title: Effect of Ezetimibe on Insulin Sensitivity and Lipid Profile in Obese and Dyslipidaemic Patients Effects of Ezetimibe/Simvastatin and Rosuvastatin on Oxidative Stress in Diabetic Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial Double-blind randomized clinical trial of the effects of ezetimibe on postprandial hyperlipidaemia and hyperglycaemia. Effects of Combined Ezetimibe and Simvastatin Therapy as Compared With Simvastatin Alone in Patients With Type 2 Diabetes The role of soluble fiber intake in patients under highly effective lipid-lowering therapy 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 The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Effect of fixed‐dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS‐ROZE (Multicenter Randomized Study of ROsuvastatin and eZEtimibe) Effect of Ezetimibe on Insulin Secretion in db/db Diabetic Mice The effects of ezetimibe on surrogate markers of cholesterol absorption and synthesis in Japanese patients with dyslipidemia. Efficacy of ezetimibe as monotherapy or combination therapy in hypercholesterolemic patients with and without diabetes. Effect of Ezetimibe on LDL-C Lowering and Atherogenic Lipoprotein Profiles in Type 2 Diabetic Patients Poorly Controlled by Statins Ezetimibe beneficially influences fasting and postprandial triglyceride-rich lipoproteins in 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. Ezetimibe alone and in combination lowers the concentration of small, dense low-density lipoproteins in type 2 diabetes mellitus. Improved endothelial function with simvastatin but unchanged insulin sensitivity with simvastatin or ezetimibe. Comparison of the effects of simvastatin vs. rosuvastatin vs. simvastatin/ezetimibe on parameters of insulin resistance.
abstract: Summary Aim : To evaluate the effect of ezetimibe on insulin sensitivity and lipid profile in obese and dyslipidaemic patients . Methods : A r and omized , double-blind , placebo-controlled clinical trial was carried out in 12 obese , dyslipidaemic patients , independently of their basal insulin sensitivity . At the beginning of the study , a metabolic profile was measured , and insulin sensitivity estimated using the euglycaemic-hyperinsulinaemic clamp technique . The volunteers were r and omly assigned to receive ezetimibe ( 10 mg/day in the morning ) or placebo for a period of 90 days . After intervention , a similar metabolic profile was measured and a second clamp study was performed . Results : Ezetimibe administration for 90 days decreased total ( 6.0 ± 0.5 vs. 4.2 ± 0.9 mmol/L , p = 0.011 ) and low-density lipoprotein ( 4.0 ± 0.7 vs. 2.2 ± 0.8 mmol/L , p=0.003 ) cholesterol concentrations without modification of insulin sensitivity ( 3.0 ± 0.6 vs. 2.9 ± 0.7 mg/kg/min , p = 0.345 ) . Conclusions : Ezetimibe significantly decreased total cholesterol and low-density lipoprotein cholesterol concentrations without affecting insulin sensitivity in obese and dyslipidaemic patients Objective . To evaluate the effects of ezetimibe/simvastatin ( EZE/SIMV ) and rosuvastatin ( ROSUV ) on oxidative stress ( OS ) markers in patients with diabetic polyneuropathy ( DPN ) . Methods . We performed a r and omized , double-blind , placebo-controlled phase III clinical trial in adult patients with Type 2 Diabetes Mellitus ( T2DM ) and DPN , as evaluated by composite scores and nerve conduction studies ( NCS ) . Seventy-four subjects with T2DM were allocated 1 : 1 : 1 to placebo , EZE/SIMV 10/20 mg , or ROSUV 20 mg for 16 weeks . All patients were assessed before and after treatment : primary outcomes were lipid peroxidation ( LPO ) , and nitric oxide ( NO ) surrogate levels in plasma ; secondary outcomes included NCS , neuropathic symptom scores , and metabolic parameters . Data were expressed as mean ± SD or SEM , frequencies , and percentages ; we used nonparametric analysis . Results . LPO levels were reduced in both statin arms after 16 weeks of treatment ( p < 0.05 versus baseline ) , without changes in the placebo group . NO levels were not significantly affected by statin treatment , although a trend towards significance concerning increased NO levels was noted in both statin arms . No significant changes were observed for the NCS or composite scores . Discussion . EZE/SIMV and ROSUV are superior to placebo in reducing LPO in subjects with T2DM suffering from polyneuropathy . This trial is registered