Achieving goal lipid levels with ezetimibe plus statin add-on or switch therapy compared with doubling the statin dose. A pooled analysis. Consistency of effect of ezetimibe/simvastatin compared with intensified lipid-lowering treatment strategies in obese and non-obese diabetic subjects Effect of Ezetimibe on LDL-C Lowering and Atherogenic Lipoprotein Profiles in Type 2 Diabetic Patients Poorly Controlled by Statins Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). Incremental cholesterol reduction with ezetimibe/simvastatin, atorvastatin and rosuvastatin in UK General Practice (IN-PRACTICE): randomised controlled trial of achievement of Joint British Societies (JBS-2) cholesterol targets. Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin. Treatment with ezetimibe plus low-dose atorvastatin compared with higher-dose atorvastatin alone: is sufficient cholesterol-lowering enough to inhibit platelets? Efficacy and Safety of Alirocumab as Add‐on Therapy in High–Cardiovascular‐Risk Patients With Hypercholesterolemia Not Adequately Controlled With Atorvastatin (20 or 40 mg) or Rosuvastatin (10 or 20 mg): Design and Rationale of the ODYSSEY OPTIONS Studies Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. Projected cost-effectiveness of ezetimibe/simvastatin compared with doubling the statin dose in the United Kingdom: findings from the INFORCE study. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Effects of switching statins on achievement of lipid goals: Measuring Effective Reductions in Cholesterol Using Rosuvastatin Therapy (MERCURY I) study. Efficacy of combination of Ezetimibe 10 mg and rosuvastatin 2.5 mg versus rosuvastatin 5 mg monotherapy for hypercholesterolemia in patients with type 2 diabetes Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. Comparison of anti-inflammatory effects and high-density lipoprotein cholesterol levels between therapy with quadruple-dose rosuvastatin and rosuvastatin combined with ezetimibe RESEARCH (Recognized effect of Statin and ezetimibe therapy for achieving LDL-C Goal), a randomized, doctor-oriented, multicenter trial to compare the effects of higher-dose statin versus ezetimibe-plus-statin on the serum LDL-C concentration of Japanese type-2 diabetes patients design and rationale Ezetimibe/simvastatin 10/40 mg versus atorvastatin 40 mg in high cardiovascular risk patients with primary hypercholesterolemia: a randomized, double-blind, active-controlled, multicenter study A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial. Comparison of the effect of simvastatin versus simvastatin/ezetimibe versus rosuvastatin on markers of inflammation and oxidative stress in subjects with hypercholesterolemia. Comparison of PCSK9 Inhibitor Evolocumab vs Ezetimibe in Statin‐Intolerant Patients: Design of the Goal Achievement After Utilizing an Anti‐PCSK9 Antibody in Statin‐Intolerant Subjects 3 (GAUSS‐3) Trial Efficacy and safety of ezetimibe added to atorvastatin versus atorvastatin uptitration or switching to rosuvastatin in patients with primary hypercholesterolemia. Effect of Ezetimibe and/or Simvastatin on Coenzyme Q10 Levels in Plasma Extended-release niacin or ezetimibe and carotid intima-media thickness. Efficacy of ezetimibe in patients with statin-resistant and statin-intolerant familial hyperlipidaemias Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. Impact of Dual Lipid-Lowering Strategy With Ezetimibe and Atorvastatin on Coronary Plaque Regression in Patients With Percutaneous Coronary Intervention: The Multicenter Randomized Controlled PRECISE-IVUS Trial. Impact of switching from different treatment regimens to a fixed-dose combination pill (polypill) in patients with cardiovascular disease or similarly high risk Effects of ezetimibe on markers of synthesis and absorption of cholesterol in high-risk patients with elevated C-reactive protein.
OBJECTIVE Evaluate the lipid-altering effects of ezetimibe added to ongoing statin therapy , statin titration , switching from statin monotherapy to a more potent statin or to ezetimibe/simvastatin . METHODS A pooled analysis of patient-level data from 17 double-blind , active or placebo-controlled studies of 8667 hypercholesterolemic adults r and omized to  ezetimibe 10 mg added to ongoing statins , statin titration ( doubling ) , or switching from ongoing statins to rosuvastatin ( 10 mg ) or to ezetimibe/simvastatin ( 10/20 and 40 mg ) . Percent change from baseline in low-density lipoprotein cholesterol ( LDL-C ) was estimated by analysis of variance . Percent of patients who achieved LDL-C and other guideline -recommended targets , and target lipid levels by baseline distance to goal were evaluated . RESULTS LDL-C percent change from baseline was -26.0 for ezetimibe added to ongoing statin therapy , -27.6 for switching from ongoing statin to ezetimibe/simvastatin , -19.7 for switching to rosuvastatin 10 mg , and -9.7 for dose doubling of the ongoing statin . For patients within 0.8 mmol/L ( 30 mg/dL ) of the target at baseline , LDL-C target attainment rates were 75.9 % for adding ezetimibe to ongoing statin , 72.8 % for switching to ezetimibe/simvastatin , 61.8 % for switching to rosuvastatin , and 44.3 % for statin dose-doubling . Similarly , improvements in other lipids and achievement of non-high-density lipoprotein cholesterol and apolipoprotein B targets among this patient group were largest for ezetimibe added to ongoing statins and switching to ezetimibe/simvastatin ; switching to rosuvastatin 10 mg and statin dose-doubling were less effective . CONCLUSIONS Adding ezetimibe to ongoing statin therapy appeared to be an effective option for patients who do not achieve lipid-lowering goals on statins alone Purpose This post hoc analysis assessed switching to ezetimibe/simvastatin 10/20 mg vs doubling the baseline statin dose to simvastatin 40 mg or atorvastatin 20 mg or switching to rosuvastatin 10 mg in subgroups of obese ( BMI ≥30 kg/m2 ) and non-obese ( BMI < 30 kg/m2 ) diabetic subjects . Methods This was a r and omized , double-blind , 12-week study of adults 18–79 years with cardiovascular disease with low-density lipoprotein cholesterol ( LDL-C ) ≥70 and ≤160 mg/dl .  Percent change in LDL-C and other lipids was estimated . Results In obese subjects ( n = 466 )  , percent changes in LDL-C and most other lipids were greater with ezetimibe/simvastatin vs doubling the baseline statin dose or switching to rosuvastatin . In non-obese subjects ( n = 342 ) , percent changes in LDL-C , total cholesterol , non-HDL-C , Apo B and Apo A-I were greater with ezetimibe/simvastatin vs doubling the baseline statin dose or switching to rosuvastatin ; and treatment with ezetimibe/simvastatin result ed in greater changes in triglycerides  vs rosuvastatin and HDL-C vs doubling the baseline statin dose . The safety profiles were generally similar . Conclusions Regardless of baseline obesity status , switching to ezetimibe/simvastatin was more effective at reducing LDL-C , total cholesterol , non-HDL-C , and Apo B vs doubling the baseline statin dose to simvastatin 40 mg or atorvastatin 20 mg or switching to rosuvastatin 10 mg Background There exists a sub population of T2DM in whom first-line doses of statin are insufficient for optimally reducing LDL-C , representing a major risk of CVD . The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles leading to residual risks . Methods Lipid changes were assessed in a r and omized , multicenter , 12-week , open-label study comparing a high-potency statin ( 10 mg of atorvastatin or 1 mg of pitavastatin ) plus ezetimibe ( EAT : n = 53 ) with a double dose of statin ( 20 mg of atorvastatin or 2 mg of pitavastatin ) ( DST : n = 56 ) in DM subjects who had failed to achieve the optimal LDL-C targets .  