Long term statin treatment reduces lipoprotein(a) concentrations in heterozygous familial hypercholesterolaemia Atorvastatin lowers lipoprotein(a) but not apolipoprotein(a) fragment levels in hypercholesterolemic subjects at high cardiovascular risk. Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian Randomization Analysis Lipoprotein(a) as a cardiovascular risk factor: current status Bezafibrate and simvastatin combination therapy for diabetic dyslipidaemia: efficacy and safety. Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2 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) Effects of gemfibrozil or simvastatin on apolipoprotein-B-containing lipoproteins, apolipoprotein-CIII and lipoprotein(a) in familial combined hyperlipidaemia. Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: a rationale for increased efforts to understand its pathophysiology and develop targeted therapies. Serially increasing change in lipoprotein(a) concentration has predictive value in acute vascular events Lipoprotein(a) in American Indians is low and not independently associated with cardiovascular disease. The Strong Heart Study. Apolipoprotein(a) kringle IV repeat number predicts risk for coronary heart disease. Increased plasma concentrations of TGF-beta1 after hormone replacement therapy. Effect of statin and fibrate treatment on inflammation in type 2 diabetes. A randomized, cross-over study. Effect of Alirocumab on Lipoprotein(a) Over ≥1.5 Years (from the Phase 3 ODYSSEY Program). Atherogenic forms of dyslipidaemia in women with polycystic ovary syndrome. Effect of gemfibrozil on lipoprotein abnormalities in chronic renal insufficiency: a controlled study in human chronic renal disease. Energy intake is associated with endotoxemia in apparently healthy men. Interactions between fibrinolysis, lipoproteins and leptin related to a first myocardial infarction Healthy Dietary Interventions and Lipoprotein (a) Plasma Levels: Results from the Omni Heart Trial Lowering of lipoprotein(a) level under niacin treatment is dependent on apolipoprotein(a) phenotype. Acute Reduction of Lipoprotein(a) by Tissue‐Type Plasminogen Activator Lipoprotein-Associated Phospholipase A2 and Its Association With Cardiovascular Outcomes in Patients With Acute Coronary Syndromes in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction) Trial Effects of eicosapentaenoic acid and docosahexaenoic acid on cardiovascular disease risk factors: a randomized clinical trial. Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a) [S] Is lipoprotein(a) an independent risk factor for ischemic heart disease in men? The Quebec Cardiovascular Study. Plasma lipoprotein-associated phospholipase A2 levels in heart failure: association with mortality in the community. Effects of bezafibrate and of 2 HMG-CoA reductase inhibitors on lipoprotein (a) level in hypercholesterolemic patients. Effect of therapeutic interventions on oxidized phospholipids on apolipoprotein B100 and lipoprotein(a). Insulin-like growth factor binding protein-1 (IGFBP-1) and IGF-I during oral and transdermal estrogen replacement therapy: relation to lipoprotein(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 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 Importance Human genetic studies have indicated that plasma lipoprotein(a ) ( Lp[a ] ) is causally associated with the risk of coronary heart disease ( CHD ) , but r and omized trials of several therapies that reduce Lp(a ) levels by 25 % to 35 % have not provided any evidence that lowering Lp(a ) level reduces CHD risk . Objective To estimate the magnitude of the change in plasma Lp(a ) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL ( ie , 1-mmol/L ) change in low-density lipoprotein cholesterol ( LDL-C ) level , a change that has been shown to produce a clinical ly meaningful reduction in the risk of CHD . Design , Setting , and Participants A mendelian r and omization analysis was conducted using  individual participant data  from 5 studies and with external validation using summarized data from 48 studies . Population -based prospect i ve cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data , whereas summarized data included 62 240 patients with CHD and 127 299 controls . Data were analyzed from November 2016 to March 2018 . Exposures Genetic LPA score and plasma Lp(a ) mass concentration . Main Outcomes and Measures Coronary heart disease .  Results Of the included study participants , 53 % were men , all were of white European ancestry , and the mean age was 57.5 years . The association of genetically predicted Lp(a ) with CHD risk was linearly proportional to the absolute change in Lp(a ) concentration . A 10-mg/dL lower genetically predicted Lp(a ) concentration was associated with a 5.8 % lower CHD risk ( odds ratio [ OR ] , 0.942 ; 95 % CI , 0.933 - 0.951 ; P = 3 × 10−37 ) , whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5 % lower CHD risk ( OR , 0.855 ; 95 % CI , 0.818 - 0.893 ; P = 2 × 10−12 ) . Thus , a 101.5-mg/dL change ( 95 % CI , 71.0 - 137.0 ) in Lp(a ) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level . The association of genetically predicted Lp(a ) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins , PCSK9 inhibitors , and ezetimibe with CHD risk . Conclusions and Relevance The clinical benefit of lowering Lp(a ) is likely to be proportional to the absolute reduction in Lp(a ) concentration . Large absolute reductions in Lp(a ) of approximately 100 mg/dL may be required to produce a clinical ly meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL ( ie , 1 mmol/L ) Aims The aims of the study were , first , to critically evaluate lipoprotein(a ) [ Lp(a ) ] as a cardiovascular risk factor and , second , to advise on screening for elevated plasma Lp(a ) , on desirable levels , and on therapeutic strategies . Methods and results The robust and specific association between