The Effect of HMG-CoA Reductase Inhibitor on Insulin Resistance in Patients Undergoing Peritoneal Dialysis Achieving goal lipid levels with ezetimibe plus statin add-on or switch therapy compared with doubling the statin dose. A pooled analysis. The effect of simvastatin-ezetimibe combination therapy on adipose tissue hormones and systemic inflammation in patients with isolated hypercholesterolemia. Treatment with ezetimibe plus low-dose atorvastatin compared with higher-dose atorvastatin alone: is sufficient cholesterol-lowering enough to inhibit platelets? 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. 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 A comparison of the efficacy of combined ezetimibe and statin therapy with doubling of statin dose in patients with remnant lipoproteinemia on previous statin therapy. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial 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 Effect of Ezetimibe and/or Simvastatin on Coenzyme Q10 Levels in Plasma Statins and Mortality Among Elderly Patients Hospitalized With Heart Failure Effects of 90-day hypolipidemic treatment on insulin resistance, adipokines and proinflammatory cytokines in patients with mixed hyperlipidemia and impaired fasting glucose. A randomised trial of three counselling strategies for lifestyle changes in patients with hypercholesterolemia treated with ezetimibe on top of statin therapy (TWICE). Ezetimibe Attenuates Atherosclerosis Associated with Lipid Reduction and Inflammation Inhibition Association of Statin Therapy with Outcomes of Acute Coronary Syndromes: The GRACE Study Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. Impact of Weight Loss on Plasma Leptin and Adiponectin in Overweight-to-Obese Post Menopausal Breast Cancer Survivors Differences in action of atorvastatin and ezetimibe in lowering low-density lipoprotein cholesterol and effect on endothelial function: randomized controlled trial. 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 Effects of 4 weeks of atorvastatin administration on the antiinflammatory cytokine interleukin-10 in patients with unstable angina. Usefulness of Nutraceuticals (Armolipid Plus) Versus Ezetimibe and Combination in Statin-Intolerant Patients With Dyslipidemia With Coronary Heart Disease. Effects of ezetimibe on plasma lipoproteins in severely hypercholesterolemic patients treated with regular LDL-apheresis and statins. Efficacy of ezetimibe in patients with statin-resistant and statin-intolerant familial hyperlipidaemias
Background Insulin resistance is associated with the progression of atherosclerosis and is reported to predict cardiovascular mortality in patients with end-stage renal disease ( ESRD ) . Although statins exert pleiotropic effects , it is uncertain whether statin therapy improves insulin resistance in these patients . In this prospect i ve r and omized controlled trial , we aim ed to evaluate the effects of statin on insulin resistance among 70 patients undergoing peritoneal dialysis ( PD ) . Methods Patients were r and omized into a statin group ( n = 35 ) or a control group ( n = 35 ) . The statin group received 10 mg per day of rosuvastatin for 6 months . We determined insulin resistance by homeostatic model assessment of insulin resistance ( HOMA-IR ) index . Serum concentrations of adipokines such as adiponectin , leptin , and resistin were measured using enzyme-linked immunosorbent ( ELISA ) assay . As inflammatory markers , high sensitive C-reactive protein ( hsCRP ) and interleukin-6 were also measured . Results There were no significant differences in baseline characteristics between the two groups . Compared to baseline value , statin treatment significantly decreased HOMA-IR index from 2.37 ± 1.08 to 2.05 ± 0.82 ( P = 0.014 ) . There was a concordant decrease in hsCRP levels in the statin group ( 2.05 ± 1.57 to 1.21 ± 0.84 mg/L , P < 0.001 ) , but such improvements were not observed in the control group . When between-group differences in these parameters were compared , hsCRP levels were more decreased in the statin group than in the control group ( P = 0.021 for between-group difference ) , whereas HOMA-IR index was not ( P = 0.189 for between-group difference ) . During this period , statin treatment did not result in the improved adipokine profiles . Conclusion This study showed that statin therapy failed to improve insulin resistance in PD patients despite a significant decline in hsCRP levels after statin treatment . Our finding suggests that reducing inflammation by statin is of limited help to fully attenuate insulin resistance in these patients 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 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 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 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 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 BACKGROUND AND PURPOSE It remains undetermined whether the addition of