with NCT02129231 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 OBJECTIVE To assess the effects of inhibited gastrointestinal cholesterol absorption in statin-treated dyslipidemic patients . RESEARCH DESIGN AND METHODS In a multicenter prospect i ve r and omized double-blind placebo-controlled trial , we primarily compared by ANCOVA the effect of 2-month ezetimibe ( 10 mg/day ) or placebo therapy on LDL cholesterol serum levels in 108 type 2 diabetic patients with albuminuria < 200 μg/min and total cholesterol concentrations > 135 mg/dl despite simvastatin treatment ( 40 mg/day ) . RESULTS Unlike placebo , ezetimibe  decreased LDL cholesterol from 99 ± 31 to 66 ± 22 mg/dl , total cholesterol from 162 ± 36 to 124 ± 30 mg/dl , and apolipoprotein B from 83 ± 22 to 64 ± 18 mg/dl ( P < 0.0001 for all changes versus placebo ) . A total of 72 and 17 % of patients on ezetimibe or placebo  achieved LDL levels < 70 mg/dl , respectively ( P < 0.0001 ) . Treatment was well tolerated . CONCLUSIONS Adding ezetimibe to simvastatin therapy helps to improve the pro-atherogenic lipoprotein profile in type 2 diabetic patients who fail to reach recommended lipid targets with statin therapy alone Background It has been demonstrated that statins can increase intestinal sterol absorption . Augments in phytosterolemia seems related to cardiovascular disease . Objective We examined the role of soluble fiber intake in endogenous cholesterol synthesis and in sterol absorption among subjects under highly effective lipid-lowering therapy . Design In an open label , r and omized , parallel- design study with blinded endpoints , subjects with primary hypercholesterolemia ( n = 116 ) were assigned to receive during 12 weeks , a daily dose of 25 g of fiber ( corresponding to 6 g of soluble fibers ) plus rosuvastatin 40 mg ( n = 28 ) , rosuvastatin 40 mg alone ( n = 30 ) , sinvastatin 40 mg plus ezetimibe 10 mg plus 25 g of fiber ( n = 28 ) , or sinvastatin 40 mg plus ezetimibe 10 mg ( n = 30 ) alone . Results The four assigned therapies produced similar changes in total cholesterol , LDL-cholesterol , and triglycerides ( p < 0.001 vs. baseline ) and did not change HDL-cholesterol . Fiber intake decreased plasma campesterol ( p < 0.001 vs. baseline ) , particularly among those patients receiving ezetimibe ( p < 0.05 vs. other groups ) , and β-sitosterol ( p = 0.03 vs. baseline ) , with a trend for lower levels in the group receiving fiber plus ezetimibe ( p = 0.07 ) . Treatment with rosuvastatin alone or combined with soluble fiber was associated with decreased levels of desmosterol ( p = 0.003 vs. other groups ) . Compared to non-fiber supplemented individuals , those treated with fibers had weight loss ( p = 0.04 ) , reduced body mass index ( p = 0.002 ) and blood glucose ( p = 0.047 ) . Conclusion Among subjects treated with highly effective lipid-lowering therapy , the intake of 25 g of fibers added favorable effects , mainly by reducing phytosterolemia . Additional benefits include improvement in blood glucose and anthropometric parameters 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 Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Summary Aim We aim ed to compare the effects of fixed‐dose combinations of ezetimibe plus rosuvastatin to rosuvastatin alone in patients with primary hypercholesterolemia , including a subgroup analysis of patients with diabetes mellitus ( DM ) or metabolic syndrome ( MetS ) . Method This multicenter eight‐week r and omized double‐blind phase III study evaluated the safety and efficacy of fixed‐dose combinations of ezetimibe 10 mg plus rosuvastatin , compared with rosuvastatin alone in patients with primary hypercholesterolemia . Four hundred and seven patients with primary hypercholesterolemia who required lipid‐lowering treatment according to the ATP III guideline were r and omized to one of the following six treatments for 8 weeks : fixed‐dose combinations with ezetimibe 10 mg daily plus rosuvastatin ( 5 , 10 , or 20 mg daily ) or rosuvastatin alone ( 5 , 10 , or 20 mg daily ) . Results Fixed‐dose combination of ezetimibe plus rosuvastatin significantly reduced LDL cholesterol , total cholesterol , and triglyceride levels compared with rosuvastatin alone . Depending on the rosuvastatin dose , these fixed‐dose combinations of ezetimibe plus rosuvastatin  provided LDL cholesterol , total cholesterol , and triglyceride reductions