Lipid variables were compared with a primary focus on LDL-C and with secondary focuses on the percentage of patients who reached the LDL-C targets and changes in the levels of RLP-C ( remnant like particle cholesterol ) and sd-LDL-C , two characteristic atherogenic risks of DM . Results The reduction of LDL-C ( % ) , the primary endpoint , differed significantly between the two groups ( -24.6 in EAT vs. -10.9 in DST ) . In the analyses of the secondary endpoints , EAT treatment brought about significantly larger reductions in sd-LDL-C ( -20.5 vs. -3.7 ) and RLP-C ( -19.7 vs. + 5.5 ) . In total , 89.4 % of the patients receiving EAT reached the optimized treatment goal compared to 51.0 % of the patients receiving DST . The changes in TC ( -16.3 vs. -6.3 ) and non-HDL-C ( -20.7 vs. -8.3 ) differed significantly between the two groups . Conclusion Ezetimibe added to high-potency statin ( 10 mg of atorvastatin or 1 mg of pitavastatin ) was more effective than the intensified-dose statin ( 20 mg of atorvastatin or 2 mg of pitavastatin ) treatment not only in helping T2DM patients attain more LDL-C reduction , but also in improving their atherogenic lipid profiles , including their levels of sd-LDL-C and RLP-C. We thus recommend the addition of ezetimibe to high-potency statin as a first line strategy for T2DM patients with insufficient statin response . Trial Registration The UMIN Clinical Trials Registry 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 AIM The aim of this study was to compare ezetimibe/simvastatin combination therapy with intensified statin monotherapy as alternative treatment strategies to achieve the Joint British Societies (JBS)-2 and National Institute for Health and Clinical Excellence low-density-lipoprotein cholesterol ( LDL-C ) target of < 2 mmol/l for secondary prevention or JBS-2 LDL-C target of < 2 mmol/l for primary prevention in high-risk patients who have failed to reach target with simvastatin 40 mg . METHODS This is a prospect i ve , double-blind study conducted in 34 UK primary care centres ; 1748 patients with established cardiovascular disease ( CVD ) , diabetes or high risk of CVD who had been taking simvastatin 40 mg for > or = 6 weeks were screened and 786 ( 45 % ) with fasting LDL-C > or = 2.0 mmol/l ( and < 4.2 mmol/l ) at screening and after a further 6-week run-in period on simvastatin 40 mg were r and omised to ezetimibe/simvastatin 10/40 mg ( as a combination tablet ; n = 261 ) , atorvastatin 40 mg ( n = 263 ) or rosuvastatin 5 mg ( n = 73 ) or 10 mg ( n = 189 ) once daily for 6 weeks . Rosuvastatin dose was based on UK prescribing instructions . The primary outcome measure was the proportion of patients achieving LDL-C < 2 mmol/l at the end of the study . RESULTS The percentage of patients ( adjusted for baseline differences ) achieving LDL-C < 2 mmol/l was 69.4 % with ezetimibe/simvastatin 10/40 mg , compared with 33.5 % for atorvastatin 40 mg [ odds ratio 4.5 ( 95 % CI : 3.0 - 6.8 ) ; p < 0.001 ] and 14.3 % for rosuvastatin 5 or 10 mg [ odds ratio 13.6 ( 95 % CI : 8.6 - 21.6 ) ; p < 0.001 ] . Similar results were observed for achievement of total cholesterol < 4.0 mmol/l . All study treatments were well tolerated . CONCLUSION Approximately 45 % of patients screened had not achieved LDL-C < 2 mmol/l after > or = 12 weeks of treatment with simvastatin 40 mg . In this group , treatment with ezetimibe/simvastatin 10/40 mg achieved target LDL-C levels in a significantly higher proportion of patients during a 6-week period than switching to either atorvastatin 40 mg or rosuvastatin 5 - 10 mg BACKGROUND Despite the efficacy of statins in lowering low-density lipoprotein cholesterol ( LDL-C ) levels , many patients who are at high risk for heart disease with hypercholesterolemia require additional LDL-C level reduction . The cholesterol absorption inhibitor , ezetimibe , has been shown to provide significant incremental reductions in LDL-C levels when co-administered with statins . This study was performed to compare the efficacy and safety of ezetimibe ( 10 mg ) plus response-based atorvastatin titration versus response-based atorvastatin titration alone in the attainment of LDL-C goals in subjects who are at high risk for coronary heart disease ( CHD ) and are not at their LDL-C goal on the starting dose of atorvastatin . METHODS This was a 14-week , multicenter , r and omized , double-blind , active-controlled study conducted in 113 clinical research centers in 21 countries . Participants were adults with heterozygous familial hypercholesterolemia ( HeFH ) , CHD , or multiple ( > or = 2 ) cardiovascular risk factors , and a LDL-C level > or = 130 mg/dL after a 6- to 10-week dietary stabilization and atorvastatin ( 10 mg/day ) open-label run-in period . Eligible subjects continued to receive atorvastatin ( 10 mg ) and were r and omized to receive blinded treatment with ezetimibe ( 10 mg/day ; n = 305 ) or an additional 10 mg/day of atorvastatin ( n = 316 ) . The atorvastatin dose in both groups was doubled after 4 weeks , 9 weeks , or both when the LDL-C level was not at its goal ( < or = 100 mg/dL ) , so that patients receiving combined therapy could reach 40 mg/day and patients receiving atorvastatin alone could reach 80 mg/day . The primary end point was the proportion of subjects achieving their LDL-C level goal at week 14 . A secondary end point was the change in LDL-C level and other lipid parameters at 4 weeks after ezetimibe co-administration with 10 mg/day of atorvastatin versus 20 mg/day of atorvastatin monotherapy . RESULTS The proportion of subjects reaching their target LDL-C level goal of < or = 100 mg/dL was significantly higher in the co-administration group than in the atorvastatin monotherapy group ( 22 % vs 7 % ; P < .01 ) . At 4 weeks , levels of LDL-C , triglycerides , and non-high-density lipoprotein cholesterol were reduced significantly more by combination therapy than by doubling the dose of atorvastatin ( LDL-C -22.8 % versus -8.6 % ; P < .01 ) . The combination regimen had a safety and tolerability profile similar to that of atorvastatin alone . CONCLUSIONS The addition of ezetimibe to the starting dose of 10 mg/day of atorvastatin followed by response-based atorvastatin dose titration to a maximum of 40 mg/day provides a more effective means for reducing LDL-C levels in patients at high risk for CHD than continued doubling of atorvastatin as high as 80 mg/day alone OBJECTIVES We sought to test the platelet inhibitory and anti-inflammatory effects of a higher statin dosage compared with combined treatment with ezetimibe plus a low statin dose . BACKGROUND