title: Ezetimibe Combined With Simvastatin Compared With Simvastatin Alone Results in a Greater Suppression of Oxidative Stress and Enhanced Fibrinolysis in Patients After Acute Coronary Events The effect of ezetimibe and simvastatin on hemostasis in patients with isolated hypercholesterolemia. Adiponectin plasma levels are increased by atorvastatin treatment in subjects at high cardiovascular risk. Double-blind randomized clinical trial of the effects of ezetimibe on postprandial hyperlipidaemia and hyperglycaemia. Achievement of Dual Low-Density Lipoprotein Cholesterol and High-Sensitivity C-Reactive Protein Targets More Frequent With the Addition of Ezetimibe to Simvastatin and Associated With Better Outcomes in IMPROVE-IT Short-term therapy with atorvastatin or fenofibrate does not affect plasma ghrelin, resistin or adiponectin levels in type 2 diabetic patients with mixed hyperlipoproteinaemia Effects of Rimonabant, as Monotherapy and in Combination With Fenofibrate or Ezetimibe, on Plasma Adipokine Levels: A Pilot Study Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease 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. Virtual histology evaluation of atherosclerosis regression during atorvastatin and ezetimibe administration: HEAVEN study. Synergistic effect of simvastatin and ezetimibe on lipid and pro-inflammatory profiles in pre-diabetic subjects Identical LDL-cholesterol lowering but non-identical effects on NF-κB activity: High dose simvastatin vs combination therapy with ezetimibe. Comparison of anti-inflammatory effects and high-density lipoprotein cholesterol levels between therapy with quadruple-dose rosuvastatin and rosuvastatin combined with ezetimibe Rapid immunomodulation by rosuvastatin in patients with acute coronary syndrome. Effects of Combination of Ezetimibe and Rosuvastatin on Coronary Artery Plaque in Patients with Coronary Heart Disease. Effects of simvastatin and ezetimibe on interleukin-6 and high-sensitivity C-reactive protein The effect of simvastatin-ezetimibe combination therapy on adipose tissue hormones and systemic inflammation in patients with isolated hypercholesterolemia. Lipid-lowering treatment and inflammatory mediators in diabetes and chronic kidney disease. Improved endothelial function with simvastatin but unchanged insulin sensitivity with simvastatin or ezetimibe. Rosuvastatin may reduce the incidence of cardiovascular events in patients with acute coronary syndromes receiving percutaneous coronary intervention by suppressing miR-155/SHIP-1 signaling pathway. Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia.
abstract: We compared the effect of simvastatin versus simvastatin combined with ezetimibe on hemostasis and inflammation after acute coronary events [ acute coronary syndromes ( ACS ) ] . In an investigator-initiated , double-blind , placebo-controlled , r and omized study , patients with ACS were assigned to 40 mg/d of simvastatin + 10 mg/d of ezetimibe ( n = 26 ) or 40 mg/d of simvastatin + placebo ( n = 28 ) administered for 2 months . Markers of coagulation ( prothrombin fragments 1.2 , thrombin-antithrombin complexes , free tissue factor pathway inhibitor ) , fibrinolysis [ plasminogen activator inhibitor-1 , clot lysis time ( CLT ) ] , platelet activation ( soluble CD40 lig and , β-thromboglobulin , thromboxane B2 ) , oxidative stress [ 8-iso-prostagl and in F2α ( 8-iso-PGF2α ) ] , and inflammation ( interleukin-6 , interleukin-18 , and interleukin-1β ) were measured within the first 12 hours of ACS and at 1 and 2 months of therapy . A final analysis comprised 20 patients in the simvastatin + ezetimibe group and 26 patients in the simvastatin + placebo group . Both groups were similar with regard to demographics , risk factors , medications , and routine laboratory results . Inflammatory , coagulation , and platelet markers did not differ between both treatment groups at all time points . Reductions in low-density lipoprotein cholesterol , CLT , plasminogen activator inhibitor-1 , and 8-iso-PGF2α were significantly greater ( by 10 % , 8.7 % , 17.5 % , and 22.4 % ) in the simvastatin + ezetimibe group after 1 month , with further decreases in CLT and 8-iso-PGF2α at 2 months ( all P < 0.05 ) . These changes were not associated with lipid and inflammatory parameters . In conclusion , compared with simvastatin alone , simvastatin + ezetimibe results in a greater suppression of oxidative stress and enhanced fibrinolysis in patients with ACS , indicating that ezetimibe might exert cholesterol-independent actions in humans ( NCT00725829 ) The aim of this study was to assess the strength of hemostatic effects of ezetimibe , administered alone or in combination with simvastatin , in patients with isolated hypercholesterolemia . One hundred and four patients with isolated primary hypercholesterolemia were r and omized to one of four treatment groups , simultaneously treated for 90 days with ezetimibe ( 10 mg daily ) , simvastatin ( 40 mg daily ) , ezetimibe ( 10 mg daily ) plus simvastatin ( 40 mg daily ) , or placebo .  