title: Effect of Alirocumab on Lipoprotein(a) Over ≥1.5 Years (from the Phase 3 ODYSSEY Program). Ezetimibe Attenuates Atherosclerosis Associated with Lipid Reduction and Inflammation Inhibition Effects of ezetimibe on plasma lipoproteins in severely hypercholesterolemic patients treated with regular LDL-apheresis and statins. Effect of Ezetimibe Coadministered With Atorvastatin in 628 Patients With Primary Hypercholesterolemia: A Prospective, Randomized, Double-Blind Trial Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies. Lipid-Modifying Efficacy and Tolerability of Anacetrapib Added to Ongoing Statin Therapy in Patients with Hypercholesterolemia or Low High-Density Lipoprotein Cholesterol. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. Effects of ezetimibe on remnant-like particle cholesterol, lipoprotein (a), and oxidized low-density lipoprotein in patients with dyslipidemia. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Efficacy of ezetimibe in patients with statin-resistant and statin-intolerant familial hyperlipidaemias Efficacy and safety of ezetimibe coadministered with lovastatin in primary hypercholesterolemia. Renal and vascular protective effects of ezetimibe in chronic kidney disease. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Effect of therapeutic interventions on oxidized phospholipids on apolipoprotein B100 and lipoprotein(a).
abstract: 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 ) Background Ezetimibe , as a cholesterol absorption inhibitor , has been shown protecting against atherosclerosis when combined with statin . However , side by side comparison has not been made to evaluate the beneficial effects of ezetimibe alone versus statin . Herein , the study aim ed to test whether ezetimibe alone would exhibit similar effects as statin and the combination therapy would be necessary in a moderate lesion size . Methods and Results ApoE-/- male mice that were fed a saturated-fat supplemented diet were r and omly assigned to different therapeutic regimens : vehicle , ezetimibe alone ( 10 mg/kg/day ) , atorvastatin ( 20 mg/kg/day ) or combination of ezetimibe and atorvastatin through the drinking water . On 28 days , mice were sacrificed and aorta and sera were collected to analyze the atherosclerotic lesion and blood lipid and cholesterol levels . As a result , ezetimibe alone exerted similar protective effects on atherosclerotic lesion sizes as atorvastatin , which was mediated by lowering serum cholesterol concentrations , inhibiting macrophage accumulation in the lesions and reducing circulatory inflammatory cytokines , such as monocyte chemoattractant protein ( MCP-1 ) and tumor necrosis factor ( TNF-α ) . In contrast to ezetimibe administration , atorvastatin alone attenuated atherosclerotic lesion which is dependent on its anti-inflammation effects . There were no significance differences in lesion areas and serum concentrations of cholesterol , oxidized LDL and inflammatory cytokines between combination therapy and monotherapy ( either ezetimibe or atorvastatin ) . There were significant correlations between the lesion areas and serum concentrations of cholesterol , MCP-1 and TNF-α , respectively . However , there were no significant correlations between the lesion areas and serum concentrations of TGF-β1 and oxLDL . Conclusions Ezetimibe alone played the same protection against a moderate atherosclerotic lesion as atorvastatin , which was associated with lowering serum cholesterol , decreasing circulating inflammatory cytokines , and inhibiting macrophage accumulation in the lesions Ezetimibe , a cholesterol absorption inhibitor , can be combined with statins to lower LDL-cholesterol . We evaluated additional ezetimibe ( 10 mg/day ) in a placebo-controlled , double blind , r and omized cross-over study in 20 patients ( age 56+/-9 years , m : f 10:10 , BMI 27.5+/-4.0 kg/m(2 ) ) suffering from severe hypercholesterolemia and CHD who were treated by statins and regular LDL-apheresis .  