Reducing the level of low-density lipoprotein cholesterol ( LDL-C ) with statins induces important pleiotropic effects such as platelet inhibition . An insufficient LDL-C reduction often is treated with ezetimibe , an intestinal cholesterol absorption inhibitor , in combination with a low statin dose . It is not known whether this combination therapy has the same pleiotropic effects as a statin monotherapy . METHODS Fifty-six patients with coronary artery disease were assigned r and omly to receive either 40 mg/day of atorvastatin or 10 mg/day of ezetimibe plus 10 mg/day of atorvastatin for 4 weeks . The levels of LDL-C , platelet activation markers after stimulation , platelet aggregation , and plasma chemokine levels ( i.e. , regulated on activation normally T-cell expressed and secreted [ RANTES ] ) were measured before and after changing lipid-lowering medication . RESULTS Platelet activation markers ( P-selectin ) after stimulation ( adenosine diphosphate ) were reduced by 40 mg/day of atorvastatin ( -5.2 + /- 1.6 arbitrary units ) but not by ezetimibe plus low-dose atorvastatin ( 2.1 + /- 1.8 arbitrary units ; p < 0.005 ) despite a similar reduction of LDL-C  ( atorvastatin -1.01 + /- 0.18 mmol/l vs. ezetimibe plus atorvastatin -1.36 + /- 0.22 mmol/l , p = NS ) . Thrombin receptor-activating peptide-induced platelet aggregation as well as plasma RANTES levels were reduced by 40 mg/day of atorvastatin but not by ezetimibe plus low-dose atorvastatin . CONCLUSIONS Platelet reactivity and a proinflammatory chemokine were reduced more by the higher atorvastatin dose than by ezetimibe plus low-dose atorvastatin . In patients with coronary artery disease , it might be important to combine ezetimibe with higher statin dosages to benefit from cholesterol-independent pleiotropic effects The phase 3 ODYSSEY OPTIONS studies ( OPTIONS I , NCT01730040 ; OPTIONS II , NCT01730053 ) are multicenter , multinational , r and omized , double‐blind , active‐comparator , 24‐week studies evaluating the efficacy and safety of alirocumab , a fully human monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 , as add‐on therapy in ∼ 650 high‐cardiovascular (CV)‐risk patients whose low‐density lipoprotein cholesterol ( LDL‐C ) levels are ≥100 mg/dL or ≥70 mg/dL according to the CV‐risk category , high and very high CV risk , respectively , with atorvastatin ( 20–40 mg/d ) or rosuvastatin ( 10–20 mg/d ) . Patients are r and omized to receive alirocumab 75 mg via a single , subcutaneous , 1‐mL injection by prefilled pen every 2 weeks ( Q2W ) as add‐on therapy to atorvastatin ( 20–40 mg ) or rosuvastatin ( 10–20 mg ) ; or to receive ezetimibe 10 mg/d as add‐on therapy to statin ; or to receive statin up‐titration ; or to switch from atorvastatin to rosuvastatin ( OPTIONS I only ) . At week 12 , based on week 8 LDL‐C levels , the alirocumab dose may be increased from 75 mg to 150 mg Q2W if LDL‐C levels remain ≥100 mg/dL or ≥70 mg/dL in patients with high or very high CV risk , respectively . The primary efficacy endpoint in both studies is difference in percent change in calculated LDL‐C from baseline to week 24 in the alirocumab vs control arms . The studies may provide guidance to inform clinical decision‐making when patients with CV risk require additional lipid‐lowering therapy to further reduce LDL‐C levels . The flexibility of the alirocumab dosing regimen allows for individualized therapy based on the degree of LDL‐C reduction required to achieve the desired LDL‐C level BACKGROUND Statin intolerance limits many patients from achieving optimal low-density lipoprotein cholesterol ( LDL-C ) concentrations . Current options for such patients include using a lower but tolerated dose of a statin and adding or switching to ezetimibe or other non-statin therapies . METHODS ODYSSEY ALTERNATIVE ( NCT01709513 ) compared alirocumab with ezetimibe in patients at moderate to high cardiovascular risk with statin intolerance ( unable to tolerate ≥2 statins , including one at the lowest approved starting dose ) due to muscle symptoms . A placebo run-in and statin rechallenge arm were included in an attempt to confirm intolerance . Patients ( n = 361 ) received single-blind subcutaneous ( SC ) and oral placebo for 4 weeks during placebo run-in . Patients reporting muscle-related symptoms during the run-in were to be withdrawn . Continuing patients were r and omized ( 2:2:1 ) to double-blind alirocumab 75 mg SC every 2 weeks ( Q2W ; plus oral placebo ) , ezetimibe 10 mg/d ( plus SC placebo Q2W ) , or atorvastatin 20 mg/d ( rechallenge ; plus SC placebo Q2W ) for 24 weeks . Alirocumab dose was increased to 150 mg Q2W at week 12 depending on week 8 LDL-C values . Primary end point was percent change in LDL-C from baseline to week 24 ( intent-to-treat ) for alirocumab vs ezetimibe . RESULTS Baseline mean ( st and ard deviation ) LDL-C was 191.3 ( 69.3 ) mg/dL ( 5.0 [ 1.8 ] mmol/L ) . Alirocumab reduced mean ( st and ard error ) LDL-C by 45.0 % ( 2.2 % ) vs 14.6 % ( 2.2 % ) with ezetimibe ( mean difference 30.4 % [ 3.1 % ] , P < .0001 ) . Skeletal muscle-related events were less frequent with alirocumab vs atorvastatin ( hazard ratio 0.61 , 95 % confidence interval 0.38 - 0.99 , P = .042 ) . CONCLUSIONS Alirocumab produced greater LDL-C reductions than ezetimibe in statin-intolerant patients , with fewer skeletal-muscle adverse events vs atorvastatin OBJECTIVE To evaluate the incremental cost-effectiveness ratio ( ICER ) of switching to ezetimibe/simvastatin ( Eze/Simva ) compared with doubling the submaximal statin doses , in patients with acute coronary syndrome ( ACS ) events in the INFORCE study . METHODS Lifetime treatment costs and benefits were computed using a Markov model . Model inputs included each patient 's cardiovascular risk factor profile and actual lipid values at baseline and 12 weeks ( endpoint ) . Cardiovascular event and drug costs were discounted at 3.5 % . Age-specific utilities were based on UK literature values and non-coronary heart disease mortality rates on the Office of National Statistics data . In the INFORCE study , 384 patients taking statins at stable doses for ≥6 weeks before hospital admission were stratified by statin dose/potency ( low , medium , and high ) and then r and omized to doubling the statin dose or switching to Eze/Simva 10/40 mg for 12 weeks . RESULTS The Eze/Simva  group ( n=195 ) had a higher mean baseline total cholesterol than the double-statin group ( n=189 ) . Analyses were adjusted for baseline characteristics . In the INFORCE study , Eze/Simva  reduced low-density lipoprotein cholesterol ( LDL-C ) by ∼30 % ( vs. 4 % with doubling statin doses ) and significantly enhanced LDL-C goal attainment . In the cost-effectiveness analysis , Eze/Simva conferred 0.218 incremental discounted quality -adjusted life year ( QALY ) at a discounted incremental cost of £ 2524 , for an ICER of £ 11,571/QALY ( 95 % confidence interval=£8181-£18,600/QALY ) . The ICER was £ 13,552/QALY , £ 11,930/QALY , and £ 10,148/QALY in the low- , medium- , and high-potency strata , respectively . CONCLUSIONS Switching to Eze/Simva 10/40 mg is projected to be a cost-effective treatment ( vs. double-statin ) in UK patients with ACS BACKGROUND Statin therapy reduces low-density lipoprotein ( LDL ) cholesterol levels and the risk of cardiovascular events , but whether the addition of ezetimibe , a nonstatin drug that reduces intestinal cholesterol absorption , can reduce the rate of cardiovascular events further is not known . METHODS We conducted a double-blind , r and omized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter ( 1.3 to 2.6 mmol per liter ) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter ( 1.3 to 3.2 mmol per liter ) if they were not receiving lipid-lowering therapy .  