Plasma lipids/lipoproteins and hemostatic cardiovascular risk factors were assessed on the day of r and omization and after 30 and 90 days of therapy . Despite improving lipid/lipoprotein profile by both simvastatin and ezetimibe , only simvastatin reduced plasma levels/activity of fibrinogen , factor VII , factor X , von Willebr and factor , and plasminogen activator inhibitor-1 . The strongest effects on plasma lipids/lipoproteins and the assessed hemostatic variables were observed when patients were treated with both simvastatin and ezetimibe . With the exception of oxidized low-density lipoproteins , the hemostatic effects of simvastatin or simvastatin plus ezetimibe did not correlate with the changes in plasma lipids/lipoproteins . Our study shows that simvastatin is a more effective agent than ezetimibe in affecting coagulation and fibrinolysis in individuals with isolated hypercholesterolemia . It also suggests that the combined administration of simvastatin and ezetimibe may bring more benefits to patients than monotherapy with only one of these agents Adiponectin can suppress atherogenesis by inhibiting the adherence of monocytes , reducing their phagocytic activity , and suppressing the accumulation of modified lipoproteins in the vascular wall . Contradictory data have been reported about the effect of statins on adiponectin plasma levels . In this work , adiponectin plasma levels were measured in 102 statin-free subjects from the Spanish population of the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration ( ACTFAST ) study , a 12-week , prospect i ve , multi-centre , open-label trial which enrolled subjects with coronary heart disease , coronary heart disease-equivalent or a 10-year coronary heart disease risk > 20 % . Subjects were assigned to atorvastatin ( 10 - 80 mg/day ) based on low-density lipoprotein (LDL)-cholesterol concentration at screening . For comparison , age and gender-matched blood donors ( N=40 ) were used as controls . Control subjects did not present hypertension , hypercholesterolemia , diabetes , metabolic syndrome and history of cardiovascular diseases . Adiponectin levels were diminished in patients at high cardiovascular risk compared with control subjects [ 4166 ( 3661 - 4740 ) vs 5806 ( 4764 - 7075 ) ng/ml respectively ; geometric mean ( 95 % CI ) ; P<0.0001 ] . In the whole population , atorvastatin treatment increased adiponectin levels [ 9.7 (3.2 - 16.7);% Change ( 95 % CI ) ; P=0.003 ] . This increment was in a dose-dependent manner ; maximal effect observed with atorvastatin 80 mg/d [ 24.7 ( 5.7 - 47.1 ) ; P=0.01 ] . Adiponectin concentrations were positively correlated with high-density lipoprotein-cholesterol both before and after atorvastatin treatment . No association was observed between adiponectin and LDL-cholesterol before and after atorvastatin treatment . In conclusion , atorvastatin increased adiponectin plasma levels in subjects at high cardiovascular risk , revealing a novel anti-inflammatory effect of this drug AIM Ezetimibe selectively blocks intestinal cholesterol absorption by inhibiting Niemann-Pick C1-like 1 ( NPC1L1 ) and reducing LDL cholesterol ( LDL-C ) . In animals , ezetimibe reversed diet-induced obesity , liver steatosis , and insulin resistance . In humans , its potential effects on liver steatosis and insulin resistance have been suggested . We investigated the effects of ezetimibe on postpr and ial hyperlipidaemia and hyperglycaemia in obese subjects with dyslipidaemia in a double-blind r and omized crossover trial . METHODS Twenty obese men with hypertriglyceridaemia were assigned r and omly to an ezetimibe- or a placebo-precedence-treated group . Subjects in the ezetimibe group were treated with ezetimibe ( 10 mg/day ) for the first 4 weeks , followed by a 4-week interval and then treated with placebo for another 4 weeks . The placebo group received these treatments in reverse order . Subjects were requested to fast for at least 12 hours and then received a st and ard meal . Blood sample s were collected at 0 , 30 , 60 , 120 , 240 , 360 and 480 minutes after the meal on Days 0 , 28 , 56 and 84 and were used to measure the lipid and glucose metabolism markers . RESULTS