ezetimibe to ongoing statin therapy is more effective than increasing the dose of statin for reducing remnant lipoprotein levels in patients with remnant lipoproteinemia on previous statin treatment . This study examined whether combined ezetimibe and statin therapy result ed in a greater improvement in remnant lipoprotein levels and endothelial function than with the dose of statin in patients with remnant lipoproteinemia on previous statin treatment . METHODS AND RESULTS A total of 63 patients with stable coronary artery disease and high levels of remnant-like lipoprotein particle cholesterol ( RLP-C ) ( ≥5.0 mg/dL ) on statin treatment were assigned r and omly to two groups and treated with either addition of ezetimibe ( 10mg/day , n=32 ) or doubling of statin dose ( n=31 ) . The lipid profiles and flow-mediated dilation ( FMD ) of the brachial artery were measured at enrollment and after 6 months of treatment . Statin and ezetimibe combined therapy reduced RLP-C and improved FMD to a greater extent than doubling the statin dose ( % reduction in RLP-C , 48 ± 18 % vs. 33 ± 24 % , respectively , p=0.01 ; % improvement in FMD , 47 ± 48 % vs. 24 ± 23 % , respectively , p=0.02 ) . CONCLUSIONS The addition of ezetimibe to ongoing statin treatment reduced RLP-C levels and improved endothelial dysfunction to a greater extent than doubling the statin dose in patients with high RLP-C levels on previous statin treatment . The present results are preliminary and should be confirmed by further studies on a larger number of study patients Aims To compare the efficacy [ low-density lipoprotein cholesterol ( LDL-C ) lowering ] and safety of alirocumab , a fully human monoclonal antibody to proprotein convertase subtilisin/kexin 9 , compared with ezetimibe , as add-on therapy to maximally tolerated statin therapy in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia . Methods and results COMBO II is a double-blind , double-dummy , active-controlled , parallel-group , 104-week study of alirocumab vs. ezetimibe .  Patients ( n = 720 ) with high cardiovascular risk and elevated LDL-C despite maximal doses of statins were enrolled ( August 2012–May 2013 ) . This pre-specified analysis was conducted after the last patient completed 52 weeks . Patients were r and omized to subcutaneous alirocumab 75 mg every 2 weeks ( plus oral placebo ) or oral ezetimibe 10 mg daily ( plus subcutaneous placebo ) on a background of statin therapy . At Week 24 , mean ± SE reductions in LDL-C from baseline were 50.6 ± 1.4 % for alirocumab vs. 20.7 ± 1.9 % for ezetimibe ( difference 29.8 ± 2.3 % ; P < 0.0001 ) ; 77.0 % of alirocumab and 45.6 % of ezetimibe patients achieved LDL-C < 1.8 mmol/L ( P < 0.0001 ) . Mean achieved LDL-C at Week 24 was 1.3 ± 0.04 mmol/L with alirocumab and 2.1 ± 0.05 mmol/L with ezetimibe , and were maintained to Week 52 . Alirocumab was generally well tolerated , with no evidence of an excess of treatment-emergent adverse events . Conclusion In patients at high cardiovascular risk with inadequately controlled LDL-C , alirocumab achieved significantly greater reductions in LDL-C compared with ezetimibe , with a similar safety profile . Trial registration clinical trials.gov Identifier : NCT01644188 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 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 — Small studies suggest that statins may improve mortality in patients with heart failure ( HF ) . Whether these results are generalizable to a broader group of patients with HF remains unclear . Our objective was to evaluate the association between statin use and survival among a national sample of elderly patients hospitalized with HF . Methods and Results — A nationwide sample of 61 939 eligible Medicare beneficiaries ≥65 years of age who were hospitalized with a primary discharge diagnosis of HF between April 1998 and March 1999 or July 2000 and June 2001 was evaluated . The analysis was restricted to patients with no contraindications to statins ( n=54 960 ) . Of these patients , only 16.7 % received statins on discharge . Older patients were less likely to receive a statin  at discharge . Patients with hyperlipidemia and those cared for by a cardiologist or cared for in a teaching hospital were more likely to receive a statin at discharge . In a Cox proportional hazards model that took into account demographic , clinical characteristics , treatments , physician specialty , and hospital characteristics , discharge statin therapy was associated with significant improvements in 1- and 3-year mortality ( hazard ratio , 0.80 ; 95 % CI , 0.76 to 0.84 ; and hazard ratio , 0.82 ; 95 % CI , 0.79 to 0.85 , respectively ) . Regardless of total cholesterol level or coronary artery disease status  , statin therapy was associated with significant differences in mortality . Conclusions — Our data demonstrate that statin therapy is associated with better long-term mortality in older patients with HF . This study suggests a