elevated Lp(a ) levels and increased cardiovascular disease (CVD)/coronary heart disease ( CHD ) risk , together with recent genetic findings , indicates that elevated Lp(a ) , like elevated LDL-cholesterol , is causally related to premature CVD/CHD . The association is continuous without a threshold or dependence on LDL- or non-HDL-cholesterol levels . Mechanistically , elevated Lp(a ) levels may either induce a prothrombotic/anti-fibrinolytic effect as apolipoprotein(a ) resembles both plasminogen and plasmin but has no fibrinolytic activity , or may accelerate atherosclerosis because , like LDL , the Lp(a ) particle is cholesterol-rich , or both . We advise that Lp(a ) be measured once , using an isoform-insensitive assay , in subjects at intermediate or high CVD/CHD risk with premature CVD , familial hypercholesterolaemia , a family history of premature CVD and /or elevated Lp(a ) , recurrent CVD despite statin treatment , ≥3 % 10-year risk of fatal CVD according to European guidelines , and /or ≥10 % 10-year risk of fatal + non-fatal CHD according to US guidelines . As a secondary priority after LDL-cholesterol reduction , we recommend a desirable level for Lp(a ) < 80th percentile ( less than ∼50 mg/dL ) . Treatment should primarily be niacin 1–3 g/day , as a meta- analysis of r and omized , controlled intervention trials demonstrates reduced CVD  by niacin treatment . In extreme cases , LDL-apheresis is efficacious in removing Lp(a ) . Conclusion We recommend screening for elevated Lp(a ) in those at intermediate or high CVD/CHD risk , a desirable level < 50 mg/dL as a function of global cardiovascular risk , and use of niacin for Lp(a ) and CVD/CHD risk reduction OBJECTIVE To determine the efficacy and safety of a statin-fibrate combination in diabetes patients . DESIGN . : An open 21-month trial in which each patient first received the single drug for 6 months and then a combination of the two for 1 year . SETTING Three lipid clinics in university-based tertiary care hospitals . PATIENTS One hundred and forty-eight patients with type 2 ( non-insulin-dependent , NIDDM ) diabetes mellitus under stable control for 3 months by means of diet and oral hypoglycaemic medication . INTERVENTION Patients from one clinic ( n = 48 ) received bezafibrate slow release ( 400 mg day-1 ) , and patients from the other two clinics ( n = 100 ) received simvastatin 20 mg day-1 . Six months later , all patients were switched to a daily combination of 400 mg bezafibrate slow release and 20 mg simvastatin for 1 year . RESULTS The combination of statin and fibrate led to a 23 % reduction in total cholesterol , 42 % reduction in triglycerides , 29 % reduction in LDL-c , 25 % increase in HDL-c , 10 % decrease in fibrinogen and 19 % reduction of Lp(a ) levels , and a decrease in the cholesterol/HDL-c ratio ( from 8.9 to 5.4 ) in all 148 patients . Cardiovascular ( CV ) event rate was significantly reduced from 9.5 % during the first 6 months of the study to less than 2 % during the last year of the study ( whilst on combination Rx ) . Side-effects with all treatments included only two patients who developed myopathy when on the combined regimen and one on the single statin regimen . However , plasma creatinine phosphokinase ( CPK ) levels doubled ( but remained within the normal range ) in most of the patients on combination therapy , compared with only a mild increase in patients receiving a single medication . CONCLUSIONS The statin and fibrate combination was found to be more efficacious than a single medication for treatment of diabetic dyslipidaemia , as evidence d by improvement in the lipoprotein profile , reductions in Lp(a ) , fibrinogen and CV event rate , and almost no clinical ly significant side-effects 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 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 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 Recent published studies have provided increasing evidence that lipoprotein(a ) [ Lp(a ) ] may be a potential causal , genetic , independent risk factor for cardiovascular disease ( CVD ) . Lp(a ) levels > 25 mg/dl are present in ∼30 % of Caucasians and 60 % to 70 % of Blacks . Lp(a ) is composed of apolipoprotein B-100 and apolipoprotein ( a ) [ ( apo(a ) ] . Circulating Lp(a ) levels are primarily influenced by the LPA gene without significant dietary or environmental effects , mediating CVD risk throughout the patient 's lifetime . Recent clinical outcomes studies , meta-analyses , and Mendelian r and omization studies , in which r and omization of Lp(a ) levels is achieved through the r and om assortment of LPA gene variants thereby removing confounders , have shown that genetically determined Lp(a ) levels are continuously and linearly related to risk of CVD . Currently , Lp(a ) pathophysiology is not fully understood , and specifically targeted therapies to lower Lp(a ) are not available . We provide a rationale for increased basic and clinical investigational efforts to further underst and Lp(a ) pathophysiology and assess whether reducing Lp(a ) levels minimizes CVD risk . First , a detailed underst and ing of Lp(a ) synthesis and clearance has not been realized . Second , several mechanisms of atherogenicity are known to varying extent , but the relative contributions of each are not known . Lp(a ) may be atherothrombotic through its low-density lipoprotein moiety , but also through apo(a ) , including its ability to be retained in the vessel wall and mediate pro-inflammatory and proapoptotic effects including those potentiated by its content of oxidized phospholipids , and antifibrinolytic effects . Finally , development of specific Lp(a)-lowering agents to potently lower Lp(a ) will allow testing of mechanistic hypotheses in animal models and the design of r and omized clinical trials to assess reduction in CVD . A convergence of academic , scientific , pharmaceutical , and National Institutes of Health priorities and efforts can make this a reality in the next decade Background : Lipoprotein(a ) ( Lp(a ) ) has been regarded in some studies as an independent risk factor of atherosclerotic vascular disease . However , the use of a baseline plasma Lp(a ) concentration as a screening tool for future acute vascular events ( AVE ) is controversial . We therefore investigated whether progressively increasing change in plasma Lp(a ) concentration is associated with the development of AVE . Methods : We investigated prospect i ve analyses of 985 participants ( 464 women and 521 men ) who had either clinical ly evident vascular disease ( VD group , n=443 ) or its risk factor(s ) ( RF group , n=542 ) .  