Lipoproteins ( cholesterol , triglycerides , LDL-cholesterol , HDL-cholesterol , VLDL-cholesterol , VLDL-triglycerides , lipoprotein(a ) ) were determined twice ( before and during ezetimibe/placebo , each given for 5 weeks ) , dietary behaviour was analyzed once ( 3-days- protocol ) during each treatment period . During ezetimibe the mean ( + /-S.D. ) preapheresis LDL-cholesterol concentration decreased from 159+/-26 mg/dl ( 4.11+/-0.67 mmol/l ) to 133+/-28 mg/dl ( 3.44+/-0.72 mmol/l ) ( -16+/-11 % , P<0.0001 , Wilcoxon test ) and the postapheresis LDL-cholesterol from 51+/-9 mg/dl ( 1.32+/-0.23 mmol/l ) to 43+/-8 mg/dl ( 1.11+/-0.21 mmol/l ) ( -14+/-25 % , P<0.05 ) , while there was no significant change during placebo .  Mean VLDL-cholesterol fell by 18+/-71 % ( P<0.05 ) during ezetimibe and was not significantly changed by placebo ( + 19+/-70 % ) . Furthermore , during ezetimibe less plasma volume was treated ( 3725+/-1560 versus 3870+/-1549 ml , P<0.05 ) . Ezetimibe had no effect on pre- and postapheresis triglyceride , HDL-cholesterol and lipoprotein(a ) levels . The effect of ezetimibe was independent of the statin dose . Dietary behaviour did not change and no side effects were observed . Thus , in patients with severe LDL-hypercholesterolemia and CHD the addition of ezetimibe to intensive lipid lowering therapy ( statins and LDL-apheresis ) result ed in a further , clinical ly significant decrease of LDL-cholesterol Background —Despite the established efficacy of statins , many patients do not achieve recommended LDL cholesterol ( LDL-C ) goals . Contributing factors may be inadequate dosing , increased risk for adverse effects with high-dose monotherapy , and increased potential for intolerance and adverse effects with combinations of available agents . Methods and Results —In a double-blind study , 628 patients with baseline LDL-C 145 to 250 mg/dL and triglycerides ≤350 mg/dL were r and omly assigned to receive 1 of the following for 12 weeks : ezetimibe ( 10 mg/d ) ; atorvastatin ( 10 , 20 , 40 , or 80 mg/d ) ; ezetimibe ( 10 mg ) plus atorvastatin ( 10 , 20 , 40 , or 80 mg/d ) ; or placebo . The primary efficacy end point was percentage reduction in LDL-C for pooled ezetimibe plus atorvastatin versus pooled atorvastatin treatment groups . Ezetimibe plus atorvastatin significantly improved LDL-C , HDL cholesterol ( HDL-C ) , triglycerides , total cholesterol : HDL-C , and high-sensitivity C-reactive protein ( hs-CRP ) compared with atorvastatin alone ( P < 0.01 ) . Coadministration of ezetimibe provided a significant additional 12 % LDL-C reduction , 3 % HDL-C increase , 8 % triglyceride reduction , and 10 % hs-CRP reduction versus atorvastatin alone . Ezetimibe plus atorvastatin  provided LDL-C reductions of 50 % to 60 % , triglyceride reductions of 30 % to 40 % , and HDL-C increases of 5 % to 9 % , depending on atorvastatin dose . LDL-C reductions with ezetimibe plus 10 mg atorvastatin ( 50 % ) and 80 mg atorvastatin alone ( 51 % ) were similar . Conclusions —Ezetimibe plus atorvastatin was well tolerated , with a safety profile similar to atorvastatin alone and to placebo . When coadministered with atorvastatin , ezetimibe provided significant incremental reductions in LDL-C and triglycerides and increases in HDL-C. Coadministration of ezetimibe and atorvastatin offers a well-tolerated and highly efficacious new treatment option for patients with hypercholesterolemia 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 Ezetimibe ( SCH 58235 ) is a novel cholesterol absorption inhibitor that selectively and potently blocks intestinal absorption of dietary and biliary cholesterol . OBJECTIVE Data from 2 multicenter , placebo-controlled , double-blind , r and omized , parallel-group , 12-week studies of ezetimibe were pooled to evaluate the drug 's effect on lipid parameters