potential role for statins as an adjunct to current HF therapy . R and omized clinical trials are required to determine the role of these agents in improving outcomes in the large and growing group of patients with HF OBJECTIVE Concerns regarding worsening insulin sensitivity associated with statin treatment have recently emerged . Therefore the aim of this study was to assess and compare the effects of 90-day monotherapies with fenofibrate and atorvastatin , as well as combined therapy , on fasting plasma glucose , insulin resistance index , adipokines ( leptin , resistin , adiponectin ) and levels of proinflammatory cytokines ( TNF-α , IL-6 ) in patients with impaired fasting glucose ( IFG ) and mixed hyperlipidemia . MATERIAL S AND METHODS 67 patients were r and omly assigned to four treatment arms : monotherapy with atorvastatin , monotherapy with fenofibrate , combined therapy ( fenofibrate and torvastatin ) or therapeutic lifestyle change . The study lasted for 90 days . All participants received counseling regarding proper diet and physical activity . RESULTS Compared to the control subjects , prediabetic patients exhibited elevated plasma levels of leptin , resistin , TNF-α and IL-6 , and a lower plasma level of adiponectin . All therapeutic interventions result ed in significant alterations in the lipid profile . Insulin resistance index ( HOMA-IR ) was reduced after treatment with fenofibrate . The effect of atorvastatin on insulin resistance was comparable to therapeutic lifestyle change alone . Therapy with hypolipidemic drugs caused increases in adiponectin levels and decreases in leptin and resistin . An additive effect of the combined treatment on plasma IL-6 level was also observed . CONCLUSIONS Fenofibrate-based treatment was associated with improved insulin sensitivity . Atorvastatin did not cause a deterioration in insulin sensitivity . Hypolipidemic therapies result ed in significant changes in the proinflammatory cytokine network as well as in adipokine levels . At the end of the study the measured parameters nearly resembled those of the healthy subjects AIMS To compare the impact of three patient counselling strategies for lifestyle changes and to assess the safety and efficacy of ezetimibe on top of statin therapy in hypercholesterolemic high risk patients . METHODS Open , cluster r and omized 3-parallel group trial . Physicians were r and omized between patient motivation on : diet or physical exercise or both . Counselling was adapted to the patient 's baseline Prochaska stage of change . High cardiovascular risk patients , with LDL-C above or equal to 3 mmol/L despite statin therapy for at least 3 months , were enrolled .  Ezetimibe ( 10mg/day ) and patient counselling were started at the same time . Target goal was defined as total cholesterol less than 5 mmol/L and LDL-C above 3 mmol/L. RESULTS Overall 428 physicians enrolled 1,496 patients . At baseline , LDL-C was 3.9+/-0.9 mmol/L and total cholesterol was 6.1+/-1.1 mmol/L. LDL-C decreased by -30.4+/-19.3 % and 869 ( 62 % ) patients achieved target goal . No difference was shown between r and omisation groups . However , improvements in diet consumption patterns were more easily obtained than improvement in physical activity stage of change in non-active patient at baseline . CONCLUSIONS The marked short-term impact ( -30 % ) on LDL-C , although similar between the three groups , slightly exceeds usual LDL-C reductions achieved by this dose of ezetimibe . Decreasing fat consumption seems easier than increasing physical activity . This study confirms the good efficacy , short-term tolerability and safety of ezetimibe on top of statins Background Ezetimibe , as a cholesterol absorption inhibitor , has been shown protecting against atherosclerosis when combined with statin . However , side by side comparison has not been made to evaluate the beneficial effects of ezetimibe alone versus statin . Herein , the study aim ed to test whether ezetimibe alone would exhibit similar effects as statin and the combination therapy would be necessary in a moderate lesion size . Methods and Results ApoE-/- male mice that were fed a saturated-fat supplemented diet were r and omly assigned to different therapeutic regimens : vehicle , ezetimibe alone ( 10 mg/kg/day ) , atorvastatin ( 20 mg/kg/day ) or combination of ezetimibe and atorvastatin through the drinking water . On 28 days , mice were sacrificed and aorta and sera were collected to analyze the atherosclerotic lesion and blood lipid and cholesterol levels . As a result , ezetimibe alone exerted similar protective effects on atherosclerotic lesion sizes as atorvastatin , which was mediated by lowering serum cholesterol concentrations , inhibiting macrophage accumulation in the lesions and reducing circulatory inflammatory cytokines , such as monocyte chemoattractant protein ( MCP-1 ) and tumor necrosis factor ( TNF-α ) . In contrast to ezetimibe administration , atorvastatin alone