Blood sample s were taken from all participants every six months to measure inflammatory markers such as Lp(a ) and C-reactive protein during a 10-year follow-up period . Results : During the follow-up , 223 new cases of myocardial infa rct ion , stroke , and peripheral arterial disease were identified . In the RF group , the relative risk of positive ∆ Lp(a ) for predicting AVE was 4.36 ( 95 % confidence interval [ CI ] 1.76 - 10.85 ; P=0.002 ) . In the VD group , the relative risk of positive ∆ Lp(a ) for predicting AVE was 6.35 ( 95 % CI 3.68 - 10.97 ; P<0.001 ) . Conclusions : These results suggest that a progressively increasing change in Lp(a ) concentration has a highly significant predictive value in AVE in both the VD and the RF groups PURPOSE To evaluate the distribution of  lipoprotein(a ) ( Lp(a ) ) and assess its association to cardiovascular disease ( CVD ) in American Indians . METHODS  Lp(a )  was measured in 3991 American Indians ( aged 45 - 74 years with no prior history of CVD at baseline ) from 13 communities in Arizona , Oklahoma , and South/North Dakota . They were followed prospect ively from 1989 to 1997 for CVD . The distribution of Lp(a ) was examined by center , sex , and diabetic status . Spearman correlation coefficients and Cox regression models were used to evaluate the association of Lp(a ) to CVD . RESULTS A total of 388 participants subsequently developed CVD .  Median Lp(a ) concentration in American Indians was 3.0 mg/dl . This was almost half of that in whites and one sixth in blacks from the CARDIA study measured by the same method . Nondiabetic participants had significantly higher Lp(a ) levels than diabetic participants for both genders . Lp(a ) levels were higher in women than in men for nondiabetic participants , but there was no gender difference for diabetic participants . Correlation analysis showed Lp(a ) was significantly negatively correlated with the degree of Indian heritage , insulin , triglycerides ( TG ) , fasting plasma glucose ( FPG ) , and 2-hour plasma glucose ( 2hPG ) , and positively with low-density lipoproteins ( LDL ) , apoprotein B ( apoB ) , and fibrinogen ( FIB ) . In Cox regression models , adjusting for other risk factors , Lp(a ) was no longer a significant predictor of CVD in either diabetic or nondiabetic participants . CONCLUSIONS The lower concentration of Lp(a ) in American Indians and the high correlation with Indian heritage confirm the concept that Lp(a ) concentration is in large part genetically determined . Lp(a ) concentration is not an independent predictor of CVD among American Indians ; it is higher in those who develop CVD because of its positive correlation with LDL , apoB , and FIB A high plasma concentration of lipoprotein(a ) [ Lp(a ) ] has been suggested as a risk factor for coronary heart disease ( CHD ) , but some recent prospect i ve studies have question ed the significance of Lp(a ) . Lp(a ) concentrations are determined to a large extent by the hypervariable apo(a ) gene locus on chromosome 6q2.7 , which contains a variable number of identical t and emly arranged transcribed kringle IV type 2 repeats . The number of these repeats correlates inversely with plasma Lp(a ) concentration . We analyzed whether apo(a ) gene variation ( kringle IV repeat number ) is associated with CHD . Apo(a ) genotypes were determined by pulsed-field gel electrophoresis/genomic blotting in CHD patients who had undergone angiography ( n = 69 ) and control subjects matched for age , sex , and ethnicity ( n = 69 ) and were related to Lp(a ) concentration , apo(a ) isoform in plasma , and disease status . Apo(a ) alleles with a low kringle IV copy number ( < 22 ) and high Lp(a ) concentration were significantly more frequent in the CHD group ( P < .001 ) , whereas large nonexpressed alleles were more frequent in control subjects . The odds ratio for CHD increased continuously with a decreasing number of kringle IV repeats and ranged from 0.3 in individuals with > 25 kringle IV repeats on both alleles to 4.6 in those with < 20 repeats on at least one allele . This provides direct genetic evidence that variation at the apo(a ) gene locus , which determines Lp(a ) levels , is also a determinant of CHD risk OBJECTIVES AND DESIGN Hormone replacement therapy ( HRT ) in postmenopausal women may reduce the cardiovascular risk . A dominant protective role of transforming growth factor beta ( TGF-beta1 ) on coronary arteries has been proposed . Lp(a ) lipoprotein may block the activation of latent TGF-beta1 . Given this background , we examined the effects of HRT on TGF-beta1 and Lp(a ) lipoprotein in 99 postmenopausal women . The women had angiographically documented coronary heart disease ( CHD ) and were r and omized to either sequential transdermal 17beta-oestradiol for 14 weeks and then medroxyprogesterone ( MPA ) for 14 days ( HRT ) or to a control group ( C ) . RESULTS Serum levels of TGF-beta1 were increased in the HRT group compared with the C group after 3 months ' treatment and this effect was sustained after 12 months . There was a significant reduction in Lp(a ) lipoprotein serum levels after 3 months ' treatment in the HRT group compared with the C group . However , after 12 months , no significant difference in changes in Lp(a ) lipoprotein serum levels was detected between the two groups . CONCLUSION The novel observation that transdermal 17beta-oestradiol in postmenopausal women increases levels of TGF-beta1 and lowers the concentration of Lp(a ) lipoprotein suggests yet another possible mechanism for the cardioprotective effect of HRT . Whereas combination therapy of oestradiol and MPA preserves the beneficial effect on TGF-beta1 , it reduces the unopposed oestradiol effects on Lp(a ) lipoprotein A r and omized , crossover study compared the effects of atorvastatin , gemfibrozil and their combination on inflammatory markers in type 2 diabetes .  