in patients with primary hypercholesterolemia . METHODS After dietary stabilization ( National Cholesterol Education Program Step I diet or a stricter diet ) , washout of lipid-altering drugs , and a 6-week placebo lead-in period , patients with baseline plasma low-density lipoprotein cholesterol ( LDL-C ) levels > or = 130 and < or = 250 mg/dL and plasma triglyceride ( TG ) levels < or = 300 mg/dL were r and omized to receive either ezetimibe 0.25 , 1 , 5 , or 10 mg , or placebo administered once daily before the morning meal in study A ( dose-response study ) or ezetimibe 5 or 10 mg or placebo administered once daily before the morning meal or at bedtime in study B ( dose-regimen study ) . RESULTS A total of 432 patients were included in this pooled analysis , 243 in study A and 189 in study B. The 5- and 10-mg doses of ezetimibe significantly reduced LDL-C levels by 15.7 % and 18.5 % , respectively ( P < 0.01 vs placebo ) and significantly increased high-density lipoprotein cholesterol ( hDL-C ) levels by 2.9 % and 3.5 % , respectively ( P < 0.05 vs placebo ) . A reduction in plasma TG levels was observed ( P = NS ) . With the 10-mg dose of ezetimibe , 67.8 % of patients achieved > or = 15 % reduction in plasma LDL-C levels , and 22.0 % achieved > or = 25 % reduction . With the 5-mg dose , 54.0 % of patients achieved > or = 15 % reduction in plasma LDL-C levels , and 15.3 % achieved > or = 25 % reduction . The decrease in plasma LDL-C levels was significantly greater with ezetimibe 10 mg compared with ezetimibe 5 mg ( P < 0.05 ) . Ezetimibe was well tolerated , with an adverse event profile similar to that of placebo . CONCLUSIONS In these two 12-week studies , ezetimibe significantly decreased plasma LDL-C levels and increased plasma HDL-C levels , with a tolerability profile similar to that of placebo To assess the effects of anacetrapib added to statin ± other lipid-modifying therapies in patients with hypercholesterolemia and not at their low-density lipoprotein cholesterol ( LDL-C ) goal ( as per National Cholesterol Education Program Adult Treatment Panel III [ NCEP ATP III ] guidelines ) and in those with low high-density lipoprotein cholesterol ( HDL-C ) . Patients on a stable dose of moderate/high-intensity statin ± other lipid-modifying therapies with LDL-C ≥70 , ≥100 , ≥130 , or ≥160 mg/dl for very high , high , moderate , and low coronary heart disease risk , respectively , or at LDL-C goal with HDL-C ≤40 mg/dl , were r and omized 1:1:1 , stratified by background therapy use ,  to anacetrapib  100 mg ( n = 153 ) , anacetrapib 25 mg ( n = 152 ) , or placebo ( n = 154 ) for 24 weeks , followed by a 12-week off-drug reversal phase . The primary end points were percent change from baseline in LDL-C ( beta-quantification method ) and HDL-C , as well as the safety profile  of anacetrapib . Both doses of anacetrapib  reduced LDL-C , non-HDL-C , apolipoprotein ( Apo ) B , and lipoprotein a and increased HDL-C and Apo AI versus placebo ( p < 0.001 for all ) . There were no meaningful differences between the anacetrapib 25 mg , 100 mg , and placebo groups in the proportions of discontinuations due to drug-related adverse events ( 0.7 % , 1.3 % vs 1.3 % ) or in abnormalities in liver enzymes ( 0 % , 0 % vs 0.7 % ) , creatine kinase elevations overall ( 0 % , 0.7 % vs 0 % ) or with muscle symptoms ( none seen ) , blood pressure , electrolytes , or adjudicated cardiovascular events ( 0.7 % , 0.7 % vs 1.3 % ) . In conclusion , treatment with anacetrapib result ed in substantial reductions in LDL-C and increases in HDL-C and was generally well tolerated OBJECTIVES The purpose of this study was to assess the efficacy and safety of ezetimibe administered with simvastatin in patients with primary hypercholesterolemia . BACKGROUND Despite the availability of statins , many patients do not achieve lipid targets . Combination therapy with lipid-lowering agents that act via