attenuated atherosclerotic lesion which is dependent on its anti-inflammation effects . There were no significance differences in lesion areas and serum concentrations of cholesterol , oxidized LDL and inflammatory cytokines between combination therapy and monotherapy ( either ezetimibe or atorvastatin ) . There were significant correlations between the lesion areas and serum concentrations of cholesterol , MCP-1 and TNF-α , respectively . However , there were no significant correlations between the lesion areas and serum concentrations of TGF-β1 and oxLDL . Conclusions Ezetimibe alone played the same protection against a moderate atherosclerotic lesion as atorvastatin , which was associated with lowering serum cholesterol , decreasing circulating inflammatory cytokines , and inhibiting macrophage accumulation in the lesions Context While the benefits of statins in the primary and secondary prevention of coronary artery disease are clear , the value of statin therapy in acute coronary syndromes is uncertain . Contribution Analyzing data from a large , international observational study of acute coronary syndromes , these investigators identified associations between statin use before and during acute coronary events and favorable outcomes . Caution s While these data suggest a potential benefit of statins during acute coronary events , trials are necessary to determine the most appropriate use of statins in the treatment of acute coronary events . The Editors Data from r and omized clinical trials support the efficacy of lipid-lowering medications , particularly statins , in the primary and secondary prevention of coronary artery disease ( 1 - 3 ) . The benefits of statins , however , were not readily apparent until after several months of therapy , suggesting that the drugs ' lipid-lowering capabilities were largely responsible . In vitro work has suggested that statins may have an abundance of pleiotropic effects ( 4 ) . These include modulation of inflammation , inhibition of platelet function and thrombosis , and enhancement of endothelial cell function . The demonstrated ability of statins to immediately affect basic pathophysiologic mechanisms has result ed in increased interest in their potential role in the setting of acute coronary syndromes . The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering ( MIRACL ) trial found that early treatment with high-dose atorvastatin modestly reduced event rates of recurrent ischemia in statin-naive patients presenting with an acute coronary syndrome ( 5 ) . These observations , while intriguing , did not conclusively establish the role of statins in patients with acute coronary syndromes . In the MIRACL trial , the failure of statins to significantly affect more concrete trial end points ( for example , death or recurrent myocardial infa rct ion [ MI ] ) was disappointing . Whether this reflected a true lack of physiologic impact of early statin treatment or merely indicated that the study was underpowered to detect differences in these end points remains unclear . In a sub study using data from the Platelet Receptor Inhibition for Ischemic Syndrome Management ( PRISM ) trial in patients with acute coronary syndromes , patients already taking statins  had better short-term outcomes ( decreased risk for death or nonfatal MI ) than those not previously receiving statin therapy , unless statin therapy was discontinued in the hospital ( 6 ) . Initiation of statin therapy after the onset of an acute coronary syndrome appeared to be less effective than treatment with statins before symptom onset . Using data from the Global Registry of Acute Coronary Events ( GRACE ) project , a large , multinational , observational study of patients with acute coronary syndromes , we examined the association between previous statin therapy  , presentation characteristics of acute coronary syndromes , and hospital outcomes . We also examined the effect of early in-hospital statin therapy ( or withdrawal of statins ) on important hospital outcomes , including death or the development of recurrent MI or stroke . Methods Full details of the GRACE rationale and methods have been published elsewhere and are outlined below ( 7 - 9 ) . Site Selection The GRACE project is design ed to reflect an unbiased population of patients with acute coronary syndromes , regardless of geographic region . Currently , 94 hospitals located in 14 countries ( Argentina , Australia , Austria , Belgium , Brazil , Canada , France , Germany , Italy , New Zeal and , Pol and , Spain , the United Kingdom , and the United States ) are participating in this observational study . Patients entered in the registry must be at least 18 years of age and alive at the time of hospital presentation ; be admitted with an acute coronary syndrome as a presumptive diagnosis ( that is , have symptoms consistent with acute ischemia ) ; and have at least 1 of the following : electrocardiographic changes consistent with