Ezetimibe significantly decreased the postpr and ial serum triglyceride excursion ( p=0.01 ) and fasting serum LDL-C , remnant-like particles(RLP ) and ApoB48 levels ( p<0.05 ) . Postpr and ial glucose excursion , serum insulin levels , serum glucose-dependent insulinotropic polypeptide ( GIP ) and active glucagon-like peptide-1 ( GLP-1 ) were not significantly affected by ezetimibe treatment . CONCLUSION Ezetimibe restored the postpr and ial dysregulation of lipid but did not affect glucose metabolism in a double-blind r and omized crossover trial Background — Statins lower low-density lipoprotein cholesterol ( LDL-C ) and high-sensitivity C-reactive protein ( hs-CRP ) ; addition of ezetimibe to statins further reduces LDL-C and hs-CRP . An analysis of the relationship between achieved LDL-C and hs-CRP targets and outcomes for simvastatin and ezetimibe/simvastatin was prespecified in Improved Reduction of Outcomes : Vytorin Efficacy International Trial ( IMPROVE-IT ) . Methods and Results — The IMPROVE-IT trial r and omly assigned 18 144 patients stabilized after acute coronary syndrome to simvastatin or ezetimibe/simvastatin .  LDL-C and hs-CRP were measured at baseline and 1 month after r and omization . Outcomes were assessed in those achieving one or both of the prespecified targets of LDL-C<70 mg/dL and hs-CRP<2 mg/L versus achieving neither target , adjusting for differences in baseline characteristics . An exploratory analysis examined targets of LDL-C<50 mg/dL and hs-CRP<1 mg/L. Patients meeting both targets at baseline , with no 1-month values , or with end points before 1 month were excluded . Of 15 179 patients , 39 % achieved the dual LDL-C ( < 70 mg/dL ) and hs-CRP ( < 2 mg/L ) targets at 1 month , 14 % met neither target , 14 % met only the hs-CRP target , and 33 % met only the LDL-C target . Those achieving dual targets had lower primary end point rates than those meeting neither target ( cardiovascular death , major coronary event , or stroke ; 38.9 % versus 28.0 % ; adjusted hazard ratio , 0.73 ; 0.66–0.81 ; P<0.001 ) . More patients treated with ezetimibe/simvastatin  met dual targets than those treated with simvastatin alone ( 50 % versus 29 % , P<0.001 ) . The association of dual-target attainment with improved outcomes was similar irrespective of treatment assignment ( P-interaction=0.65 ) . Similar findings were observed using the exploratory targets . Conclusions — Significantly more patients treated with ezetimibe/simvastatin  met prespecified and exploratory dual LDL-C and hs-CRP targets than patients treated with simvastatin alone . Reaching both LDL-C and hs-CRP targets was associated with improved outcomes after multivariable adjustment . Clinical Trial Registration — URL : http://www . clinical trials.gov ; Unique identifier : NCT00202878 Lipid-lowering therapy is associated with  reduced cardiovascular risk .  The aim of the present study was to investigate whether lipid-lowering therapy might be associated with changes in the concentrations of metabolically important hormone concentrations . We performed a r and omised cross-over open-label trial with atorvastatin ( 10 mg/day ) and fenofibrate ( 200 mg/day ) , each for 6 weeks separated by a 6-week washout period in 13 patients ( 5 men , 8 women , age 60.0±6.8 years , body mass index 30.0±3.0 kg/m2 ) with type 2 diabetes mellitus and mixed hyperlipoproteinaemia .  Plasma ghrelin ( RIA , Phoenix Pharmaceuticals , Mountain View , CA , USA ) , adiponectin ( ELISA , Biovendor , Heidelberg , Germany ) as well as resistin ( ELISA , Linco Research , St. Charles , MO , USA ) concentrations were measured before and after atorvastatin as well as before and after fenofibrate . Ghrelin ( 462±84 pg/ml before vs. 464±102 pg/ml after atorvastatin , n.s . ; 454±85 pg/ml before vs. 529±266 pg/ml after fenofibrate , n.s . ) , resistin ( 24.4±7.4 pg/ml before vs. 23.7±9.1 pg/ml after atorvastatin , n.s . ; 23.4±8.2 pg/ml before vs. 19.9±5.5 pg/ml after fenofibrate , n.s . ) , adiponectin ( 10.89±5.33 pg/ml before vs. 12.41±5.75 pg/ml after atorvastatin , n.s . ; 12.58±9.87 pg/ml before vs. 10.27±5.23 pg/ml after fenofibrate , n.s . ) and insulin levels did not change significantly during lipid-lowering therapy . In patients with type 2 diabetes and mixed hyperlipoproteinaemia , short-term atorvastatin as well as fenofibrate therapy had no significant effects on adiponectin , ghrelin or resistin levels Weight loss and hypolipidemic drugs can improve lipid and adipokine levels . We assessed the effects of rimonabant , alone and in combination with fenofibrate or ezetimibe , on adipokine levels in