a complementary pathway may allow additional patients to achieve recommended cholesterol goals . METHODS After dietary stabilization , a 2- to 12-week washout period , and a 4-week , single-blind , placebo lead-in period , patients with baseline low-density lipoprotein cholesterol ( LDL-C ) > or = 145 mg/dl to < or = 250 mg/dl and triglycerides ( TG ) < or = 350 mg/dl were r and omized to one of the following 10 groups administered daily for 12 consecutive weeks : ezetimibe 10 mg ; simvastatin 10 , 20 , 40 , or 80 mg ; ezetimibe 10 mg plus simvastatin 10 , 20 , 40 , or 80 mg ; or placebo . The primary efficacy variable was percentage reduction from baseline to end point in direct LDL-C for the pooled ezetimibe plus simvastatin groups versus pooled simvastatin groups . RESULTS Ezetimibe plus simvastatin significantly improved LDL-C ( p < 0.01 ) , high-density lipoprotein cholesterol ( HDL-C ) ( p = 0.03 ) , and TG ( p < 0.01 ) compared with simvastatin alone . Ezetimibe plus simvastatin ( pooled doses ) provided an incremental 13.8 % LDL-C reduction , 2.4 % HDL-C increase , and 7.5 % TG reduction compared with pooled simvastatin alone . Coadministration of ezetimibe and simvastatin provided LDL-C reductions of 44 % to 57 % , TG reductions of 20 % to 28 % , and HDL-C increases of 8 % to 11 % , depending on the simvastatin dose . Ezetimibe 10 mg plus simvastatin 10 mg and simvastatin 80 mg alone each provided a 44 % LDL-C reduction . The coadministration of ezetimibe with simvastatin was well tolerated , with a safety profile similar to those of simvastatin and of placebo . CONCLUSIONS When coadministered with simvastatin , ezetimibe provided significant incremental reductions in LDL-C and TG , as well as increases in HDL-C. Coadministration of ezetimibe with simvastatin was well tolerated and comparable to statin alone AIM Ezetimibe is a novel cholesterol absorption inhibitor that reduces the level of low-density lipoprotein (LDL)-cholesterol ( C ) . The effects of ezetimibe on remnant-like particle (RLP)-C , lipoprotein ( a ) [ Lp(a ) ] , and oxidized LDL ( Ox-LDL ) levels have not been examined . METHODS Fifty patients with dyslipidemia were treated with 10 mg/day of ezetimibe . At baseline and 12 weeks after treatment with ezetimibe , we measured the levels of RLP-C , Lp(a ) , Ox-LDL , and high-sensitivity C-reactive protein ( hs-CRP ) . RESULTS The mean levels of total cholesterol ( TC ) , LDL-C , triglycerides ( TG ) , and apolipoprotein ( apo ) B , respectively , showed a significant decrease from 229+/-39 to 191+/-37 mg/dL ( -16 % , p<0.0001 ) , from 151+/-34 to 118+/-33 mg/dL ( -22 % , p<0.0001 ) , from 162+/-82 to 135+/-55 mg/dL ( -7 % , p<0.01 ) , and from 116+/-22 to 94+/-21 mg/dL ( -18 % , p<0.0001 ) after 12 weeks of treat-ment with ezetimibe . The mean level of RLP-C and median level of hs-CRP also decreased signifi-cantly from 6.8+/-4.0 to 4.8+/-2.5 mg/dL ( -21 % , p<0.0001 ) and from 0.6 to 0.4 mg/L ( -33 % , p<0.05 ) . The median level of Lp(a ) decreased significantly from 14 to 10 mg/dL ( -29 % , p<0.05 ) in patients treated with ezetimibe monotherapy . CONCLUSIONS Ezetimibe was effective for reducing the levels of TC , LDL-C , TG , and RLP-C.  Ezeti-mibe could be a potential therapeutic option for decreasing the Lp(a ) level The efficacy and safety of ezetimibe , a new cholesterol absorption inhibitor , was evaluated in this r and omized , double-blind , placebo-controlled trial of 892 patients with primary hypercholesterolemia . After > or = 2 weeks on the National Cholesterol Education Program ( NCEP ) Step I or a stricter diet and a 4- to 8-week single-blind placebo lead-in , patients with low-density lipoprotein ( LDL ) cholesterol 130 to 250 mg/dl and triglycerides < or = 350 mg/dl were r and omized 3:1 to receive ezetimibe 10 mg or placebo orally each morning for 12 weeks . The primary efficacy end point was the percent reduction in direct