C-reactive protein ( CRP ) , lipoprotein-associated phospholipase A2 ( Lp-PLA2 ) , secretory phospholipase A2 ( sPLA2 ) , interleukin 8 ( IL8 ) , monocyte chemotactic protein 1 ( MCP1 ) and tumor necrosis factor α ( TNFα ) were measured . Both lipid-lowering drugs had positive , complementary and additive effects on inflammatory markers , which were closely related to baseline inflammatory status Elevated lipoprotein(a ) [ Lp(a ) ] is independently associated with increased cardiovascular risk . However , treatment options for elevated Lp(a ) are limited . Alirocumab , a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 , reduced low-density lipoprotein cholesterol ( LDL-C ) by up to 62 % from baseline in phase 3 studies , with adverse event rates similar between alirocumab and controls . We evaluated the effect of alirocumab on serum Lp(a ) using pooled data from the phase 3 ODYSSEY program : 4,915 patients with hypercholesterolemia from 10 phase 3 studies were included . Eight studies evaluated alirocumab 75 mg every 2 weeks ( Q2W ) , with possible increase to 150 mg Q2W at week 12 depending on LDL-C at week 8 ( 75/150 mg Q2W ) ; the other 2 studies evaluated alirocumab 150-mg Q2W from the outset . Comparators were placebo or ezetimibe . Eight studies were conducted on a background of statins , and 2 studies were carried out with no statins . Alirocumab was associated with significant reductions in Lp(a ) , regardless of starting dose and use of concomitant statins . At week 24 , reductions from baseline were 23 % to 27 % with alirocumab 75/150-mg Q2W and 29 % with alirocumab 150-mg Q2W ( all comparisons p < 0.0001 vs controls ) . Reductions were sustained over 78 to 104 weeks . Lp(a ) reductions with alirocumab were independent of race , gender , presence of familial hypercholesterolemia , baseline Lp(a ) , and LDL-C concentrations , or use of statins . In conclusion , in addition to marked reduction in LDL-C , alirocumab leads to a significant and sustained lowering of Lp(a ) OBJECTIVE Dyslipidaemia is very common in patients with polycystic ovary syndrome ( PCOS ) but , beyond plasma lipids , atherogenic lipoprotein ( Lp ) and apolipoprotein ( apo ) alterations are still ill defined . DESIGN We measured concentrations of apoB , Lp(a ) and small , dense low-density lipoprotein ( LDL )  in 42 patients with PCOS [ age : 28 + /- 7 years , body mass index ( BMI ): 27 + /- 5 kg/m(2 ) ] vs. 37 age- and BMI -matched healthy controls . METHODS Elevated  Lp(a ) levels  considered were those > 30 mg/dl while elevated apoB concentrations were those > 100 g/l . RESULTS Polycystic ovary syndrome showed increased triglycerides levels ( p = 0.0011 ) and lower high-density lipoprotein (HDL)-cholesterol concentrations ( p = 0.0131 ) while total- and LDL cholesterol were similar . PCOS also showed smaller LDL size ( p = 0.0005 ) , higher levels of total small , dense LDL ( p < 0.0001 ) , higher concentrations of Lp(a ) , as considered as absolute values ( p = 0.0143 ) and log-transformed ( p = 0.0014 ) , while no differences were found in apoB levels . Elevated Lp(a ) concentrations were found in 24 % of PCOS , while elevated apoB levels were relatively uncommon ( 14 % ) . Spearman correlation analysis revealed that Lp(a ) concentrations were weakly correlated only with HDL-cholesterol levels ( r = -0.378 , p = 0.0431 ) . In addition , 36 % of patients with PCOS with normal plasma lipid profile showed elevated levels of Lp(a ) , apoB or small , dense LDL . CONCLUSIONS Atherogenic Lp abnormalities may be found in one-third of women with PCOS who have a normal lipid pattern . Future prospect i ve studies are needed to test to which extent such atherogenic forms of dyslipidaemia may contribute to the increased cardiovascular risk in young women with PCOS BACKGROUND Renal dyslipoproteinemia is characterized by the accumulation of intact and partially metabolized triglyceride-rich lipoproteins . Reduced lipolytic enzyme activities may be one of the major pathophysiological mechanisms contributing to a retarded catabolism of these lipoproteins in patients with renal insufficiency . OBJECTIVE To evaluate the effect of gemfibrozil treatment on renal dyslipoproteinemia . STUDY DESIGN A r and omized , controlled open study with 2 parallel groups . OUTCOME VARIABLES Plasma concentrations of lipids , apolipoproteins and lipoprotein particles . PATIENTS AND METHODS Fifty-seven non-nephrotic , non-diabetic patients with moderately advanced renal insufficiency were r and omized to either treatment with gemfibrozil at dosages from 300 to 900 mg/day ( n = 28 ) or dietary counseling ( n = 29 ) . The intervention period was 12 months . Plasma concentrations of lipids , apolipoproteins and apoA- and apoB-containing lipoprotein particles were determined at the entry and after 6 and 12 months of treatment . RESULTS No serious adverse effects occurred during the study . Six patients experienced mild gastrointestinal symptoms and prematurely withdrew from the drug treatment . In the group treated with gemfibrozil the plasma concentrations of triglycerides , total cholesterol , very low density lipoprotein ( VLDL ) and low