obese/overweight patients with dyslipidemia . Overweight/obese patients ( n = 60 , body mass index = 27 - 40 kg/m2 ) with mixed dyslipidemia were recruited . Patients received a hypocaloric diet and were r and omized to rimonabant 20 mg/d ( group R , n = 20 ) , rimonabant 20 mg/d plus fenofibrate 200 mg/d ( group RF , n = 20 ) , or rimonabant 20 mg/d plus ezetimibe 10 mg/d ( group RE , n = 20 ) . After 3 months , leptin concentration was significantly reduced in all groups ( —38 % , P < .005 ; —40 % , P < .005 ; and —44 % , P < .001 in the R , RF , and RE groups , respectively ) . Total adiponectin remained unaltered . Visfatin concentration decreased significantly only in the RE and RF groups ( —18 % and —38 % , respectively ; P < .047 ) . Treatment with rimonabant may improve adipokine levels in overweight/obese patients with dyslipidemia . The addition of fenofibrate or ezetimibe may reinforce this effect Background Hyperlipidemia , insulin resistance , and oxidative stress can heavily contribute to the initiation and progression of nonalcoholic fatty liver disease ( NAFLD ) . Currently , there is no established treatment for this disease . Recently , several studies have shown that ezetimibe ( EZ ) , a lipid-lowering drug , attenuates liver steatosis in an experimental NAFLD model . This study was design ed to assess the efficacy of long-term EZ monotherapy in patients with NAFLD . Methods A total of 45 patients with newly diagnosed liver biopsy-proven NAFLD were treated with EZ ( 10 mg/day ) for 24 months . NAFLD-related biochemical parameters , imaging by computerized tomography , and liver biopsy were studied before and after treatment . Results Ezetimibe therapy significantly improved NAFLD-related metabolic parameters including visceral fat area , fasting insulin , homeostasis model assessment of insulin resistance ( HOMA-R ) , triglycerides , total cholesterol , low-density lipoprotein cholesterol ( LDL-Ch ) , oxidative-LDL , the net electronegative charge modified-LDL , profiles of lipoprotein particle size and fatty acids component , and estimated desaturase activity .  EZ therapy also significantly lowered serum alanine aminotransferase and high-sensitivity C-reactive protein levels , whereas no significant changes were found in serum type IV collagen 7S , adiponectin , leptin , and resistin levels . Histological features of steatosis grade ( P = 0.0003 ) , necroinflammatory grade ( P = 0.0456 ) , ballooning score ( P = 0.0253 ) , and NAFLD activity score ( NAS ) ( P = 0.0007 ) were significantly improved from baseline . However , the fibrosis stage was not significantly ( P = 0.6547 ) changed . Conclusion The results in this study suggest that the long-term EZ therapy can lead to improvement in metabolic , biochemical , and histological abnormalities of NAFLD . Therefore , EZ may be a promising agent for treatment of NAFLD 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 ) BACKGROUND There is no study focusing on changes in coronary atherosclerosis during dual lipid-lowering therapy with statin and ezetimibe . METHODS AND RESULTS Eighty-nine patients with stable angina r and omized in a 1:1 ratio to Group A ( aggressive therapy : atorvastatin  80 mg , ezetimibe 10 mg ) and Group S  ( st and ard therapy )  were analyzed . Treatment period was 12 months . Coronary arteries were examined by intravascular ultrasound and virtual histology . We found a decrease in the percent atheroma volume ( PAV ) ( -0.4 % ) in Group A compared with an increase ( + 1.4 % ) in Group S ( P=0.014 ) and this was accompanied by an increased frequency of combined atherosclerosis regression ( increased lumen volume+decreased PAV ) in group A ( 40.5 % ) compared with group S ( 14.9 % ) ( P=0.007 ) . The target low-density lipoprotein cholesterol level < 2mmol/L , presence of at least 4 of 5 atherosclerotic risk factors , and decreased level of vascular cellular adhesive molecule were independent predictors of plaque regression . There were no significant differences in plaque composition between the 2 groups over the study duration . However , during analysis of the 2 groups together , fibrous and fibro-fatty tissues decreased and dense calcification and necrotic core increased during follow-up . CONCLUSIONS Dual lipid-lowering therapy starts atherosclerosis regression , but does not lead to significant changes in plaque composition . The continuous shift in plaque from fibro and fibro-fatty to necrotic with calcification was present in both groups Background Ezetimibe specifically blocks the absorption of dietary and biliary cholesterol and plant sterols . Synergism of ezetimibe-statin