plasma LDL cholesterol from baseline to end point . A total of 434 men and 458 women ( ages 18 to 85 years ) received r and omized treatment ( 666 ezetimibe 10 mg , 226 placebo ) . Demographics and baseline characteristics were similar between treatment groups . Ezetimibe significantly reduced direct LDL cholesterol by a mean of 16.9 % , compared with an increase of 0.4 % with placebo ( p < 0.01 ) . Subgroup analysis indicated that response to ezetimibe was generally consistent across all subgroups , regardless of risk-factor status , gender , age , race , or baseline lipid profile . Ezetimibe effects on LDL cholesterol occurred early ( 2 weeks ) and persisted throughout the 12-week treatment period . Compared with placebo , ezetimibe 10 mg also significantly improved calculated LDL cholesterol , apolipoprotein B , total cholesterol , triglycerides , high-density lipoprotein ( HDL ) cholesterol , and HDL(3 ) cholesterol ( p < 0.01 ) . Ezetimibe was well tolerated . There were no differences in laboratory or clinical safety parameters , or gastrointestinal , liver , or muscle side effects from that of placebo . Ezetimibe 10 mg/day is well tolerated , reduces LDL cholesterol approximately 17 % , and improves other key lipid parameters OBJECTIVE To compare the efficacy and safety of 10 mg of ezetimibe coadministered with simvastatin with the safety and efficacy of simvastatin monotherapy for patients with hypercholesterolemia . PATIENTS AND METHODS This multicenter double-blind , placebo-controlled , factorial study enrolled 887 patients with hypercholesterolemia ( low-density lipoprotein cholesterol [ LDL-C ] , 145 - 250 mg/dL ; triglycerides , < or = 350 mg/dL ) . Patients were r and omized to 1 of 10 treatments -- placebo , ezetimibe at 10 mg/d , simvastatin at 10 , 20 , 40 , or 80 mg/d , or simvastatin at 10 , 20 , 40 , or 80 mg/d plus ezetimibe at 10 mg/d for 12 weeks . The study began March 13 , 2001 , and ended January 8 , 2002 . The primary efficacy end point was the mean percent change in LDL-C levels from baseline to study end point ( last available postbaseline LDL-C measurement ) for the pooled ezetimibe/simvastatin group vs the pooled simvastatin monotherapy group . RESULTS Coadministration of ezetimibe/simvastatin was significantly ( P<.001 ) more effective than simvastatin alone in reducing LDL-C levels for the pooled ezetimibe/simvastatin vs pooled simvastatin analysis and at each specific dose comparison . The decrease in LDL-C levels with coadministration of ezetimibe and the lowest dose of simvastatin , 10 mg , was similar to the decrease with the maximum dose of simvastatin , 80 mg . A significantly ( P<.001 ) greater proportion of patients in the ezetimibe/simvastatin group achieved target LDL-C levels compared with those in the monotherapy group . Treatment with ezetimibe/simvastatin also led to greater reductions in total cholesterol , triglyceride , non-high-density lipoprotein cholesterol , and apolipoprotein B levels compared with simvastatin alone ; both treatments increased high-density lipoprotein cholesterol levels similarly . The safety and tolerability profiles for the ezetimibe/simvastatin and monotherapy groups were similar . CONCLUSION Through dual inhibition of cholesterol absorption and synthesis , coadministration of ezetimibe/simvastatin offers a highly efficacious and well-tolerated lipid-lowering strategy for treating patients with primary hypercholesterolemia ABSTRACT Objective : To investigate the efficacy of the cholesterol absorption inhibitor ezetimibe in patients with refractory familial hyperlipidaemia or intolerant to statin therapy . Methods : This prospect i ve study assessed the safety and efficacy of ezetimibe in 200 patients with refractory familial hyperlipidaemias not achieving a low-density-lipoprotein ( LDL ) cholesterol < 3 mmol/L ( 116 mg/dL ) including 22 % intolerant to all statin therapy , many consuming