of 56%–63 % , 37%–43 % , and 19%–24 % , respectively . Moreover , the effect of combination treatment on cholesterol levels was more pronounced in patients with DM or MetS than in non‐DM or non‐MetS patients , respectively , whereas the effect of rosuvastatin alone did not differ between DM vs non‐DM or MetS vs non‐MetS patients . Conclusion Fixed‐dose combinations of ezetimibe and rosuvastatin provided significantly superior efficacy  to rosuvastatin alone in lowering LDL cholesterol , total cholesterol , and triglyceride levels . Moreover , the reduction rate was greater in patients with DM or Objective . To investigate the effect of ezetimibe on the insulin secretion in db/db mice . Methods . The db/db diabetic mice aged 8 weeks were r and omly assigned into 2 groups and intragastrically treated with ezetimibe or placebo for 6 weeks . The age matched db/m mice served as controls . At the end of experiment , glucose tolerance test was performed and then the pancreas was collected for immunohistochemistry . In addition , in vitro perfusion of pancreatic islets was employed for the detection of insulin secretion in the first phase . Results . In the ezetimibe group , the fasting blood glucose was markedly reduced , and the total cholesterol ( TC ) and low-density lipoprotein cholesterol ( LDL-C ) were significantly lowered when compared with those in the control group ( P < 0.05 ) . At 120 min after glucose tolerance test , the area under curve in the ezetimibe group was significantly smaller than that in the control group ( P < 0.05 ) , but the AUCINS0−30 was markedly higher . In vitro perfusion of pancreatic islets revealed the first phase insulin secretion was improved . In addition , the insulin expression in the pancreas in the ezetimibe group was significantly increased as compared to the control group . Conclusion . Ezetimibe can improve glucose tolerance , recover the first phase insulin secretion , and protect the function of β cells in mice AIM To demonstrate the clinical benefit of inhibiting intestinal cholesterol absorption , we evaluated the effects of ezetimibe on surrogate markers of cholesterol absorption and synthesis , lipid and glucose metabolism , and markers of obesity and inflammation . METHODS A total of 120 patients with dyslipidemia ( 46 men ; mean age 66.5 years ) , who had not achieved the low density lipoprotein cholesterol ( LDL-C ) goal recommended by the Japan Atherosclerosis Society Guideline despite diet and exercise or any statin therapy , were enrolled and additionally treated with ezetimibe ( 10 mg/day ) for 12 weeks . RESULTS Compared to the baseline , LDL-C was reduced by 19.2 % ( p<0.001 ) after ezetimibe monotherapy and by 24.7 % ( p<0.001 ) after co-administration with ezetimibe and any statin . Ezetimibe therapy decreased cholesterol absorption markers and increased a cholesterol synthesis marker . Treatment with ezetimibe reduced the fasting serum insulin level ( p<0.05 ) and HbA1c ( p<0.05 ) , increased serum adiponectin ( p<0.01 ) , and showed a significant decrease of high-sensitive C-reactive protein ( hsCRP , p<0.01 ) . No adverse events occurred during the study . CONCLUSION Thus , cholesterol absorption inhibition by ezetimibe is an important therapeutic strategy since LDL-C and cholesterol absorption markers had a positive correlation . Ezetimibe not only reduced the serum LDL-C level but also improved glucose metabolism as well as obesity and inflammation markers . These findings support the benefit of ezetimibe as a new option for the treatment of dyslipidemia Ezetimibe selectively inhibits dietary and biliary cholesterol absorption and reduces serum cholesterol levels when administered alone ( monotherapy ) and along with common lipid-regulating agents ( combination therapy ) . To evaluate the effect of ezetimibe therapy on the lipid profile , glucose metabolism , and levels of cholesterol absorption and synthesis markers , we administered 10 mg ezetimibe to 50 hypercholesterolemic patients with or without diabetes . The serum levels of low-density lipoprotein cholesterol and total cholesterol were significantly reduced at 4 and 12 weeks of ezetimibe therapy in diabetic patients of both the monotherapy and combination-therapy groups and in nondiabetic patients of the combination-therapy group . The serum levels of the cholesterol absorption markers were significantly reduced , while those