an acute coronary syndrome , serial increases in serum biochemical markers of cardiac necrosis , or documentation of coronary artery disease ( 7 - 9 ) . The qualifying acute coronary syndrome must not be precipitated by a significant noncardiovascular comorbid condition ( for example , trauma or surgery ) . To ensure the enrollment of an unbiased sample , the first 10 to 20 consecutive patients ( depending on each site 's patient volume ) are recruited from each site on a monthly basis . Where required , study investigators received approval from their local hospital ethics or institutional review board . Data Collection At each site , a trained coordinator collected data using a st and ardized case-report form . Data on demographic characteristics , medical history , presenting symptoms , duration of prehospital delay , biochemical and electrocardiographic findings , treatment practice s , and hospital outcome were collected . St and ardized definitions of all patient-related variables and clinical diagnoses were used . All cases were assigned to 1 of the following categories : ST-segment elevation MI , nonST-segment elevation MI , unstable angina , and other cardiac or noncardiac diagnoses that have been previously described ( 7 - 9 ) . St and ardized definitions were also used for selected hospital complications and outcomes . Patient Sample For the current study , patients who were subsequently found to have noncardiac or other cardiac ( nonacute coronary syndrome ) primary diagnoses and those who transferred into or out of GRACE registry hospitals were excluded from further consideration . Treatments defined as previous use were those taken by the patient on a long-term basis at home and within 7 days of the presenting event , based on the review of information contained in medical records and abstract ed by trained study physicians and nurses . Treatments received in the hospital ( within the first 24 hours or thereafter ) were categorized as within hospital . Agents prescribed for use after discharge from participating hospitals were categorized as at discharge . Patient treatment categories were defined according to the following groupings : no previous treatment with statins and no treatment with statins during hospitalization , no previous therapy with statins but statin therapy  instituted during hospitalization , previous therapy with statins and statin therapy continued during hospitalization , and previous  therapy with statins but statin therapy not continued during the index hospitalization . Statistical Analysis We used the chi-square tests for discrete variables to analyze differences in demographic and clinical characteristics , treatment practice s , clinical presentation ( ST-segment elevation vs. nonST-segment elevation , large infa rct [ creatine phosphokinase level > 2 times the upper limit of normal ] vs. small infa rct ) , subsequent diagnosis ( ST-segment elevation MI , nonST-segment elevation MI , unstable angina ) , and hospital complications ( death , congestive heart failure or pulmonary edema , cardiogenic shock , stroke , ventricular tachycardia or ventricular fibrillation , and cardiac arrest ) in relation to statin use . The Wilcoxon rank-sum test was used to analyze differences between respective comparison groups for continuous variables . While controlling for potentially confounding variables , we performed multivariate regression analyses to examine the association between previous statin therapy and hospital presentation ( ST-segment elevation vs. no ST-segment elevation , creatine phosphokinase level 2 times normal vs. creatine phosphokinase level < 2 times the upper limit of normal ) , as well as any association between previous or in-hospital statin therapy and hospital outcomes ( death , recurrent MI or MI after 24 hours , and stroke ) or a composite end point of all 3 outcomes . C and i date variables for inclusion in the regression models evaluating previous statin use and hospital presentation included patient age , sex , smoking status , diabetes , history of vascular disease ( previous MI , stroke , positive angiogram , peripheral vascular disease , percutaneous coronary intervention , or coronary artery bypass graft surgery ) , hypertension , hyperlipidemia , and previous therapies ( aspirin , angiotensin-converting enzyme [ ACE ] inhibitors , -blockers , and other lipid-lowering agents ) . C and i date variables for regression models evaluating previous or in-hospital statin use and hospital outcomes included all of the previously listed characteristics plus characteristics present at the time of hospital admission ( heart rate , systolic blood pressure , Killip class , ST-segment elevation or left bundle-branch block pattern , and positive cardiac enzymes ) and receipt of in-hospital therapies ( aspirin and other antiplatelet agents , -blockers , unfractionated heparin , low-molecular-weight heparin , glycoprotein IIb/IIIa inhibitors , cardiac