The combination of simvastatin ( 40 mg ) and ezetimibe ( 10 mg ) ( simvastatin-ezetimibe ) was compared with simvastatin ( 40 mg ) and placebo ( simvastatin monotherapy ) . The primary end point was a composite of cardiovascular death , nonfatal myocardial infa rct ion , unstable angina requiring rehospitalization , coronary revascularization ( ≥30 days after r and omization ) , or nonfatal stroke . The median follow-up was 6 years . RESULTS The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter ( 1.4 mmol per liter ) in the simvastatin-ezetimibe group , as compared with 69.5 mg per deciliter ( 1.8 mmol per liter ) in the simvastatin-monotherapy group ( P<0.001 ) . The Kaplan-Meier event rate for the primary end point at 7 years was 32.7 % in the simvastatin-ezetimibe group , as compared with 34.7 % in the simvastatin-monotherapy group ( absolute risk difference , 2.0 percentage points ; hazard ratio , 0.936 ; 95 % confidence interval , 0.89 to 0.99 ; P=0.016 ) . Rates of prespecified muscle , gallbladder , and hepatic adverse effects and cancer were similar in the two groups . CONCLUSIONS When added to statin therapy , ezetimibe result ed in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes . Moreover , lowering LDL cholesterol to levels below previous targets provided additional benefit . ( Funded by Merck ; IMPROVE-IT Clinical Trials.gov number , NCT00202878 . ) BACKGROUND Reduction in low-density lipoprotein cholesterol ( LDL-C ) improves clinical outcomes in patients with chronic coronary artery disease and acute coronary syndromes ( ACSs ) . The combination of ezetimibe/simvastatin produces greater reductions in LDL-C compared to simvastatin monotherapy . The IMProved Reduction of Outcomes : Vytorin Efficacy International Trial ( IMPROVE-IT ) is a multicenter , r and omized , double-blind , active-control trial design ed to test the hypothesis that the addition of ezetimibe to statin therapy , using ezetimibe/simvastatin , will translate into increased clinical benefit on cardiovascular outcomes relative to simvastatin monotherapy in patients with ACS . STUDY DESIGN The study will recruit up to 18,000 moderate- to high-risk patients stabilized after ACS . Patients are r and omized in a 1:1 ratio to once-daily doses of either ezetimibe/simvastatin 10/40 mg or simvastatin monotherapy 40 mg . Follow-up visits are at 1 and 4 months , and every 4 months thereafter . If consecutive measures of LDL-C are > 79 mg/dL at follow-up visits , the simvastatin dose will be increased to 80 mg in a double-blind manner . The primary end point is the first occurrence of cardiovascular death , nonfatal myocardial infa rct ion , rehospitalization for unstable angina , coronary revascularization ( occurring at least 30 days after r and omization ) , or stroke . Patients will be followed for a minimum of 2.5 years and until at least 5,250 patients experience a primary end point . SUMMARY IMPROVE-IT will determine whether the addition of ezetimibe to statin therapy , using ezetimibe/simvastatin , improves cardiovascular outcomes compared with simvastatin monotherapy in patients after ACS . In addition , the difference in achieved LDL-C levels between the groups will provide data on whether the target for LDL-C lowering should be reduced further BACKGROUND In a multinational trial ( 4522IL/0081 ) , we assessed the effects of switching to low doses of rosuvastatin from commonly used doses of atorvastatin , simvastatin , and pravastatin on low-density lipoprotein cholesterol ( LDL-C ) goal achievement in high-risk patients . METHODS Hypercholesterolemic patients ( n = 3140 ) with coronary heart disease , atherosclerosis , or type 2 diabetes were r and omized to open-label rosuvastatin 10 mg , atorvastatin 10 or 20 mg , simvastatin 20 mg , or pravastatin 40 mg for 8 weeks . Patients either remained on these treatments for another 8 weeks or switched treatments from atorvastatin 10 mg , simvastatin 20 mg , and pravastatin 40 mg to rosuvastatin 10 mg or from atorvastatin 20 mg to rosuvastatin 10 or 20 mg . The primary efficacy measure was the proportion of patients reaching the Joint European Societies ' LDL-C goal ( < 116 mg/dL ) at week 16 . For measures of cholesterol goal achievement , treatment arms were compared using logistic-regression analysis . RESULTS Significant improvement in LDL-C goal achievement was found for patients who switched to rosuvastatin 10 mg , compared with patients who remained on atorvastatin 10 mg ( 86 % vs 80 % , P < .05 ) , simvastatin 20 mg ( 86 % vs 72 % , P < .0001 ) , and pravastatin 40 mg ( 88 % vs 66 % , P < .0001 ) , and between patients switched to rosuvastatin 20 mg and those who remained on atorvastatin 20 mg ( 90 % vs 84 % , P < .01 ) . Similar results were found for achievement of the European combined LDL-C and total cholesterol goals and National Cholesterol Education Program Adult Treatment Panel III LDL-C goals . All statins were well tolerated over 16 weeks . CONCLUSIONS We demonstrated that switching to a more efficacious statin is an effective strategy to improve lipid goal achievement in patients requiring lipid-lowering therapy Background Statins are used to treat hypercholesterolemia in patients with type 2 diabetes mellitus , but many of these patients fail to achieve the target LDL-C level . Recent reports have suggested that a synergistic effect can be obtained by concomitant administration of the cholesterol absorption inhibitor ezetimibe and a statin . However , in patients with type 2 diabetes who are already being treated with satins , it remains unclear whether it is more effective to add ezetimibe or to increase the statin dose . Therefore , this study was performed to examine the effects of these two regimens on LDL-C and lipoproteins . Methods The subjects were type 2 diabetic patients under treatment with rosuvastatin ( 2.5 mg daily ) , who had LDL-C levels ≥80 mg/dL. They were r and omly allocated to a group that received add-on therapy with ezetimibe at 10 mg/day ( combination group , n = 40 ) or an increase of the rosuvastatin dose to 5 mg/day ( dose escalation group , n = 39 ) . These two groups were compared at baseline and after 12 weeks of treatment . Results The percent change of LDL-C was −31 % in the combination group and −12 % in the dose escalation group . Both groups showed a significant decrease , but the decrease was greater in the combination group . In both groups , there was a significant decrease in the levels of small dense LDL-C , oxidized LDL and remnant-like lipoprotein cholesterol . For all of these parameters , the percent changes were greater in the combination group . Only the combination group showed a significant decrease of triglycerides . Multivariate analysis was performed to identify factors associated with reaching an LDL-C level < 80 mg/dL. As a result , add-on therapy with ezetimibe was extracted as a factor related to improvement of LDL-C. Conclusions Compared with increasing the dose of rosuvastatin , the combination of rosuvastatin and ezetimibe not only achieves quantitative but also qualitative improvement of serum lipid levels in type 2 diabetic patients , suggesting that this combination could suppress the progression of atherosclerosis . Trial registration IMPORTANCE In phase 2 studies , evolocumab , a fully human monoclonal antibody to PCSK9 , reduced LDL-C levels in patients receiving statin therapy . OBJECTIVE To evaluate the efficacy and tolerability of evolocumab when used in combination with a moderate- vs high-intensity statin . DESIGN , SETTING , AND PATIENTS Phase 3 , 12-week , r and omized , double-blind , placebo- and ezetimibe-controlled study conducted between January and December of 2013 in patients with primary hypercholesterolemia and mixed dyslipidemia at 198 sites in 17 countries . INTERVENTIONS Patients ( n = 2067 ) were r and omized to 1 of 24 treatment groups in 2 steps . Patients were initially r and omized to a daily , moderate-intensity ( atorvastatin [ 10 mg ] , simvastatin [ 40 mg ] , or rosuvastatin [ 5 mg ] ) or high-intensity ( atorvastatin [ 80 mg ] , rosuvastatin [ 40 mg ] ) statin . After a 4-week lipid-stabilization period , patients ( n = 1899 ) were r and omized to compare evolocumab ( 140 mg every 2 weeks or 420 mg monthly ) with placebo ( every 2 weeks or monthly ) or ezetimibe ( 10 mg or placebo daily ; atorvastatin patients only ) when added to statin therapies . MAIN OUTCOMES AND MEASURES Percent change from baseline in low-density lipoprotein cholesterol ( LDL-C ) level at the mean of weeks 10 and 12 and at week 12 . RESULTS Evolocumab  reduced LDL-C levels by 66 % ( 95 % CI , 58 % to 73 % ) to 75 % ( 95 % CI , 65 % to 84 % ) ( every 2 weeks ) and by 63 % ( 95 % CI , 54 % to 71 % ) to 75 % ( 95 % CI , 67 % to 83 % ) ( monthly ) vs placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups ; the LDL-C reductions at week 12 were comparable . For moderate-intensity statin groups , evolocumab every 2 weeks reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean of 39 to 49 mg/dL ; monthly evolocumab reduced LDL-C from a baseline mean of 123 to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-intensity statin groups , evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 35 to 38 mg/dL ; monthly evolocumab reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 33 to 35 mg/dL. Adverse events were reported in 36 % , 40 % , and 39 % of evolocumab- , ezetimibe- , and placebo-treated patients , respectively . The most common adverse events in evolocumab-treated patients were back pain , arthralgia , headache , muscle spasms , and pain in extremity ( all < 2 % ) . CONCLUSIONS AND RELEVANCE In this 12-week trial conducted among patients with primary hypercholesterolemia and mixed dyslipidemia , evolocumab added to moderate- or high-intensity statin therapy result ed in additional LDL-C lowering . Further studies are needed to evaluate the longer-term clinical outcomes and safety of this approach for LDL-C lowering . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01763866 Background Statins are frequently administered to reduce low-density lipoprotein cholesterol ( LDL-C ) and vascular inflammation , because LDL-C and high sensitive C-reactive protein ( hs-CRP ) are associated with high risk for cardiovascular events . When statins do not reduce LDL-C to desired levels in high-risk patients with coronary artery disease ( CAD ) , ezetimibe can be added or the statin dose can be increased . However , which strategy is more effective for treating patients with CAD has not been established . The present study compares anti-inflammatory effects and lipid profiles in patients with CAD and similar LDL-C levels who were treated by increasing the statin dose or by adding ezetimibe to the original rosuvastatin dose to determine the optimal treatment for such patients . Methods 46 patients with high-risk CAD and LDL-C and hs-CRP levels of > 70 mg/dL and > 1.0 mg/L , respectively , that were not improved by 4 weeks of rosuvastatin ( 2.5 mg/day ) were r and omly assigned to receive 10 mg ( R10 , n = 24 ) of rosuvastatin or 2.5 mg/day of rosuvastatin combined with 10 mg/day of ezetimibe ( R2.5/E10 , n = 22 ) for 12 weeks . The primary endpoint was a change in hs-CRP . Results Baseline characteristics did not significantly differ between the groups . At 12 weeks , LDL-C and inflammatory markers ( hs-CRP , interleukin-6 , tumour necrosis factor-alpha and pentraxin 3 ) also did not significantly differ between the two groups ( LDL-C : R10 vs. R2.5/E10 : -19.4 ± 14.2 vs. -22.4 ± 14.3 mg/dL ) . However , high-density lipoprotein cholesterol ( HDL-C ) was significantly improved in the R10 , compared with R2.5/E10 group ( 4.6 ± 5.9 vs. 0.0 ± 6.7 mg/dL ; p < 0.05 ) . Conclusion Both enhanced therapies exerted similar anti-inflammatory effects under an equal LDL-C reduction in patients with high-risk CAD despite 2.5 mg/day of rosuvastatin . However , R10 elevated HDL-C more effectively than R2.5/E10.Trial registration Aims Hypercholesterolemia coexisting with diabetes still requires clinical intervention to manage the high risk of cardiovascular disease it poses . No second-step strategy is established , however , for cases where strong statins fail to bring cholesterol down to target levels . In this study we seek to demonstrate the superior effect of ezetimibe in combination with strong statins to reduce LDL-C in Japanese patients suffering from both T2DM and hyper LDL-cholesterolemia . Methods T2DM out patients ( 109 patients from 16 institutes ) who failed to achieve the target LDL-C value were recruited and r and omly assigned to two groups , a double-dose-statin group and ezetimibe-plus-statin group . Follow-ups were scheduled at 0 , 12 , 26 , and 52 weeks . The primary endpoint was the percentage change in the level of LDL-C from baseline to 12 weeks . Interim results We could successfully create r and omized ( gender , age , LDL-C , HbA1c , etc . ) two groups except for slight differences in apolipoprotein-B and sd-LDL . Conclusions RESEARCH is the first prospect i ve , parallel-group , multicenter study comparing a double dose of strong statin with ezetimibe plus strong statin for T2DM patients . The RESEARCH study will provide reliable evidence with which to establish a clinical strategy for diabetics who fail to achieve the target LDL-C value Background A considerable number of patients with severely elevated LDL-C do not achieve recommended treatment targets , despite treatment with statins . Adults at high cardiovascular risk with hypercholesterolemia and LDL-C ≥ 2.59 and ≤ 4.14 mmol/L ( N = 250 ) , pretreated with atorvastatin 20 mg were r and omized to ezetimibe/simvastatin 10/40 mg or atorvastatin 40 mg for 6 weeks . The percent change in LDL-C and other lipids was assessed using a constrained longitudinal data analysis method with terms for treatment , time , time-by-treatment interaction , stratum , and time-by-stratum interaction . Percentage of subjects achieving LDL-C < 1.81 mmol/L , < 2.00 mmol/L , or < 2.59 mmol/L was assessed using a logistic regression model with terms for treatment and stratum . Tolerability was assessed . Results Switching to ezetimibe/simvastatin result ed in significantly greater changes in LDL-C ( -26.81 % vs.