sterol-containing products . Results : Ezetimibe monotherapy result ed in 7 % and 11 % reductions in LDL-cholesterol and apolipoprotein B respectively . Ezetimibe-statin combination therapy  reduced LDL-cholesterol by an additional 11 ± 27 % and apolipoprotein B by 11 ( + 79 to –18)% . There was a similar response between various sub-groups but a wide variation within groups with the greatest effect seen in patients under-responding to statins . The number of patients achieving the LDL‐C target of 3 mmol/L rose from 5.5 % to 18 % . Non-significant effects included a 5 ( + 78 to –470)% reduction in triglycerides , 8 ± 36 % increment in HDL‐cholesterol , 21 ( + 35 to –82)% reduction in C-reactive protein and a 1 ( + 20 to –50)% increase in alanine transaminase . No effects were seen on creatinine , creatine kinase , or insulin resistance . Fourteen patients ( 7 % ) discontinued ezetimibe : seven due to gastrointestinal side-effects , one patient developed an ezetimibe-induced hypercholesterolaemia ( × 1.5 ) , one developed ezetimibe-induced hypertriglyceridaemia ( × 7 ) and five discontinued for other reasons . Conclusion : Ezetimibe is a useful addition to statins in patients with familial hyperlipidaemias but shows a highly variable response profile This multicenter , r and omized , double-blind , placebo-controlled clinical study assessed the efficacy and safety of ezetimibe administered with lovastatin in primary hypercholesterolemia .  After dietary stabilization , a 2- to 12-week washout period , and a 4-week single-blind placebo lead-in period , 548 patients with low-density lipoprotein ( LDL ) cholesterol > or = 145 mg/dl ( 3.75 mmol/L ) and < or = 250 mg/dl ( 6.47 mmol/L ) and triglycerides < or = 350 mg/dl ( 3.99 mmol/L ) were r and omized to one of the following , administered daily for 12 weeks :  ezetimibe 10 mg ; lovastatin 10 , 20 , or 40 mg ; ezetimibe 10 mg plus lovastatin 10 , 20 , or 40 mg ; or placebo . The primary efficacy variable was percentage decrease in direct LDL cholesterol from baseline to end point for pooled ezetimibe plus lovastatin versus pooled lovastatin alone . Ezetimibe plus lovastatin significantly improved concentrations of LDL cholesterol , high-density lipoprotein ( HDL ) cholesterol , and triglycerides compared with lovastatin alone ( p < 0.01 ) . The coadministration of ezetimibe provided an incremental 14 % LDL cholesterol decrease , a 5 % HDL cholesterol increase , and a 10 % decrease in triglycerides compared with pooled lovastatin alone . Ezetimibe plus lovastatin provided mean LDL cholesterol decreases of 33 % to 45 % , median triglyceride decreases of 19 % to 27 % , and mean HDL cholesterol increases of 8 % to 9 % , depending on the statin dose . The coadministration of ezetimibe 10 mg plus the starting dose of lovastatin ( 10 mg ) provided comparable efficacy to high-dose lovastatin ( 40 mg ) across the lipid profile ( LDL cholesterol , HDL cholesterol , and triglycerides ) .  Ezetimibe plus lovastatin was well tolerated , with a safety profile similar to both lovastatin alone and placebo . The coadministration of ezetimibe and lovastatin may offer a new treatment option in lipid management of patients with hypercholesterolemia OBJECTIVE Dyslipidemia is a risk factor for not only cardiovascular diseases ( CVD ) , but also chronic kidney disease ( CKD ) . Ezetimibe , a cholesterol absorption inhibitor , lowers cholesterol levels by inhibiting both extrinsic and intrinsic cholesterol absorption via the gastrointestinal duct . However , very few studies have examined its efficacy and safety for patients with dyslipidemia complicated with CKD . METHODS Thirty-seven dyslipidemic patients ( low density lipoprotein cholesterol ( LDL-C ) levels ≥120 mg/dL ) complicated with CKD were given ezetimibe ( 10 mg/day ) for twenty-four weeks . The efficacy and safety of the therapy , including the anti-atherosclerotic and renal protective