density ( LDL ) cholesterol decreased significantly by 47 , 13 , 43 and 14 % , respectively , in comparison to baseline . High density lipoprotein ( HDL ) cholesterol increased significantly by 18 % . ApoB , apoC-III , apoC-III in heparin-manganese precipitate ( reflecting apoC-III in VLDL and LDL ) and apoE decreased significantly by 21 , 18 , 26 and 49 % , respectively . Furthermore , gemfibrozil treatment result ed in the reduction of plasma concentrations of complex ( LP-Bc ) and simple ( LP-B ) apoB-containing lipoprotein particles by 22 and 7 % , respectively . However , these changes were not statistically significant . There was a slight , insignificant increase in the levels of LP-A-I : A-II particles and no change in the levels of LP-A-I particles . In contrast to the effect of the pharmacological intervention , the dietary counseling only result ed in minor changes in the plasma lipid and apolipoprotein profiles . The only significant changes were a 10 % increase in HDL cholesterol and a 35 % decrease in apoE. CONCLUSIONS Gemfibrozil treatment significantly reduces both plasma lipids and apoB , apoC-III and apoE concentrations in patients with moderately advanced renal insufficiency . The results of this study indicate that gemfibrozil enhances the clearance of apoB-containing triglyceride-rich lipoproteins BACKGROUND The bridge between food intake and weight is not fully understood . Recently , the role of gut microbiota and bacterial lipopolysacharides ( LPS ) in weight has been noted . OBJECTIVE The objective was to evaluate the relation between plasma LPS concentration and food intake . DESIGN A dietary survey was conducted in 1015 subjects r and omly recruited in France . The participants were given oral and written instructions on how to keep a consecutive 3-d food record . Plasma LPS was measured in a sub sample of 201 men . To assess , under controlled conditions , the differential impact of various high-energy diets , plasma LPS concentrations were measured in mice fed a high-fat or a high-carbohydrate diet over a 4-wk period . RESULTS In humans , no significant relation was observed between cardiovascular disease risk factors , carbohydrate and protein intakes , and plasma LPS concentration . Conversely , positive correlations were observed with fat and energy intakes . In a multivariate analysis , endotoxemia was independently associated with energy intake . Compared with the control mice , mice fed a high-energy diet showed an increase in plasma LPS . However , in mice fed a high-carbohydrate diet , the increase in plasma LPS was blunted compared with mice fed a high-fat diet . CONCLUSIONS In this large sample of healthy men from a population -based sample , we found a link between food intake and plasma LPS . Experimental data suggest that fat was more efficient in transporting bacterial LPS from the gut lumen into the bloodstream . The results of this study add to the knowledge of mechanisms responsible for relations between food intake and metabolic diseases Background The summarized importance of haemostatic and metabolic variables ( insulin , lipids including lipoprotein ( a ) [ Lp(a ) ] and leptin ) in predicting first  myocardial infa rct  ion , as well as possible interactions among these variables , have not been reported . Design A prospect i ve case-control study nested within the Northern Sweden Health and Disease Cohort . Methods Sixty-two men diagnosed with a first myocardial infa rct ion were sex- and age-matched with 124 controls .  Conditional logistic regression was conducted including established risk factors , plasma levels of  plasminogen activator inhibitor-1 ( PAI-1 ) , tissue plasminogen activator ( tPA ) mass concentration , von Willebr and factor , insulin , proinsulin , specific insulin , apolipoprotein A-I ( apo A-I ) , Lp(a ) , and leptin . Interaction analysis was also performed for tPA , apo A-I , Lp(a ) , leptin and proinsulin . Results Smoking , low plasma levels of apo A-I and high plasma levels of cholesterol , Lp(a ) , tPA , PAI-1 , proinsulin and leptin were associated with myocardial infa rct ion in univariate conditional logistic regression analysis . High tPA [ odds ratio ( OR ) , 21.3 ; 95 % confidence interval ( CI ) , 2.04 - 222 ] and Lp(a ) ( OR , 7.21 ; 95 % CI , 1.31 - 39.8 ) and low apo A-I ( OR , 0.15 ; 95 % CI , 0.02 - 0.93 ) remained significant risk determinants in multivariate analysis with smoking habits , body mass index , hypertension , cholesterol , and diabetes included as covariates . There were non-significant synergic interactions between high Lp(a ) and leptin and tPA , respectively , and between high Lp(a ) and low apo A-I. Conclusion Plasma levels of tPA , Lp(a ) , and apo A-I are independently associated with subsequent development of a first myocardial infa rct ion in men Background Increased lipoprotein(a ) [ Lp(a ) ] levels are associated with atherosclerotic cardiovascular disease . Studies of dietary interventions on changes in Lp(a ) are sparse . We aim ed to compare the effects of three healthy dietary interventions differing in macronutrient content on Lp(a ) concentration . Methods Secondary analysis of a r and omized , 3-period crossover feeding study including 155 ( 89 blacks ; 66 whites ) individuals . Participants were given DASH-type healthy diets rich in carbohydrates [ Carb ] , in protein [ Prot ] or in unsaturated fat [ Unsat Fat ] for 6 weeks each . Plasma Lp(a ) concentration was assessed at baseline and after each diet . Results Compared to baseline , all interventional diets increased mean Lp(a ) by 2 to 5 mg/dl . Unsat Fat increased Lp(a ) less than Prot with a difference of 1.0 mg/dl ( 95 % CI , −0.5 , 2.5 ; p = 0.196 ) in whites and 3.7 mg/dl ( 95 % CI , 2.4 , 5.0 ; p<0.001 ) in blacks ( p-value between races = 0.008 ) ; Unsat Fat increased Lp(a ) less than Carb with a difference of −0.6 mg/dl , 95 % CI , −2.1 , 