therapy on LDL-cholesterol has been demonstrated , but data concerning the pleiotropic effects of this combination are controversial . Objective This open-label trial evaluated whether the combination of simvastatin and ezetimibe also results in a synergistic effect that reduces the pro-inflammatory status of pre-diabetic subjects . Methods Fifty pre-diabetic subjects were r and omly assigned to one of 2 groups , one receiving ezetimibe ( 10 mg/day ) , the other , simvastatin ( 20 mg/d ) for 12 weeks , followed by an additional 12-week period of combined therapy . Blood sample s were collected at baseline , 12 and 24 weeks . RESULTS : Total cholesterol , LDL-cholesterol and apolipoprotein B levels decreased in all the periods analyzed ( p < 0.01 ) , but triglycerides declined significantly only after combined therapy . Both drugs induced reductions in C-reactive protein , reaching statistical significance after combining ezetimibe with the simvastatin therapy ( baseline 0.59 ± 0.14 , simvastatin monotherapy 0.48 ± 0.12 mg/dL and 0.35 ± 0.12 mg/dL , p < 0.023 ) . Such a reduction was independent of LDL-cholesterol change . However , mean levels of TNF-α and interleukin-6 and leukocyte count did not vary during the whole study . Conclusion Expected synergistic lowering effects of a simvastatin and ezetimibe  combination on LDL-cholesterol , apolipoprotein B and triglycerides levels were confirmed in subjects with early disturbances of glucose metabolism . We suggest an additive effect of this combination also on inflammatory status based on the reduction of C-reactive protein . Attenuation of pro-inflammatory conditions may be relevant in reducing cardiometabolic risk . Title/ID of trial registration Effect of simvastatin and ezetimibe on lipid and inflammation/NCT01103648 OBJECTIVE Lowering LDL-cholesterol by statins has been proven to be associated with reduction of proinflammatory regulators e.g. activation of the transcription factor NF-κB. To our knowledge , anti-inflammatory potential of newer cholesterol lowering agents such as ezetimibe is less intensively studied . Therefore we analyzed the effects of equipotent LDL-lowering therapy with simvastatin alone compared to a combination with ezetimibe on NF-κB activation in peripheral blood mononuclear cells ( P BMC s ) of patients with type 2 diabetes . METHODS Thirty-one patients with type 2 diabetes were included in a double-blind , r and omized trial receiving either 80 mg simvastatin ( sim80 ; n = 10 ) or a combination of 10 mg simvastatin and 10 mg ezetimibe ( sim10eze10 ; n = 11 ) or placebo ( n = 9 ) for eight weeks . NF-κB binding activity and inflammatory markers ( IL-6 , hsCRP ) were analyzed at baseline and after eight weeks of treatment . NF-κB binding activity was analyzed by electrophoretic mobility shift assay . IL-6 and hsCRP were measured by ELISA . RESULTS After eight weeks of treatment LDL-cholesterol was lowered to the same extent in both treatment groups ( p = 0.40 ) but not in placebo . However , patients  taking sim80  showed a significant reduction of mononuclear NF-κB binding activity compared to baseline ( p = 0.009 ) while no effect was observed in the sim10eze10 group ( p = 0.79 ) . Similar differences in anti-inflammatory effects were also observed when analyzing hsCRP ( sim80 : p = 0.03 ; sim10eze10 : p = 0.40 ) and IL-6 levels  ( sim80 : p = 0.15 ; sim10eze10 : p = 0.95 ) . CONCLUSION High dose simvastatin therapy reduces proinflammatory transcription factor NF-κB binding activity and hsCRP levels , while combination of low dose simvastatin with ezetimibe result ing in a similar LDL-reduction does not affect these inflammatory markers 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 HMG-CoA reductase inhibitors ( statins ) reduce cardiovascular mortality and morbidity in patients with stable coronary artery disease as well as acute coronary syndrome ( ACS ) . It is unclear how rapidly the beneficial effects of statins occur in patients with ACS and whether these drug properties are related to lipid lowering . METHODS AND RESULTS Patients with troponin-positive ACS ( n=35 ) were r and omized to 20 mg/day rosuvastatin therapy or to placebo treatment . Anti-inflammatory effects of rosuvastatin measured by lymphocyte intracellular cytokine production were taken before initiation of treatment and on days 1 , 3 , and 42 . Compared with placebo , rosuvastatin treatment significantly reduced plasma concentrations of pro-inflammatory cytokines TNF-alpha and IFN-gamma at 72 h. Rosuvastatin also induced a rapid and significant reduction of TNF-alpha and IFN-gamma production in stimulated