-11.81 % ) , total cholesterol ( -15.97 % vs.-7.73 % ) , non-HDL-C ( -22.50 % vs.-10.88 % ) , Apo B ( -17.23 % vs.-9.53 % ) , and Apo A-I ( 2.56 % vs.-2.69 % ) vs. doubling the atorvastatin dose ( all p ≤ 0.002 ) , but not HDL-C , triglycerides , or hs-CRP . Significantly more subjects achieved LDL-C < 1.81 mmol/L ( 29 % vs. 5 % ) , < 2.00 mmol/L ( 38 % vs. 9 % ) or < 2.59 mmol/L ( 69 % vs. 41 % ) after switching to ezetimibe/simvastatin vs. doubling the atorvastatin dose ( all p < 0.001 ) . The overall safety profile appeared generally comparable between treatment groups . Conclusions In high cardiovascular risk subjects with hypercholesterolemia already treated with atorvastatin 20 mg but not at LDL-C < 2.59 mmol/L , switching to combination ezetimibe/simvastatin 10/40 mg provided significantly greater LDL-C lowering and greater achievement of LDL-C targets compared with doubling the atorvastatin dose to 40 mg . Both treatments were generally well-tolerated . Trial registration Registered at clinical trials.gov : OBJECTIVE To determine the extent of reduction in low-density lipoprotein cholesterol ( LDL-C ) level and improvement in National Cholesterol Education Program Adult Treatment Panel III ( NCEP ATP III ) LDL-C goal attainment when ezetimibe was added to ongoing statin therapy in a diverse population of community-based patients . PATIENTS AND METHODS In this multicenter , double-blind , placebo-controlled trial ( from January 2003 to August 2003 ) , hypercholesterolemic patients ( from 299 US primary care and specialty practice s ) with LDL-C levels exceeding NCEP ATP III goals were r and omized ( 2:1 ) to receive  ezetimibe ( 10 mg/d ) or placebo in addition to their ongoing statin therapy for 6 weeks . RESULTS In a study of 3030 r and omized patients , ezetimibe added to statin therapy significantly reduced the LDL-C level by an additional 25.8 % in the total population , compared with an additional 2.7 % reduction with placebo plus statin ( treatment difference , -23.1 % ; P<.001 ) ; the treatment difference ranged from -19.9 % to -24.0 % ( P<.001 ) in each NCEP ATP III risk category subgroup . Significantly ( P<.001 ) more patients ( 71.0 % ) treated with ezetimibe added to statin reached their NCEP ATP III target LDL-C level compared with those treated with placebo plus statin ( 20.6 % ) . The addition of ezetimibe also result ed in improvement in other lipid parameters and high-sensitivity C-reactive protein levels . These benefits were consistent across sex , race , age , statin br and , and dose subgroups . Ezetimibe plus statin therapy was well tolerated , with a safety profile similar to placebo plus statin . CONCLUSION Across multiple subgroups , ezetimibe added to statin therapy consistently produced significant additional improvements in LDL-C levels and goal attainment , as well as in other lipoproteins , compared with addition of placebo . The addition of ezetimibe to statin therapy should be considered for patients not achieving their NCEP ATP III LDL-C goals while receiving statin therapy alone OBJECTIVES Statins may exhibit anti-inflammatory and antioxidant effects . Whether different statins at equivalent doses or the combination of low-dose statin with ezetimibe have comparable anti-inflammatory and antioxidant effects is unknown . The aim of this study was to compare the effects of simvastatin , simvastatin/ezetimibe or rosuvastatin at equivalent low-density lipoprotein cholesterol lowering doses on inflammation and oxidative stress indices in subjects with hypercholesterolemia . METHODS This was a pre-specified analysis of a prospect i ve , r and omized , open-label , blinded endpoint ( PROBE ) study . We enrolled one hundred and fifty three ( n = 153 ) hypercholesterolemic subjects who were r and omized to receive simvastatin 40 mg or simvastatin/ezetimibe 10/10 mg or rosuvastatin 10 mg daily .  Plasma 8-Epi prostagl and in F2 alpha ( 8-epiPGF2a ) , oxidized LDL ( oxLDL ) and lipoprotein-associated phospholipase A2 ( Lp-PLA2 ) activity and mass were measured at baseline and following 12 weeks of treatment . RESULTS A significant reduction in plasma 8-isoprostane and oxLDL levels was observed in all treatment groups [ by 10 % , 8 % and 6 % ( p < 0.05 compared with baseline ) and 41 % , 40 % and 39 % ( p < 0.001 compared with baseline ) in simvastatin , simvastatin/ezetimibe and rosuvastatin groups , respectively ] . In all treatment groups a significant reduction in total plasma Lp-PLA2 activity and mass was observed ( by 36 % , 31 % and 38 % and 36 % , 32 % and 32 % for simvastatin , simvastatin/ezetimibe and rosuvastatin , respectively , p < 0.001 compared with baseline ) . No intergroup differences were observed . CONCLUSIONS Simvastatin 40 mg , simvastatin/ezetimibe 10/10 mg and rosuvastatin 10 mg significantly reduced 8-epiPGF2a , oxLDL and Lp-PLA2 activity and mass to a similar extent Statins are the accepted st and ard for lowering low‐density lipoprotein cholesterol ( LDL‐C ) . However , 5 % to 10 % of statin‐treated patients report intolerance , mostly due to muscle‐related adverse effects . Challenges exist to objective identification of statin‐intolerant patients . Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) , result ing in marked LDL‐C reduction . We report the design of Goal Achievement After Utilizing an Anti‐PCSK9 Antibody in Statin‐Intolerant Subjects 3 ( GAUSS‐3 ) , a phase 3 , multicenter , r and omized , double‐blind , ezetimibe‐controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose . The study incorporates a novel atorvastatin‐controlled , double‐blind , crossover phase to objective ly identify statin intolerance . Eligible patients had LDL‐C above the National Cholesterol Education Project Adult Treatment Panel III target level for the appropriate coronary heart disease risk category and were unable to tolerate ≥3 statins or 2 statins ( one of which was atorvastatin ≤10 mg/d ) or had a history of marked creatine kinase elevation accompanied by muscle symptoms while on 1 statin . This trial has 2 co‐ primary endpoints : mean percent change from baseline in LDL‐C at weeks 22 and 24 and percent change from baseline in LDL‐C at week 24 . Key secondary efficacy endpoints include change from baseline in LDL‐C , percent of patients attaining LDL‐C < 70 mg/dL ( 1.81 mmol/L ) , and percent change from baseline in total cholesterol , non – high‐density lipoprotein cholesterol , and apolipoprotein B. Recruitment of 511 patients was completed on November 28 , 2014 Hypercholesterolemic patients ( n = 1,547 ) at high atherosclerotic cardiovascular disease risk with low-density lipoprotein cholesterol ( LDL-C ) levels ≥100 and ≤160 mg/dl while treated with atorvastatin 10 mg/day entered a multicenter , r and omized , double-blind , active-controlled , clinical trial using two 6-week study periods . Period I compared the efficacy/safety of ( 1 ) adding ezetimibe 10 mg ( ezetimibe ) to stable atorvastatin 10 mg , ( 2 ) doubling atorvastatin to 20 mg , or ( 3 ) switching to rosuvastatin 10 mg . Subjects in the latter 2 groups who persisted with elevated LDL-C levels ( ≥100 and ≤160 mg/dl ) after period I , entered period II ; subjects on atorvastatin 20 mg had ezetimibe added to their atorvastatin 20 mg , or uptitrated their atorvastatin to 40 mg ; subjects on rosuvastatin 10 mg switched to atorvastatin 20 mg plus ezetimibe or uptitrated their rosuvastatin to 20 mg . Some subjects on atorvastatin 10 mg plus ezetimibe continued the same treatment into period II . At the end of period I , ezetimibe plus atorvastatin 10 mg reduced LDL-C significantly more than atorvastatin 20 mg or rosuvastatin 10 mg ( 22.2 % vs 9.5 % or 13.0 % , respectively , p < 0.001 ) . At the end of period II , ezetimibe plus atorvastatin 20 mg reduced LDL-C significantly more than atorvastatin 40 mg ( 17.4 % vs 6.9 % , p < 0.001 ) ; switching from rosuvastatin 10 mg to ezetimibe plus atorvastatin 20 mg reduced LDL-C significantly more than uptitrating to rosuvastatin 20 mg ( 17.1 % vs 7.5 % , p < 0.001 ) . Relative to comparative treatments , ezetimibe added to atorvastatin 10 mg ( period I ) or atorvastatin 20 mg ( period II ) produced significantly greater percent attainment of LDL-C targets < 100 or < 70 mg/dl , and significantly greater percent reductions in total cholesterol , non-high-density lipoprotein cholesterol , most lipid and lipoprotein ratios , and apolipoprotein B ( except ezetimibe plus atorvastatin 20 vs atorvastatin 40 mg ) . Reports of adverse experiences were generally similar among groups . In conclusion , treatment of hypercholesterolemic subjects at high cardiovascular risk with ezetimibe added to atorvastatin 10 or 20 mg produced significantly greater improvements in key lipid parameters and significantly greater attainment of LDL-C treatment targets than doubling atorvastatin or switching to ( or doubling ) rosuvastatin at the compared doses Abstract Background : HMG-CoA reductase inhibitors ( ‘ statins ’ ) have been associated with a decrease in ubidecarenone ( ubiquinone ) levels , a lipophilic enzyme also known as coenzyme Q10 ( CoQ10 ) , due to inhibition of mevalonate synthesis . There is speculation that a decrease in CoQ10 levels may be associated with statin-induced myopathy . The cholesterol absorption inhibitor ezetimibe increases endogenous cholesterol synthesis . The purpose of this study was to examine ( i ) the effects of ezetimibe and simvastatin on plasma CoQ10 levels and ( ii ) whether ezetimibe coadministered with simvastatin abrogates the suggested statin-induced decrease in the CoQ10 plasma levels . Methods : Seventy-two healthy male subjects were enrolled in a single-centre , r and omised , parallel-group study with three arms . Subjects received ezetimibe 10 mg/day , simvastatin 40 mg/day or the combination of ezetimibe 10 mg/day plus simvastatin 40 mg/day for 14 days . Results : Baseline CoQ10 ( 0.99 ± 0.30 mg/L ) levels for the combined groups remained unchanged in the ezetimibe group ( 0.95 ± 0.24 mg/L ) , and significantly decreased in the simvastatin and combination groups ( 0.82 ± 0.18 mg/L , p = 0.0002 and 0.7 ± 0.22 mg/L , p < 0.0001 , respectively ) . There was a correlation between the percentage change in the levels of low-density lipoprotein-cholesterol ( LDL-C ) and the percentage change in CoQ10 levels in all treatment groups ( correlation coefficient [ R ] = 0.67 , p < 0.0001 ) . The ratios of CoQ10 levels to LDL-C levels were significantly increased in all treatment groups ( p < 0.0001 ) . CoQ10 level was independent of cholesterol synthesis or absorption markers . Conclusions : Simvastatin and the combination of simvastatin and ezetimibe significantly decrease plasma CoQ10 levels whereas ezetimibe monotherapy does not . There is a significant correlation between the CoQ10 level decrease and the decrease in total and LDL-C levels in all three treatment groups , suggesting that the CoQ10 decrease may reflect the decrease in the levels of its lipoprotein carriers and might not be statin-specific . The statin-associated CoQ10 reduction is not abrogated through ezetimibe coadministration . Changes of CoQ10 levels are independent of cholesterol synthesis and absorption BACKGROUND Treatment added to statin monotherapy to further modify the lipid profile may include combination therapy to either raise the high-density lipoprotein ( HDL ) cholesterol level or further lower the low-density lipoprotein ( LDL ) cholesterol level . METHODS We enrolled patients who had coronary heart disease or a coronary heart disease risk equivalent , who were receiving long-term statin therapy , and in whom an LDL cholesterol level under 100 mg per deciliter ( 2.6 mmol per liter ) and an HDL cholesterol level under 50 mg per deciliter for men or 55 mg per deciliter for women ( 1.3 or 1.4 mmol per liter , respectively ) had been achieved . The patients were r and omly assigned to receive extended-release niacin ( target dose , 2000 mg per day ) or ezetimibe ( 10 mg per day ) . The primary end point was the between-group difference in the change from baseline in the mean common carotid intima-media thickness after 14 months . The trial was terminated early , on the basis of efficacy , according to a prespecified analysis conducted after 208 patients had completed the trial . RESULTS The mean HDL cholesterol level in the niacin group increased by 18.4 % over the 14-month study period , to 50 mg per deciliter ( P < 0.001 ) , and the mean LDL cholesterol level in the ezetimibe group decreased by 19.2 % , to 66 mg per deciliter ( 1.7 mmol per liter ) ( P < 0.001 ) . Niacin therapy significantly reduced LDL cholesterol and triglyceride levels ;  ezetimibe reduced the HDL cholesterol and triglyceride levels . As compared with ezetimibe , niacin had greater efficacy regarding the change in mean carotid intima-media thickness over 14 months ( P = 0.003 ) , leading to significant reduction of both mean ( P = 0.001 ) and maximal carotid intima-media thickness ( P < or = 0.001 for all comparisons ) . Paradoxically , greater reductions in the LDL cholesterol level in association with ezetimibe were significantly associated with an increase in the carotid intima-media thickness ( R = -0.31 , P < 0.001 ) . The incidence of major cardiovascular events was lower in the niacin group than in the ezetimibe group ( 1 % vs. 5 % , P = 0.04 by the chi-square test ) . CONCLUSIONS This comparative-effectiveness trial shows that the use of extended-release niacin causes a significant regression of carotid intima-media thickness when combined with a statin and that niacin is superior to ezetimibe . ( Clinical Trials.gov number , NCT00397657 . 