0.9 ; p = 0.441 ) in whites and −1.5 mg/dl ( 95 % CI , −0.2 , −2.8 ; p = 0.021 ) in blacks ( p-value between races = 0.354 ) . Prot increased Lp(a ) more than Carb with a difference of 0.4 mg/dl ( 95 % CI , −1.1 , 1.9 ; p = 0.597 ) in whites and 2.2 mg/dl ( 95%CI , 0.9 , 3.5 ; p = 0.001 ) in blacks ( p-value between races = 0.082 ) . Conclusion Diets high in unsaturated fat increased Lp(a ) levels less than diets rich in carbohydrate or protein with greater changes in blacks than whites . Our results suggest that substitutions with dietary mono- and polyunsaturated fatty acids in healthy diets may be preferable over protein or carbohydrates with regards to Lp(a ) . Trial Registration Clinical trials.gov BACKGROUND Lipoprotein(a ) [ Lp(a ) ] is a cardiovascular risk factor ; in addition to being a low-density lipoprotein (LDL)-like particle , it contains highly heterogeneous apolipoprotein(a ) [ apo(a ) ] . No prior studies have evaluated extended-release ( ER ) niacin effect on Lp(a ) level depending on apo(a ) phenotype . METHODS For this 24-week , prospect i ve , open-label clinical trial we recruited 30 men ( mean age 46.2 ± 7.5 years ) with Lp(a ) levels > 20 mg/dL. No participant had previously received lipid lowering therapy  , and started ER niacin 500 mg with stepwise dose increasing up to 1.5 - 2.0 g. Subjects were evaluated for Lp(a ) , lipids , high-sensitivity C-reactive protein , lipoprotein-associated phospholipase A2 ( Lp-PLA2 ) , and fibrinolytic markers ( plasminogen activator inhibitor-1 , tissue plasminogen activator/plasminogen activator inhibitor-1 complex , plasmin-antiplasmin complex ) . Patients were divided into two groups with major low- ( LMW ) or high-molecular weight ( HMW ) apo(a ) isoforms determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of plasma under reducing conditions followed by immunoblotting . RESULTS At baseline , groups were comparable in age , lipid , inflammatory and fibrinolytic biomarkers levels . There was a significant difference in baseline Lp(a ) concentrations : 92 ± 29 mg/dL versus 54 ± 46 mg/dL in LMW and HMW apo(a ) groups , respectively , p < 0.01 . During the course of niacin treatment Lp(a ) decreased by 28 % ( p < 0.003 ) , Lp-PLA2 by 22 % ( p < 0.001 ) , C-reactive protein by 24 % ( p = 0.07 ) in LMW apo(a ) group , whereas no changes in Lp(a ) and biomarkers levels were obtained in HMW apo(a ) group . CONCLUSION High-dose ER niacin declines elevated Lp(a ) level in male subjects with low- but not high-molecular weight apo(a ) phenotype Background Lipoprotein(a ) [ Lp(a ) ] is a low density lipoprotein-like particle whose apolipoprotein B ( apo B ) moiety is disulfide-linked to apo(a ) , a plasminogen-like inhibitor of fibrinolysis in vitro . We hypothesized that plasma concentrations of Lp(a ) are acutely affected by intravenous tissue-type plasminogen activator ( t-PA ) . Methods and Results Patients with unstable angina were r and omized to receive either intravenous t-PA ( n = 15 ) or placebo ( n = 11 ) . Two-way ANOVA using repeated measures revealed a significant effect of t-PA on concentrations of Lp(a ) ( p=0.026 ) . There was a 48 % fall in Lp(a ) from baseline concentrations in the t-PA group at 12 hours ( p=0.031 ) but not at 72 hours . Lp(a ) in the placebo group was unchanged . Conclusions We conclude that t-PA produces a sharp and substantial but reversible reduction in plasma Lp(a ) . These data suggest that Lp(a ) concentration is not as static in vivo as had been believed and might be acutely modifiable through some mechanism that induces its removal from the freely circulating state Background — Lipoprotein-associated phospholipase A2 ( Lp-PLA2 ) is associated with the risk of cardiovascular ( CV ) events in population -based studies . The prognostic value of Lp-PLA2 in patients with acute coronary syndromes ( ACS ) has not been established . Methods and Results — Plasma levels of Lp-PLA2 activity were measured at baseline ( n=3648 ) and 30 days ( n=3265 ) in patients r and omized to atorvastatin 80 mg/d or pravastatin 40 mg/d after ACS in the PROVE IT-TIMI 22 ( PRavastatin Or atorVastatin  Evaluation and Infection Therapy – Thrombolysis In Myocardial Infa rct ion ) trial . The primary end point was death , myocardial infa rct ion , unstable angina , revascularization , or stroke ( mean follow-up 24 months ) . At baseline after ACS , the risk of recurrent CV events was similar across all quintiles of Lp-PLA2 activity ( Ptrend=0.88 ) . Overall , mean levels of Lp-PLA2 were lower at 30 days of follow-up than at baseline ( 35.7 versus 40.9 nmol · min−1 · mL−1 , P<0.001 ) . In particular , treatment with atorvastatin 80 mg/d was associated with a 20 % reduction in Lp-PLA2 activity ( P<0.001 ) , whereas Lp-PLA2 rose 3.6 % with pravastatin 40 mg/d ( P<0.001 ) . Patients with 30-day Lp-PLA2 activity in the highest quintile were at significantly increased risk of recurrent CV events compared with those in the lowest quintile ( 26.4 % versus 17.6 % , Ptrend=0.002 ) . After adjustment for cardiac risk factors , treatments , achieved low-density lipoprotein ( LDL ) , and C-reactive protein , Lp-PLA2 activity in the highest quintile remained independently associated with a higher risk of recurrent CV events ( adjusted hazard ratio 1.33 , 95 % confidence interval [ CI ] 1.01 to 1.74 ) . Conclusions — Lp-PLA2 is not useful for risk stratification when measured early after ACS . At 30 days , Lp-PLA2 activity is significantly lowered with high-dose statin therapy and is associated with an increased risk of CV events independent of C-reactive protein and LDL cholesterol levels BACKGROUND Eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) , the primary omega-3 fatty acids in fish oil , have been shown to reduce cardiovascular disease ( CVD ) risk . OBJECTIVE This study aim ed to examine the independent effects of EPA and DHA on lipid and apolipoprotein levels , as well as on inflammatory biomarkers of CVD risk , using doses often used in the general population . DESIGN A blinded , r and omized 6-week trial was performed in 121 healthy , normolipidemic subjects who received olive oil placebo 6g/d , EPA 600mg/d , EPA 1800mg/d , or DHA 600mg/d .  