all times , while simvastatin regimen yielded only minor modifications . HDL-C was only slightly increased by simvastatin ;  Lp[a ] plasma levels were almost unaffected . Small fibrinogen ( t0 , t2 , t6 , t8 ) , PAI-1 ( t6 ) and AT III ( t0-t8 ) increases were observed after gemfibrozil , while simvastatin did not significantly modify these parameters . CONCLUSIONS In the post-pr and ial phase , gemfibrozil and simvastatin induce different metabolic effects that beneficially influence the lipid pattern , whereas fibrinolytic and coagulative parameters display minor variations of undetermined significance Background — Lipoprotein(a ) [ Lp(a ) ] is a low-density lipoprotein – like particle largely independent of known risk factors and predictive of cardiovascular disease . Statins may offset the risk associated with elevated Lp(a ) , but it is unknown whether Lp(a ) is a determinant of residual risk in the setting of low low-density lipoprotein cholesterol after potent statin therapy . Methods and Results — Baseline and on-treatment Lp(a ) concentrations were assessed in 9612 multiethnic participants in the JUPITER trial ( Justification for the Use of Statins in Prevention : An Intervention Trial Evaluating Rosuvastatin ) before and after r and om allocation to rosuvastatin 20 mg/d or placebo , with outcomes reported for whites ( n=7746 ) .  Lp(a ) concentrations ( median [ 25th–75th percentile ] , in nmol/L ) were highest in blacks ( 60 [ 34–100 ] ) , then Asians ( 38 [ 18–60 ] ) , Hispanics ( 24 [ 11–46 ] ) , and whites ( 23 [ 10–50 ] ; P<0.001 ) . Although the median change in Lp(a ) with rosuvastatin and placebo was zero , rosuvastatin nonetheless result ed in a small but statistically significant positive shift in the overall Lp(a ) distribution ( P<0.0001 ) . Baseline Lp(a ) concentrations were associated with incident cardiovascular disease ( adjusted hazard ratio per 1-SD increment in Ln[Lp(a ) ] , 1.18 ; 95 % confidence interval , 1.03–1.34 ; P=0.02 ) . Similarly , on-statin Lp(a ) concentrations were associated with residual risk of cardiovascular disease ( adjusted hazard ratio , 1.27 ; 95 % confidence interval , 1.01–1.59 ; P=0.04 ) , which was independent of low-density lipoprotein cholesterol and other factors . Rosuvastatin significantly reduced incident cardiovascular disease among participants with baseline Lp(a ) greater than or equal to the median ( hazard ratio , 0.62 ; 95 % confidence interval , 0.43–0.90 ) and Lp(a ) less than the median ( hazard ratio , 0.46 ; 95 % confidence interval , 0.30–0.72 ) , with no evidence of interaction . Similar results were obtained when analyses included nonwhites . Conclusion — Among white JUPITER participants treated with potent statin therapy , Lp(a ) was a significant determinant of residual risk . The magnitude of relative risk reduction with  rosuvastatin was similar among participants with high or low Lp(a ) . Clinical Trials Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00239681
target: Conclusions Fibrates have a significantly greater effect in reducing plasma Lp(a ) concentrations than statins .
  Addition of fibrates to statins can enhance the Lp(a)-lowering effect of statins
background: Background Raised plasma lipoprotein(a ) ( Lp(a ) ) concentration is an independent and causal risk factor for atherosclerotic cardiovascular disease .
  Several types of pharmacological approaches are under evaluation for their potential to reduce plasma Lp(a ) levels .
  There is suggestive evidence that statins and fibrates , two frequently employed lipid-lowering drugs , can lower plasma Lp(a ) .
  The present study aims to compare the efficacy of fibrates and statins in reducing plasma concentrations of Lp(a ) using a meta- analysis of r and omized head-to-head trials .