effects , were then examined . RESULTS Significant decreases were observed in the levels of LDL-C ( 158.9 ± 26.9 mg/dL→123.0 ± 31.8 mg/dL ; p<0.0001 ) , remnant-like lipoprotein cholesterol ( 9.3 ± 5.3 mg/dL→7.3 ± 3.8 mg/dL ; p<0.05 ) and lipoprotein ( a ) ( 22.0 ± 16.1 mg/dL→16.4 ± 11.0 mg/dL ; p<0.01 ) . The estimated glomerular filtration rate did not change , but the urine protein to creatinine ratio decreased significantly ( 1,107.3 ± 1,454.2 mg/gCre→732.1 ± 1,237.8 mg/gCre ; p<0.05 ) . No changes were observed in the carotid intima media thickness , but the brachial-ankle pulse wave velocity decreased significantly ( 1,770.4 ± 590.3 cm/sec→1,702.5 ± 519.9 cm/sec ; p<0.05 ) . No adverse events were observed . CONCLUSION Ezetimibe can be safely administered even to patients with CKD . The results of this study indicate that ezetimibe may provide some renal protection and suppress the complications of CVD in CKD patients BACKGROUND Elevated lipoprotein(a ) ( Lp[a ] ) is a highly prevalent ( around 20 % of people ) genetic risk factor for cardiovascular disease and calcific aortic valve stenosis , but no approved specific therapy exists to substantially lower Lp(a ) concentrations . We aim ed to assess the efficacy , safety , and tolerability of two unique antisense oligonucleotides design ed to lower Lp(a ) concentrations . METHODS We did two r and omised , double-blind , placebo-controlled trials . In a phase 2 trial ( done in 13 study centres in Canada , the Netherl and s , Germany , Denmark , and the UK ) , we assessed the effect of IONIS-APO(a)Rx , an oligonucleotide targeting apolipoprotein(a ) . Participants with elevated Lp(a ) concentrations ( 125 - 437 nmol/L in cohort A ; ≥438 nmol/L in cohort B ) were r and omly assigned ( in a 1:1 ratio in cohort A and in a 4:1 ratio in cohort B ) with an interactive response system to escalating-dose subcutaneous IONIS-APO(a)Rx ( 100 mg , 200 mg , and then 300 mg , once a week for 4 weeks each ) or injections of saline placebo , once a week , for 12 weeks . Primary endpoints were mean percentage change in fasting plasma Lp(a ) concentration at day 85 or 99 in the per- protocol population ( participants who received more than six doses of study drug ) and safety and tolerability in the safety population . In a phase 1/2a first-in-man trial , we assessed the effect of IONIS-APO(a)-LRx , a lig and -conjugated antisense oligonucleotide design ed to be highly and selectively taken up by hepatocytes , at the BioPharma Services phase 1 unit ( Toronto , ON , Canada ) . Healthy volunteers ( Lp[a ] ≥75 nmol/L ) were r and omly assigned to receive a single dose of 10 - 120 mg IONIS-APO(a)LRx subcutaneously in an ascending-dose design or placebo ( in a 3:1 ratio ; single-ascending-dose phase ) , or multiple doses of 10 mg , 20 mg , or 40 mg IONIS-APO(a)LRx subcutaneously in an ascending-dose design or placebo ( in an 8:2 ratio ) at day 1 , 3 , 5 , 8 , 15 , and 22 ( multiple-ascending-dose phase ) . Primary endpoints were mean percentage change in fasting plasma Lp(a ) concentration , safety , and tolerability at day 30 in the single-ascending-dose phase and day 36 in the multiple-ascending-dose phase in participants who were r and omised and received at least one dose of study drug . In both trials , the r and omised allocation sequence was generated by Ionis Biometrics or external vendor with a permuted-block r and omisation method . Participants , investigators , sponsor personnel , and clinical research organisation staff who analysed the data were all masked to the treatment assignments . Both trials are registered with Clinical Trials.gov , numbers NCT02160899 and NCT02414594 . FINDINGS From June 25 , 2014 , to Nov 18 , 2015 , we enrolled 64 participants to the phase 2 trial ( 51 in cohort A and 13 in cohort B ) . 