The EPA was derived from genetically modified yeast . RESULTS The subjects tolerated the supplements well with no safety issues ; and the expected treatment-specific increases in plasma EPA and DHA levels were observed . Compared to placebo , the DHA group had significant decreases in postpr and ial triglyceride ( TG ) concentrations ( -20 % , -52.2mg/dL , P=0.03 ) , significant increases in fasting and postpr and ial low-density lipoprotein cholesterol ( LDL-C ) ( + 18.4 % , 17.1mg/dL , P=0.001 ) , with no significant changes in inflammatory biomarkers . No significant effects were observed in the EPA 600mg/d group . The high-dose EPA group had significant decreases in lipoprotein-associated phospholipase A2 concentrations ( Lp-PLA2 ) ( -14.1 % , -21.4ng/mL , P=0.003 ) . CONCLUSIONS The beneficial effects of EPA 1800mg/d on CVD risk reduction may relate in part to the lowering of Lp-PLA2 without adversely affecting LDL-C. In contrast , DHA decreased postpr and ial TG , but raised LDL-C. Our observations indicate that these dietary fatty acids have divergent effects on cardiovascular risk markers We carried out a genome-wide association study ( GWAS ) of LDL-c response to statin using data from participants in the Collaborative Atorvastatin Diabetes Study ( CARDS ; n = 1,156 ) , the Anglo-Sc and inavian Cardiac Outcomes Trial ( ASCOT ; n = 895 ) , and the observational phase of ASCOT ( n = 651 ) , all of whom were prescribed atorvastatin 10 mg .  Following genome-wide imputation , we combined data from the three studies in a meta- analysis . We found associations of LDL-c response  to atorvastatin that reached genome-wide significance at rs10455872 ( P = 6.13 × 10−9 ) within the LPA gene and at two single nucleotide polymorphisms ( SNP ) within the APOE region ( rs445925 ; P = 2.22 × 10−16 and rs4420638 ; P = 1.01 × 10−11 ) that are proxies for the ε2 and ε4 variants , respectively , in APOE . The novel association with the LPA SNP was replicated in the PROspect i ve Study of Pravastatin in the Elderly at Risk ( PROSPER ) trial ( P = 0.009 ) . Using CARDS data , we further showed that atorvastatin therapy did not alter lipoprotein(a ) [ Lp(a ) ] and that Lp(a ) levels accounted for all of the associations of SNPs in the LPA gene and the apparent LDL-c response levels . However , statin therapy had a similar effect in reducing cardiovascular disease ( CVD ) in patients in the top quartile for serum Lp(a ) levels ( HR = 0.60 ) compared with those in the lower three quartiles ( HR = 0.66 ; P = 0.8 for interaction ) . The data emphasize that high Lp(a ) levels affect the measurement of LDL-c and the clinical estimation of LDL-c response . Therefore , an apparently lower LDL-c response  to statin therapy may indicate a need for measurement of Lp(a ) . However , statin therapy seems beneficial even in those with high Lp(a ) OBJECTIVES This study was undertaken to determine whether lipoprotein(a ) [ Lp(a ) ] is an independent risk factor for ischemic heart disease ( IHD ) and to establish the relation of Lp(a ) to the other lipid fractions . BACKGROUND Several , but not all , studies have shown that elevated Lp(a ) concentrations may be associated with IHD ; very few have been prospect i ve . METHODS A 5-year prospect i ve follow-up study was conducted in 2,156 French Canadian men 47 to 76 years old , without clinical evidence of IHD .  Lipid measurements obtained at baseline included total cholesterol , low density lipoprotein ( LDL ) cholesterol , high density lipoprotein ( HDL ) cholesterol , apoprotein B and Lp(a ) .  During the follow-up period , there were 116 first IHD events ( myocardial infa rct ion , angina , death ) . Adjusted proportional hazards models were used to estimate the relative risk for the different variables . The cohort was also classified according to Lp(a ) levels and other lipid risk factor tertiles to evaluate the relation of elevated Lp(a ) levels to these risk factors . A cutoff value of 30 mg/dl was used for Lp(a ) . Risk ratios were calculated using the group with low Lp(a ) levels and the first tertile of lipid measures as a reference . RESULTS Lp(a ) was not an independent risk factor for IHD but seemed to increase the deleterious effects of mildly elevated LDL cholesterol and elevated total cholesterol and apoprotein B levels and seemed to counteract the beneficial effects associated with elevated HDL cholesterol levels . CONCLUSIONS In this cohort , Lp(a ) was not an independent risk factor for IHD but appeared to increase the risk associated with other lipid risk factors OBJECTIVE Lipoprotein-associated phospholipase A2 ( Lp-PLA2 ) is a useful inflammatory marker of cardiovascular risk , yet little is known of its prognostic role in heart failure ( HF ) . We evaluated the association of Lp-PLA2 with mortality in subjects with HF and assessed its incremental value for risk discrimination over established risk factors and biomarkers . METHODS Residents of Olmsted County , MN , diagnosed with HF between September 2003 and April 2007 ( n=646 , mean age 76 years , 51 % women ) were prospect ively enrolled and followed-up .  