T-lymphocytes at 72 h. When compared with placebo , rosuvastatin inhibited the Th-1-immune response measured at 72 h. CONCLUSION Rosuvastatin exerts rapid immunomodulatory effects on the level of T-cell activation in patients with ACS BACKGROUND In approximately 80 % of cardiovascular disease-related deaths , patients suffer from coronary atherosclerotic heart disease . Ezetimibe is the first intestinal cholesterol absorption inhibitor . Its combination with statins for treating coronary atherosclerotic heart disease has attracted attention worldwide . METHODS The study group comprised 106 patients with coronary atherosclerotic heart disease and hyperlipidaemia . Each was r and omly assigned to one of two groups : ( 1 ) Ezetimibe ( 10 mg , once a night ) plus rosuvastatin ( 10 mg , once a night ) ( n=55 ) or ( 2 ) Rosuvastatin alone ( 10 mg , once a night ) ( n=51 ) . The primary endpoint was new or recurrent myocardial infa rct ion , unstable angina pectoris , cardiac death , and stroke . Blood lipid , high-sensitivity C-reactive protein ( hsCRP ) , interleukin-6 ( IL-6 ) , and matrix metalloproteinase-9 ( MMP-9 ) levels were measured before treatment and at one , six and 12 months after treatment . Coronary plaque size and compositional changes were determined using intravascular ultrasonography . RESULTS The combination of ezetimibe plus rosuvastatin decreased total cholesterol , low-density lipoprotein cholesterol , hsCRP , IL-6 , and MMP-9 levels at six and 12 months after treatment . Statistical significance was detected between two groups . At 12 months , the plaque burden , plaque cross-sectional area , and percentage of necrotic plaque composition were significantly lower in the combination group than in rosuvastatin alone group ( P<0.05 ) . And compared with rosuvastatin alone group , the primary endpoint decreased more effectively in combination group . CONCLUSIONS The combination of ezetimibe and rosuvastatin apparently diminishes lipid levels and plaque burden and improves plaque stability , which may be associated with the potent inhibitory effects of ezetimibe and rosuvastatin on inflammatory cytokines Abstract Objectives . Statins decrease cardiovascular events mainly by lowering cholesterol but anti-inflammatory effects also play a role . The effects of the cholesterol absorption inhibitor ezetimibe on markers of inflammation remain unclear . We performed an exploratory post-hoc analysis whether these drugs influence the pro-inflammatory markers interleukin-6 and high-sensitivity C-reactive protein in subjects with very-low cardiovascular risk . Design . Single center , r and omized , parallel 3-group study in 72 healthy men without apparent cardiovascular disease ( age 32 ± 9 years , BMI 25.7 ± 3.2 kg/m2 ) . Each group of 24 subjects received a 14-day treatment with either simvastatin 40 mg , ezetimibe 10 mg , or their combination .  Results . Baseline IL-6 and hsCRP concentrations in the total cohort were 0.72 ± 0.57 ng/l and 0.40 ± 0.65 mg/l , respectively , with no differences between the 3 groups . Median changes ( interquartile range ) in IL-6 and hsCRP concentrations were −22 % ( −43 to 0 % ) and −30 % ( −44 to + 19 % ) after simvastatin , −5 % ( −36 to + 30 % ) and + 9 % ( −22 to + 107 % ) after ezetimibe , and + 15 % ( −15 to + 86 % ) and + 1 ( −30 to + 49 % ) after the combination . Using a generalized linear model , the multivariable adjusted overall P-values for these changes were 0.008 ( IL-6 ) and 0.1 ( hsCRP ) . Conclusions . Simvastatin  decreases the pro-inflammatory markers IL-6 and almost significantly hsCRP while ezetimibe monotherapy or the combination with simvastatin has no effect . Trial registration : Clinical Trials.gov identifier : NCT00317993 BACKGROUND Pleiotropic effects of ezetimibe have only been investigated in a few studies . The aim of this article was to compare the effects of simvastatin and the combined treatment with simvastatin and ezetimibe on low- grade systemic inflammation and plasma levels of selected adipokines in patients with isolated hypercholesterolemia . METHODS The study included 69 patients with elevated cholesterol levels , who were allocated to one of the three groups treated for 12 weeks , respectively , with simvastatin ( 40 mg daily ) , simvastatin ( 40 mg daily ) plus ezetimibe ( 10 mg daily ) , or placebo .  