of the cholesterol synthesis markers were significantly increased at 12 weeks of ezetimibe therapy . No significant differences were noted in the values of the parameters of glucose metabolism in all patients . We also investigated the clinical characteristics of patients who exhibited a good response to ezetimibe  ( ezetimibe responders ) ; however , multivariate regression analysis did not reveal a correlation between ezetimibe efficacy and patient characteristics such as gender , age , BMI , diabetic condition , method of ezetimibe administration , and the initial absolute values of cholesterol absorption/ synthesis markers levels . In conclusion , ezetimibe therapy significantly improved the lipid profile without disturbing glucose metabolism . We were unable to identify the specific characteristics of ezetimibe responders among our subjects . However , we may interpret this result as suggesting that ezetimibe can be used in any population to lower low-density lipoprotein cholesterol levels Background There exists a sub population of T2DM in whom first-line doses of statin are insufficient for optimally reducing LDL-C , representing a major risk of CVD . The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles leading to residual risks . Methods Lipid changes were assessed in a r and omized , multicenter , 12-week , open-label study comparing a high-potency statin ( 10 mg of atorvastatin or 1 mg of pitavastatin ) plus ezetimibe ( EAT : n = 53 ) with a double dose of statin ( 20 mg of atorvastatin or 2 mg of pitavastatin ) ( DST : n = 56 ) in DM subjects who had failed to achieve the optimal LDL-C targets .  Lipid variables were compared with a primary focus on LDL-C and with secondary focuses on the percentage of patients who reached the LDL-C targets and changes in the levels of RLP-C ( remnant like particle cholesterol ) and sd-LDL-C , two characteristic atherogenic risks of DM . Results The reduction of LDL-C ( % ) , the primary endpoint , differed significantly between the two groups ( -24.6 in EAT vs. -10.9 in DST ) . In the analyses of the secondary endpoints , EAT treatment brought about significantly larger reductions in sd-LDL-C ( -20.5 vs. -3.7 ) and RLP-C ( -19.7 vs. + 5.5 ) . In total , 89.4 % of the patients receiving EAT reached the optimized treatment goal compared to 51.0 % of the patients receiving DST . The changes in TC ( -16.3 vs. -6.3 ) and non-HDL-C ( -20.7 vs. -8.3 ) differed significantly between the two groups . Conclusion Ezetimibe added to high-potency statin ( 10 mg of atorvastatin or 1 mg of pitavastatin ) was more effective than the intensified-dose statin ( 20 mg of atorvastatin or 2 mg of pitavastatin ) treatment not only in helping T2DM patients attain more LDL-C reduction , but also in improving their atherogenic lipid profiles , including their levels of sd-LDL-C and RLP-C. We thus recommend the addition of ezetimibe to high-potency statin as a first line strategy for T2DM patients with insufficient statin response . Trial Registration The UMIN Clinical Trials Registry INTRODUCTION Type 2 diabetes is associated with atherogenic abnormalities of postpr and ial triglyceride-rich lipoproteins . This study evaluated whether ezetimibe , by inhibiting intestinal cholesterol absorption , influences chylomicrons and VLDL particles at fasting and after a st and ard meal . METHODS By a double blind cross-over design 15 subjects with type 2 diabetes and hypercholesterolaemia followed in r and om order a 6-week treatment with ezetimibe 10mg+simvastatin 20 mg ( EZE+S ) or placebo+simvastatin 20 mg ( P+S ) and , after a 6-week wash-out period , crossed over to the other treatment ( NCT00699023 ) . At the end of each period lipids , apoB-48 , and apoB-100 concentrations in plasma and lipoprotein fractions ( separated by discontinuous density gradient ultracentrifugation ) were determined before and over 6h following a high-fat test meal . RESULTS Compared with P+S , EZE+S induced , ( a ) beside a greater decrease in LDL cholesterol , ( b ) a significant decrease in chylomicron lipid content both at fasting and postpr and ially ( 4.4 ± 2.7 vs. 8.3 ± 8.7 mg/dl × 6 h total AUC for cholesterol , p < 0.05 ; 18 ± 12 vs. 29 ± 24 mg/dl triglyceride concentrations at 6h , p < 0.05 ) , ( c ) a significant decrease in chylomicron postpr and ial apoB-48 ( 0.03 ± 0.03 vs. 0.09 ± 0.08 mg/l at 4 h , p < 0.05 ) , and ( d ) significant