Plasma Lp-PLA2 levels  were measured at baseline and evaluated along with known risk indicators . RESULTS Lp-PLA2 was positively associated with male gender and low-density lipoprotein cholesterol and inversely associated with statin use and diabetes . During follow-up ( median 21 months ) , 213 deaths occurred . Elevated Lp-PLA2 was associated with an increased risk of mortality ( hazard ratio (HR)=1.57 ; 95 % confidence interval ( CI ) : 1.03 - 2.37 ; P=0.035 , per 1-unit increase in the log-transformed values ) . The relationship differed markedly by age ( P(interaction)=0.003 ) , with a strong association in patients under 80 years ( covariate-adjusted HR=3.83 ; 95 % CI : 1.93 - 7.61 ; P<0.001 ) and none in older ones ( covariate-adjusted HR=0.82 ; 95 % CI : 0.44 - 1.51 ; P=0.55 ) . For the younger subjects , an improvement in the model 's discriminatory power was obtained by adding Lp-PLA2 to established risk indicators and biomarkers ( area under the receiver operating characteristic curve , 0.709 - 0.744 , P(difference)=0.008 ) . CONCLUSION In this community-based cohort of patients with HF , Lp-PLA2 was strongly and independently associated with mortality and contributed incrementally to risk discrimination in patients under 80 years of age Lp(a ) level is relatively stable in each individual and is mainly under genetic control . Attempts made to lower Lp(a ) with pharmacological means gave conflicting results . In order to further evaluate the effect of hypocholesterolemic drugs on Lp(a ) level , 66 patients with primary hypercholesterolemia were selected . The vast majority of the patients had Lp(a ) concentration at the low end of the range of distribution , 7 had undetectable Lp(a ) levels and only 2 had Lp(a ) higher than 30 mg/dl . No relationship was found between Lp(a ) level and serum and lipoprotein lipids . In 12 patients serum cholesterol was well controlled by diet alone and the patients continued the diet for up to 8 months . The other patients were r and omly subdivided into 3 groups of therapy . The first group received slow release bezafibrate 400 mg once a day , the second one pravastatin 20 mg once a day and the third one simvastatin 10 - 40 mg once a day . Drug therapy lasted for 8 months . At the end of the period , 22 of 29 patients treated with the 2 HMG-CoA reductase inhibitors had Lp(a ) higher than baseline . The difference was statistically significant in both groups of patients . No significant change in Lp(a ) was observed in diet and in bezafibrate group . Serum and LDL cholesterol significantly decreased in all the 3 drug groups . The increase in Lp(a ) after the 2 HMG-CoA reductase was small enough to have negligible effects on cardiovascular risk , but raises the problem of the role of LDL receptor in the catabolism of Lp(a ) BACKGROUND Oxidized phospholipids ( OxPL ) on apolipoprotein B-100 ( OxPL-apoB ) reflect the biological activity of lipoprotein(a ) ( Lp[a ] ) and predict cardiovascular disease events . However , studies with statins and low-fat diets show increases in OxPL-apoB and Lp(a ) . OBJECTIVE This study evaluated changes in OxPL-apoB and Lp(a ) with extended-release niacin ( N ) , ezetimibe/simvastatin ( E/S ) and combination E/S/N. A systematic literature review of previously published trials , measuring both OxPL-apoB and Lp(a ) after therapeutic interventions , was also performed . METHODS OxPL-apoB and Lp(a ) were measured in 591 patients at baseline and 24 weeks after therapy with N , E/S , or E/S/N in a previously completed r and omized trial of hypercholesterolemic patients . The literature review included 12 trials and 3896 patients evaluating statins , low-fat diets , antisense to apolipoprotein(a ) and lipid apheresis . RESULTS Niacin decreased OxPL-apoB levels ( median [ interquartile range ] ; 3.5 [ 2.2 - 9.2 ] nM to 3.1 [ 1.8 - 7.2 ] nM , P < .01 ) and Lp(a ) ( 10.9 [ 4.6 - 38.4 ] to 9.3 [ 3.1 - 32.9 ] mg/dL , P < .01 ) . In contrast , E/S and E/S/N significantly increased OxPL-apoB ( 3.5 [ 2.1 - 7.8 ] to 4.9 [ 3.0 - 11.1 ] nM , P < .01 ) and ( 3.3 [ 1.9 - 9.3 ] to 4.3 [ 2.6 - 11.2 ] nM , P < .01 ) , respectively and Lp(a ) ( 11.5 [ 6.1 - 36.4 ] to 14.9 [ 6.6 - 54.6 ] mg/dL , P < .01 ) and ( 11.3 [ 5.4 - 43.8 ] to 11.6 [ 5.9 - 52.8 ] mg/dL , P < .01 ) , respectively . The systematic review of statins and diet demonstrated 23.8 % and 21.3 % mean increases in OxPL-apoB and 10.6 % and 19.4 % increases in Lp(a ) , respectively . However 44.1 % and 52.0 % decreases in OxPL-apoB and Lp(a ) , respectively , were present with Lp(a)-lowering therapies . CONCLUSIONS This study demonstrates differential changes in OxPL-apoB and Lp(a ) with various lipid-lowering approaches . These changes in OxPL-apoB and Lp(a ) may provide insights into the results and interpretation of recent cardiovascular disease outcomes trials Low levels of insulin-like growth factor binding protein-1 ( IGFBP-1 ) have recently been associated with several risk factors for cardiovascular disease . The effects of estrogen replacement therapy ( ERT ) on plasma IGFBP-1 levels are , however , unclear . A double-blind , placebo-controlled study for 6 months was conducted in 73 hysterectomized postmenopausal women r and omized into two groups : oral estradiol ( E2 ) valerate , 2 mg/day ( n = 35 ) and transdermal E2 gel , 1 mg/day ( n=38 ) . Plasma IGFBP-1 , insulin-like growth factor-I ( IGF-I ) and lipoprotein(a ) ( Lp(a ) ) were determined at baseline , 3 and 6 months . The groups were similar for age and BMI . The baseline levels of estrone ( E1 ) , E2 , IGFBP-1 , IGF-I and Lp(a ) did not differ between the groups . During treatment , serum estradiol concentrations increased in both groups . During oral ERT , IGFBP-1 levels increased by 104 % ( P<0.001 ) , whereas IGF-I levels decreased by 13 % ( mean , P<0.05 ) . IGF-I and IGFBP-1 levels remained unchanged in the transdermal group . Lp(a ) levels decreased by 23 % ( median , P<0.001 ) in the oral group , but were unaffected by transdermal therapy . The change in IGFBP-1 concentrations during oral ERT showed an inverse correlation to that in Lp(a ) ( r = -0.40 , P<0.05 , Spearman correlation ) . In conclusion , oral ERT seems to enhance plasma levels of IGFBP-1 , which may be one reason for the reduced Lp(a ) levels
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 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 .