Plasma levels of lipids , apolipoproteins , glucose homeostasis markers , leptin , adiponectin , visfatin , tumor necrosis factor-α ( TNF-α ) , free fatty acids ( FFA ) , and high-sensitive C-reactive protein ( hsCRP ) were determined on the allocation day and after 12 weeks of therapy . RESULTS Apart from improving lipid profile , simvastatin administered alone or in combination with ezetimibe , decreased plasma levels of hsCRP , FFA , leptin , visfatin , and TNF-α , as well as increased plasma levels of adiponectin . The combination therapy was superior to simvastatin in influencing plasma lipids/lipoproteins , hsCRP , FFA , and the investigated adipokines . The effect of the combination therapy , but not of simvastatin , on systemic inflammation and plasma adipokines was stronger in insulin-resistant than in insulin-sensitive subjects . CONCLUSIONS The obtained results suggest that insulin-resistant patients with hypercholesterolemia and high cardiovascular risk may benefit the most from the combined treatment with simvastatin and ezetimibe BACKGROUND Inflammation may contribute to the high cardiovascular risk in diabetes mellitus ( DM ) and chronic kidney disease ( CKD ) . Monocyte chemoattractant protein-1 ( MCP-1 ) facilitates the recruitment of monocytes into atherosclerotic lesions and is involved in diabetic nephropathy . Interferon gamma ( IFNγ ) is important in atherosclerosis and increases the synthesis of chemokines including MCP-1 . Lipid-lowering treatment ( LLT ) with statins may have anti-inflammatory effects , and ezetimibe cotreatment provides additional cholesterol lowering . METHODS After a placebo run-in period , the effects of simvastatin alone ( S ) or simvastatin + ezetimibe ( S+E ) were compared in a r and omized , double-blind , cross-over study on inflammatory parameters . Eighteen DM patients with estimated glomerular filtration rate ( eGFR ) 15 - 59 mL/min × 1·73 m(2 ) ( CKD stages 3 - 4 ) ( DM-CKD ) and 21 DM patients with eGFR > 75 mL/min ( DM only ) were included . RESULTS At baseline , monocyte chemoattractant protein 1 ( MCP-1 ) ( P = 0·03 ) , IFNγ ( P = 0·02 ) , tumour necrosis factor-α ( TNFα ) ( P < 0·01 ) and soluble vascular adhesion molecule ( sVCAM ) ( P = 0·001 ) levels were elevated in DM-CKD compared with DM-only patients . LLT with S and S+E reduced MCP-1 levels ( P < 0·01 by anova ) and IFNγ levels ( P < 0·01 ) in DM-CKD patients but not in DM-only patients . Reductions were most pronounced with the combination treatment . CONCLUSIONS DM patients with CKD stages 3 - 4 had increased inflammatory activity compared with DM patients with normal GFR . Lipid-lowering treatment decreased the levels of MCP-1 and IFNγ in DM patients with concomitant CKD , which may be beneficial with regard to the progression of both atherosclerosis and diabetic nephropathy In addition to their expected effects on lipid profile , lipid-lowering agents may reduce cardiovascular events because of effects on nonclassic risk factors such as insulin resistance and inflammation . Ezetimibe specifically blocks the absorption of dietary and biliary cholesterol as well as plant sterols . Although it is known that an additional reduction of low-density lipoprotein cholesterol ( LDL-C ) levels can be induced by the combination of ezetimibe with statins , it is not known if this can enhance some pleiotropic effects , which may be useful in slowing the atherosclerotic process . This study assessed the effects of simvastatin and ezetimibe , in monotherapy or in combination , on markers of endothelial function and insulin sensitivity . Fifty prediabetic subjects with normo- or mild-to-moderate hypercholesterolemia were r and omly allocated to 2 groups receiving either ezetimibe ( 10 mg/d ) or simvastatin ( 20 mg/d ) for 12 weeks , after which the drugs were combined for both groups for an additional 12-week period . Clinical and laboratory parameters were measured at baseline and after 12 and 24 weeks of therapy . Homeostasis model assessment of insulin resistance index and the area under the curve of insulin were calculated . As expected , both groups receiving drugs in isolation significantly reduced total cholesterol , LDL-C , apolipoprotein B , and triglyceride levels ; and additional reductions were found after the combination period ( P < .05 ) . After 12 weeks of monotherapy , plasminogen activator inhibitor-1 levels and urinary albumin excretion were lower in the simvastatin than in the ezetimibe group . No change in homeostasis model assessment of insulin resistance index , area under the curve of insulin , and adiponectin levels was observed after either the monotherapies or the combined therapy . However , simvastatin combined with ezetimibe provoked significant reductions in E-selectin and intravascular cellular adhesion molecule-1 levels that were independent of LDL-C changes . Our findings support cl aims that simvastatin may be beneficial in preserving endothelial function in prediabetic subjects with normo- or mild-to-moderate hypercholesterolemia . Alternatively , a deleterious effect of ezetimibe on the endothelial function is suggested , considering the increase in intravascular cellular adhesion molecule-1 and E-selectin levels .  