fasting and postpr and ial decreases in the cholesterol content of VLDL , IDL , and LDL , as shown by the significant reduction of the cholesterol/triglyceride ratio in these lipoproteins . CONCLUSIONS A 6-week treatment with ezetimibe and simvastatin , compared to simvastatin alone , positively influences lipoprotein profile both at fasting and postpr and ially in type 2 diabetic patients by favouring the production of cholesterol-poor chylomicrons and VLDL particles that have less atherogenic potential 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 OBJECTIVE The effectiveness of the cholesterol absorption inhibitor ezetimibe on LDL subfractions and ultimately on the atherosclerotic risk profile remains controversial . We thus determined the concentration of atherogenic small , dense LDL ( sdLDL ) in patients with type 2 diabetes and an elevated cardiovascular risk profile . RESEARCH DESIGN AND METHODS Multicenter , r and omized , open-label 6-week study investigating the effect of ezetimibe 10 mg ( E ) , simvastatin 20 mg ( S ) and the combination of ezetimibe-/simvastatin 10/20 mg ( C ) on the concentration of sdLDL separated from fresh plasma by gradient ultracentrifugation in patients with type 2 diabetes ( NCT01384058 ) . RESULTS Fifty-six patients were screened for sdLDL , 41 were r and omized , and 40 patients ( 12 E , 14 S and 14 C ) completed the study .  Total and LDL cholesterol fell by 14 % ( p=0.004 ) and 15 % ( p=0.006 ) with E , 22 % ( p<0.001 ) and 32 % ( p<0.001 ) with S , and 32 % ( p<0.001 ) and 44 % ( p<0.001 ) with C , respectively . E reduced the concentration of sdLDL by 20 % ( p=0.043 ) whereas S and C reduced sdLDL by 24 % ( p=0.020 ) and 33 % ( p=0.003 ) , respectively , and non-sdLDL by 28 % ( p=0.004 ) and 42 % ( p<0.001 ) , respectively . However , the further drop in sdLDL by adding E to S was not significant . CONCLUSION Ezetimibe alone and in combination with simvastatin reduced the concentration of atherogenic sdLDL in patients with type 2 diabetes 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 BACKGROUND Statin treatment may be associated with adverse effects on glucose metabolism . Whether this is a class effect is not known . In contrast , ezetimibe monotherapy may beneficially affect insulin sensitivity . OBJECTIVE The aim of this study was to compare the effects of three different regimens of equivalent low-density lipoprotein cholesterol ( LDL-C ) lowering capacity on glucose metabolism . METHODS A total of 153 patients ( 56 men ) , who had not achieved the LDL-C goal recommended by the National Cholesterol Education Program Adult Treatment Panel III ( NCEP-ATP III ) despite a 3-month dietary and lifestyle intervention , were r and omly allocated to receive open-label simvastatin 40 mg or rosuvastatin 10 mg or simvastatin/ezetimibe 10/10 mg for 12 weeks . The primary end point was changes in homeostasis model assessment of insulin resistance ( HOMA-IR ) . Secondary endpoints consisted of changes in fasting insulin levels , fasting plasma glucose ( FPG ) , glycosylated haemoglobin ( HbA(1c ) ) , the HOMA of β-cell function ( HOMA-B ) ( a marker of basal insulin secretion by pancreatic β-cells ) , LDL-C and high sensitivity C reactive protein ( hsCRP ) . RESULTS At week 12 , all three treatment regimens were associated with significant increases in HOMA-IR and fasting insulin levels ( p < 0.05 compared with baseline ) . No significant difference was observed between groups . No change in FPG , HbA(1c ) and HOMA-B levels compared with baseline were noted in any of the three treatment groups . Changes in serum lipids and hsCRP were similar across groups . CONCLUSION To the extent that simvastatin 40 mg , rosuvastatin 10 mg and simvastatin/ezetimibe 10/10 mg are associated with adverse effects on insulin resistance , they appear to be of the same magnitude
target: Conclusions Compared with high-dose statin therapy , ezetimibe with low-dose statin for more than 3 months may have a beneficial tendency of effects on glycemic control
background: Purpose Given the increased risk of incident diabetes and the side effects on glycemic control with statin treatment , statin and ezetimibe combination therapy has been widely used .
  However , whether the same concern exists in ezetimibe remains uncertain .
  This meta- analysis aim ed to investigate the influence of ezetimibe treatment on glycemic control .