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 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 BACKGROUND Despite st and ard statin therapy , a majority of patients retain a high " residual risk " of cardiovascular events . OBJECTIVES The aim of this study was to evaluate the effects of ezetimibe plus atorvastatin versus atorvastatin monotherapy on the lipid profile and coronary atherosclerosis in Japanese patients who underwent percutaneous coronary intervention ( PCI ) . METHODS This trial was a prospect i ve , r and omized , controlled , multicenter study . Eligible patients who underwent PCI were r and omly assigned to atorvastatin alone or atorvastatin plus ezetimibe ( 10 mg ) daily . Atorvastatin was uptitrated with a treatment goal of low-density lipoprotein cholesterol ( LDL-C ) < 70 mg/dl . Serial volumetric intravascular ultrasound was performed at baseline and again at 9 to 12 months to quantify the coronary plaque response in 202 patients . RESULTS The combination of atorvastatin/ezetimibe result ed in lower levels of LDL-C  than atorvastatin monotherapy ( 63.2 ± 16.3 mg/dl vs. 73.3 ± 20.3 mg/dl ; p < 0.001 ) . For the absolute change in percent atheroma volume ( PAV ) , the mean difference between the 2 groups ( -1.538 % ; 95 % confidence interval [ CI ] : -3.079 % to 0.003 % ) did not exceed the pre-defined noninferiority margin of 3 % , but the absolute change in PAV did show superiority for the dual lipid-lowering strategy ( -1.4 % ; 95 % CI : -3.4 % to -0.1 % vs. -0.3 % ; 95 % CI : -1.9 % to 0.9 % with atorvastatin alone ; p = 0.001 ) . For PAV , a significantly greater percentage of patients who received atorvastatin/ezetimibe  showed coronary plaque regression ( 78 % vs. 58 % ; p = 0.004 ) . Both strategies had acceptable side effect profiles , with a low incidence of laboratory abnormalities and cardiovascular events . CONCLUSIONS Compared with st and ard statin monotherapy , the combination of statin plus ezetimibe showed greater coronary plaque regression , which might be attributed to cholesterol absorption inhibition-induced aggressive lipid lowering . ( Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound [ PRECISE-IVUS ] ; NCT01043380 ) Aims Cardiovascular fixed-dose combination pills , or polypills , may help address the widespread lack of access and adherence to proven medicines . Initiation of polypill-based care typically entails switching from current separately taken medications . Given the heterogeneity in usual care , there is interest in the impact of polypill treatment across different patterns of prior medication regimen . Methods A total of 2004 participants with established cardiovascular disease or estimated 5-year cardiovascular risk of over 15 % were r and omised to polypill-based treatment ( aspirin 75 mg , simvastatin 40 mg , lisinopril 10 mg and either atenolol 50 mg or hydrochlorothiazide 12.5 mg ) or usual care . Baseline medications were classified by potency relative to polypill components . Estimated cardiovascular risk reduction was calculated by combining risk factor changes with results seen in meta-analyses of previous r and omised trials . Results For cholesterol reduction conferred by polypills , there was a dose response across baseline statin groups , with mean low-density lipoprotein (LDL)-cholesterol differences of 0.37 , 0.22 , 0.14 and 0.07 mmol/L among patients taking no statin , less potent , equipotent and more potent statin at baseline , respectively . Similarly there were differences in mean systolic BP of 5.4 , 6.2 , 3.3 and 1.8 mmHg among patients taking 0 , 1 , 2 or 3 BP-lowering agents . Among patients taking more potent statins at baseline , there was no significant difference in LDL-cholesterol but there were benefits for BP and aspirin adherence . Similar results were seen among patients taking 3 BP-lowering agents at baseline . Switching to a polypill-based strategy result ed in estimated cardiovascular relative risk reductions across a wide range of usual care patterns of antiplatelet , statin and BP-lowering therapy prescribing . Conclusion Adherence benefits from switching to a polypill result ed in risk factor changes that were at least as good as usual care across a wide variety of treatment patterns , including equally potent or more potent regimens . The benefits of switching to polypill-based care were greatest among those stepped up from partial treatment or less potent treatment AIMS High-risk subjects with elevated C-reactive protein ( CRP ) are at high risk for cardiovascular events and frequently require potent statins or combined lipid-lowering therapy to achieve lipid targets and decrease inflammation . Our study aim ed at evaluating the effects of three lipid-modifying therapies on LDL-cholesterol , CRP levels and markers of cholesterol absorption and synthesis . MAIN METHODS A prospect i ve intervention study was performed in high cardiovascular risk individuals receiving atorvastatin 10 mg daily for four weeks . Those with CRP≥2.0mg/L were r and omized to another four-week treatment period with atorvastatin 40 mg , ezetimibe 10 mg or the combination of atorvastatin 40 mg / ezetimibe 10 mg  . Lipids , markers of cholesterol absorption ( campesterol and β-sitosterol ) , and synthesis ( desmosterol ) , as well as CRP were quantified at baseline and end of study . KEY FINDINGS One hundred and twenty two individuals were included .  Atorvastatin alone or combined with ezetimibe  reduced both LDL-cholesterol and CRP ( P<0.002 vs. baseline ; Wilcoxon ) ; ezetimibe did not modify CRP . Ezetimibe-based therapies  reduced absorption markers and their ratios to cholesterol ( P<0.0001 vs. baseline , for all ; Wilcoxon ) , whereas atorvastatin alone increased campesterol/cholesterol and β-sitosterol/cholesterol ratios ( P<0.05 vs. baseline ; Wilcoxon ) . In addition , ezetimibe also increased desmosterol and desmosterol/cholesterol ratio ( P<0.0001 vs. baseline ; Wilcoxon ) . SIGNIFICANCE These results contribute to underst and ing the link between cellular cholesterol homeostasis , inflammation and lipid-modifying therapies . Our findings highlight the broader benefit of combined therapy with a potent statin and ezetimibe  decreasing inflammation , and preventing increase in cholesterol bio synthesis , an effect not observed with ezetimibe alone
Similar trends were observed for changes in total cholesterol .
Implication sGiven the available data , the addition of ezetimibe to ongoing simvastatin , atorvastatin , or rosuvastatin monotherapy offers greater reduction in LDL-C among patients at high risk of CVD compared to doubling the initial statin dose
Purpose While statins are used as first-line treatments for high-risk patients with hypercholesterolemia , statin monotherapy is often insufficient to achieve target low-density lipoprotein cholesterol ( LDL-C ) levels .
Second-line treatment options include up-titration of statin dose , switching to a more potent statin , or combination therapy , e.g. , with ezetimibe .
The aim of this study was to evaluate the efficacy of adding ezetimibe to simvastatin , atorvastatin , or rosuvastatin monotherapy versus doubling the dosage or switching to a higher-potency statin in a population of patients with hypocholesterolemia at high risk of cardiovascular disease ( CVD ) and who had been previously treated with a statin .