Simvastatin and ezetimibe , in isolation or in combination , do not interfere with insulin sensitivity PURPOSE The beneficial effect of rosuvastatin against percutaneous coronary intervention ( PCI ) related procedural myocardial injury has been determined mostly in patients with acute coronary syndromes ( ACS ) . However , the detailed therapeutic mechanism has not been well studied . METHODS Patients with ACS receiving PCI ( n = 159 ) were r and omized to control group ( placebo treatment ) or to rosuvastatin group ( 20 mg 12 h before PCI , and a further 20 mg 2 h preprocedure dose ) . Levels of INF-γ , TNF-α , IL-6 , miR-155/SHIP-1 , and CD4(+)FoxP3(+)Treg in peripheral blood were detected before PCI and 24 h after PCI . Clinical data of these patients were also collected in this prospect i ve study . RESULTS Compared with placebo , rosuvastatin treatment significantly reduced the incidence of periprocedural myocardial infa rct ion ( PMI ) and levels of cardiac troponin I ( cTnI ) associated with decreased relative expression of serum miR-155 , levels of inflammatory cytokines ( INF-γ , TNF-α , and IL-6 ) , increased SHIP-1 expression and CD4(+)FoxP3(+)Treg percentage values ( P < 0.05 ) . In addition , patients with rosuvastatin pretreatment also reduced incidence of 30 days major adverse cardiac events ( MACE ) compared to the patients with placebo treatment ( 16 patients vs. 28 patients , P = 0.038 ) . CONCLUSIONS Our study suggests that high loading dose rosuvastatin pretreatment may reduce the incidence of cardiovascular events and levels of inflammatory markers in patients with ACS receiving PCI , which may be explained at least in part , by mechanism involving suppression of miR-155/SHIP-1 signaling pathway This study compared the efficacy and safety of co-administered ezetimibe + simvastatin with atorvastatin monotherapy in adults with hypercholesterolemia . Seven hundred eighty-eight patients were r and omized 1:1:1 to 3 treatment groups ; each group was force-titrated over four 6-week treatment periods : ( 1 ) 10 mg of atorvastatin as the initial dose was titrated to 20 , 40 , and 80 mg ; ( 2 ) co-administration of 10 mg of ezetimibe and 10 mg of simvastatin ( 10/10 mg ) was titrated to 10/20 , 10/40 , and 10/80 mg of ezetimibe + simvastatin ; and ( 3 ) co-administration of 10/20 mg of ezetimibe + simvastatin was titrated to 10/40 mg ( for 2 treatment periods ) and 10/80 mg of ezetimibe + simvastatin . Key efficacy measures included percent changes in low-density lipoprotein cholesterol ( LDL ) and high-density lipoprotein cholesterol ( HDL ) from baseline to the ends of ( 1 ) treatment periods 1 and 2 ( for LDL cholesterol ) comparing co-administration of 10/20 mg and 10/10 mg of ezetimibe + simvastatin with 10 mg of atorvastatin and ( 2 ) treatment period 4 ( for LDL cholesterol and HDL cholesterol ) comparing co-administration of 10/80 mg of ezetimibe + simvastatin with 80 mg of atorvastatin .  Baseline LDL and HDL cholesterol levels were comparable between treatment groups . At the end of treatment period 1 , the mean decrease of LDL cholesterol was significantly ( p < /=0.001 ) greater for co-administration of 10/10 mg and 10/20 mg of ezetimibe + simvastatin than for 10 mg of atorvastatin . At the end of treatment period 4 and after comparing maximum doses , co-administration of 10/80 mg of ezetimibe + simvastatin was superior to 80 mg of atorvastatin in the percent LDL cholesterol decrease ( -59.4 % vs -52.5 % , p < 0.001 ) and HDL cholesterol increase ( 12.3 % vs 6.5 % ; p < 0.001 ) . All treatments were well tolerated . Thus , a greater LDL cholesterol decrease and HDL cholesterol increase were attained by treating patients with co-administration of ezetimibe and simvastatin than with atorvastatin
target: CONCLUSIONS The results suggested that ezetimibe add-on to statin therapy is associated with an enhanced TNF-α-lowering effect  compared with statin monotherapy .
background: AIMS Statins are known to influence the status of adipokines , which play a key role in the pathophysiology of cardiometabolic diseases .
  As the effect of ezetimibe as an add-on to statin therapy on the impact of statins on plasma adipokines levels is currently unclear , the aim of the present study was to investigate this through a meta- analysis of controlled trials .