35 were r and omly assigned to IONIS-APO(a)Rx and 29 to placebo . At day 85/99 , participants assigned to IONIS-APO(a)Rx had mean Lp(a ) reductions of 66·8 % ( SD 20·6 ) in cohort A and 71·6 % ( 13·0 ) in cohort B ( both p<0·0001 vs pooled placebo ) . From April 15 , 2015 , to Jan 11 , 2016 , we enrolled 58 healthy volunteers to the phase 1/2a trial of IONIS-APO(a)-LRx .  Of 28 participants in the single-ascending-dose phase , three were r and omly assigned to 10 mg , three to 20 mg , three to 40 mg , six to 80 mg , six to 120 mg , and seven to placebo . Of 30 participants in the multiple-ascending-dose phase , eight were r and omly assigned to 10 mg , eight to 20 mg , eight to 40 mg , and six to placebo . Significant dose-dependent reductions in mean Lp(a ) concentrations were noted in all single-dose IONIS-APO(a)-LRx groups at day 30 . In the multidose groups , IONIS-APO(a)-LRx result ed in mean reductions in Lp(a ) of 66 % ( SD 21·8 ) in the 10 mg group , 80 % ( SD 13·7 % ) in the 20 mg group , and 92 % ( 6·5 ) in the 40 mg group ( p=0·0007 for all vs placebo ) at day 36 . Both antisense oligonucleotides were safe . There were two serious adverse events ( myocardial infa rct ions ) in the IONIS-APO(a)Rx phase 2 trial , one in the IONIS-APO(a)Rx and one in the placebo group , but neither were thought to be treatment related . 12 % of injections with IONIS-APO(a)Rx were associated with injection-site reactions .  IONIS-APO(a)-LRx was associated with no injection-site reactions .  INTERPRETATION IONIS-APO(a)-LRx is a novel , tolerable , potent therapy to reduce Lp(a ) concentrations . IONIS-APO(a)-LRx might mitigate Lp(a)-mediated cardiovascular risk and is being developed for patients with elevated Lp(a ) concentrations with existing cardiovascular disease or calcific aortic valve stenosis . FUNDING Ionis Pharmaceuticals AIMS To evaluate the efficacy and safety of ezetimibe 10 mg administered with pravastatin in patients with primary hypercholesterolemia . METHODS AND RESULTS After dietary stabilization , 2 - 12 week screening/washout period , and 4-week , single-blind , placebo lead-in period , 538 patients with baseline LDL-C > or = 3.8 to < or = 6.5 mmol/l and TG < or = 4.0 mmol/l were r and omized to one of eight possible treatments administered daily for 12 weeks : ezetimibe 10 mg ; pravastatin 10 , 20 , or 40 mg ; ezetimibe 10 mg plus pravastatin 10 , 20 , or 40 mg ; or placebo . The primary efficacy endpoint was percent reduction in LDL-C from baseline to study endpoint for ezetimibe 10 mg plus pravastatin ( pooled doses ) compared to pravastatin alone ( pooled doses ) and ezetimibe alone . The combined use of ezetimibe and pravastatin result ed in significant incremental reductions in LDL-C and TG compared to pooled pravastatin alone ( p<0.01 ) . Coadministration therapy reduced LDL-C by 34 - 41 % , TG by 21 - 23 % , and increased HDL-C by 7.8 - 8.4 % , depending on the dose of pravastatin . The combined regimen was well tolerated , with a safety profile similar to pravastatin alone and placebo . CONCLUSIONS When coadministered with pravastatin , ezetimibe provided significant incremental reductions in LDL-C and TG and was well tolerated with a safety profile similar to pravastatin alone 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
target: Conclusions Ezetimibe monotherapy ( 10 mg/day ) showed a small ( 7.06 % ) but statistically significant reduction in the plasma levels of Lp(a ) in patients with primary hypercholesterolemia .
  According to current literature , this magnitude of reduction seems to have no clinical relevance .
background: Background and Aims Ezetimibe reduces plasma low-density lipoprotein cholesterol ( LDL-C ) levels by up to 20 % .
  However , its effect on plasma lipoprotein(a ) [ Lp(a ) ] concentrations in patients with primary hypercholesterolemia has not been defined .
  Objective Therefore , we performed a systematic review and meta- analysis to assess this effect based on the available r and omized controlled trials ( RCTs ) .