catheterization , percutaneous coronary intervention , or coronary artery bypass graft surgery ) . C and i date variables possibly associated with the outcomes of interest ( P < 0.25 after univariate analysis ) were included in the multivariate models . Variables for which the P value exceeded 0.05 were eliminated in a stepwise fashion so that only those that had a statistically significant association with the outcome of interest were included in the final regression models . Because of their clinical relevance and potential importance , age , sex , and history of hyperlipidemia were retained in the final multivariable models for clinical outcomes regardless of statistical significance . Final models were evaluated for goodness of fit by the HosmerLemeshow test . Because between-hospital variation in use of statin treatment could be considerable and potentially affect our study results , we adjusted for hospital r and om effects on the observed outcomes . We used a generalized estimating equation modeling technique , assuming patients were repeated measures within each hospital . Variable 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 Women who are obese at the time of breast cancer diagnosis have higher overall mortality than normal weight women and some evidence implicates adiponectin and leptin as contributing to prognostic disadvantage . While intentional weight loss is thought to improve prognosis , its impact on these adipokines is unclear . This study compared the pattern of change in plasma leptin and adiponectin in overweight-to-obese post-menopausal breast cancer survivors during  weight loss .  Given the controversies about what dietary pattern is most appropriate for breast cancer control and regulation of adipokine metabolism , the effect of a low fat versus a low carbohydrate pattern was evaluated using a non-r and omized , controlled study design .  Anthropometric data and fasted plasma were obtained monthly during the six-month weight loss intervention . While leptin was associated with fat mass , adiponectin was not , and the lack of correlation between leptin and adiponectin concentrations throughout weight loss implies independent mechanisms of regulation . The temporal pattern of change in leptin but not adiponectin was affected by magnitude of weight loss . Dietary pattern was without effect on either adipokine . Mechanisms not directly related to dietary pattern , weight loss , or fat mass appear to play dominant roles in the regulation of circulating levels of these adipokines BACKGROUND The aim of this study was to compare the effect on endothelial function of increasing statin dose to add-on ezetimibe in patients with coronary artery disease ( CAD ) already treated with statin . METHODS AND RESULTS Two-hundred and forty-three patients with CAD and low-density lipoprotein cholesterol ( LDL-C ) ≥70 mg/dl even after treatment with atorvastatin ( 10 mg ) were prospect ively r and omized to the ezetimibe addition ( 10 mg ) group ( A10E10 ; n=117 ) or to the double atorvastatin dose ( to 20 mg ; A20 ; n=133 ) group for 12 weeks . Primary endpoint was change in endothelial function measured by logarithmic-scale reactive hyperemia index ( L_RHI ) . After treatment , high-sensitivity C-reactive protein ( hs-CRP ) and all lipids except triglyceride and high-density lipoprotein cholesterol were significantly reduced in both groups . The mean percent changes in LDL-C for the A10E10 and A20 groups were -25.8 % and -9.1 % , respectively ( P<0.001 ) . L_RHI increased from 0.47 to 0.62 in the A20 group ( P<0.001 ) , but not in the A10E10 group ( from 0.45 to 0.48 , P=0.399 ) . Absolute change in L_RHI was significantly higher in the A20 than A10E10 group ( 0.02±0.29 vs. 0.16±0.27 , P<0.001 ) . CONCLUSIONS Statin and ezetimibe have different effects on endothelial function independent from LDL-C-lowering effects 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 Atherosclerosis is currently considered a chronic inflammatory disease of the vessel wall . Systemic markers of inflammation have been shown to be of significant prognostic relevance for assessing the risk of atherosclerotic disease progression (1)(2)(3)(4 ) . Previous data showed that proinflammatory markers , such as C-reactive protein ( CRP ) , play an important role in acute coronary events (5)(6)(7 ) and that decreased plasma concentrations of antiinflammatory cytokines , for example , interleukin-10 ( IL-10 ) were also associated with acute coronary syndrome ( ACS ) (8)(9)(10 ) . Statins , 3-hydroxy-3-methyglutaryl-coenzyme A reductase inhibitors , represent a well-established class of drugs that effectively lower serum cholesterol concentrations and are widely used for the treatment of cardiovascular disease (11)(12)(13 ) . In addition to their cholesterol-lowering activity , statins have been demonstrated to possess pleiotropic effects , including antiinflammatory effects (14)(15)(16)(17 ) . Results obtained in numerous investigations have suggested that administration of statins could modify concentrations of CRP and other proinflammatory cytokines with a concurrent decrease in cardiovascular events . However , the potential influence of statins on the antiinflammatory cytokine IL-10 in patients with ACS has not been investigated . In the present study , 42 patients with unstable angina ( UA ) were r and omly assigned immediately after admission to st and ard therapy  plus either 20 mg/day atorvastatin or placebo . The st and ard therapy included aspirin , beta-blockers , heparin/low – molecular-weight heparin , angiotensin-converting enzyme inhibitors , and oral nitrates . The protocol s of the study were approved by the Ethics Review Board of the Hospital , and all patients gave written , informed consent . The patients with UA presented with  ischemic chest pain  at rest in the absence of extracardiac cause with ST-segment depression ≥0.1 mV in 2 or more contiguous leads on 12-lead electrocardiograms at administration . Echocardiography was performed in all patients to exclude patients with an impaired left Statins are extensively used to treat dyslipidemia , but , because of their low tolerability profile , they are discontinued in a significant proportion of patients . Ezetimibe and nutraceuticals have been introduced as alternative therapies and have proved to be effective and well tolerated . A single-blind , single-center , r and omized , prospect i ve , and parallel group trial comparing a combination of nutraceuticals ( red yeast rice , policosanol , berberine , folic acid , coenzyme Q10 and astaxanthin ) , called Armolipid Plus , and ezetimibe for 3 months in terms of efficacy and tolerability . Patients who did not achieve their therapeutic target ( low-density lipoprotein cholesterol < 100 mg/dl ) could add the alternative treatment on top of r and omized treatment for another 12 months : 100 patients who are dyslipidemic with ischemic heart disease treated with percutaneous coronary intervention were enrolled ( ezetimibe n = 50 , nutraceutical n = 50 ) . Efficacy ( lipid profile ) and tolerability ( adverse events , transaminases , and creatine kinase ) were assessed after 3 and 12 months . After 3 months , 14 patients in the nutraceutical group achieved their therapeutic target , whereas none of the patients in the ezetimibe group did . At 1-year follow-up , 58 patients ( 72.5 % ) of the combined therapy group ( n = 86 ) and 14 ( 100 % ) of the nutraceutical group reached the therapeutic goal . No patients experienced important undesirable effects . In conclusion , nutraceuticals alone or in combination with ezetimibe are well tolerated and improve the lipid profile in statin-intolerant patients with coronary heart disease . Further studies are needed to assess long-term effects of nutraceuticals on mortality Ezetimibe , a cholesterol absorption inhibitor , can be combined with statins to lower LDL-cholesterol . We evaluated additional ezetimibe ( 10 mg/day ) in a placebo-controlled , double blind , r and omized cross-over study in 20 patients ( age 56+/-9 years , m : f 10:10 , BMI 27.5+/-4.0 kg/m(2 ) ) suffering from severe hypercholesterolemia and CHD who were treated by statins and regular LDL-apheresis .  Lipoproteins ( cholesterol , triglycerides , LDL-cholesterol , HDL-cholesterol , VLDL-cholesterol , VLDL-triglycerides , lipoprotein(a ) ) were determined twice ( before and during ezetimibe/placebo , each given for 5 weeks ) , dietary behaviour was analyzed once ( 3-days- protocol ) during each treatment period . During ezetimibe the mean ( + /-S.D. ) preapheresis LDL-cholesterol concentration decreased from 159+/-26 mg/dl ( 4.11+/-0.67 mmol/l ) to 133+/-28 mg/dl ( 3.44+/-0.72 mmol/l ) ( -16+/-11 % , P<0.0001 , Wilcoxon test ) and the postapheresis LDL-cholesterol from 51+/-9 mg/dl ( 1.32+/-0.23 mmol/l ) to 43+/-8 mg/dl ( 1.11+/-0.21 mmol/l ) ( -14+/-25 % , P<0.05 ) , while there was no significant change during placebo .  Mean VLDL-cholesterol fell by 18+/-71 % ( P<0.05 ) during ezetimibe and was not significantly changed by placebo ( + 19+/-70 % ) . Furthermore , during ezetimibe less plasma volume was treated ( 3725+/-1560 versus 3870+/-1549 ml , P<0.05 ) . Ezetimibe had no effect on pre- and postapheresis triglyceride , HDL-cholesterol and lipoprotein(a ) levels . The effect of ezetimibe was independent of the statin dose . Dietary behaviour did not change and no side effects were observed . Thus , in patients with severe LDL-hypercholesterolemia and CHD the addition of ezetimibe to intensive lipid lowering therapy ( statins and LDL-apheresis ) result ed in a further , clinical ly significant decrease of LDL-cholesterol 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
CONCLUSIONS The results suggested that ezetimibe add-on to statin therapy is associated with an enhanced TNF-α-lowering effect  compared with statin monotherapy .
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 .