Fixed‐dose combination ezetimibe+atorvastatin lowers LDL‐C equivalent to co‐administered components in randomized trials: use of a dose–response model

Co‐administration of ezetimibe with atorvastatin is a generally well‐tolerated treatment option that reduces LDL‐C levels and improves other lipids with greater efficacy than doubling the atorvastatin dose. The objective of the study was to demonstrate the equivalent lipid‐modifying efficacy of fixed‐dose combination (FDC) ezetimibe/atorvastatin compared with the component agents co‐administered individually in support of regulatory filing. Two randomized, 6‐week, double‐blind cross‐over trials compared the lipid‐modifying efficacy of ezetimibe/atorvastatin 10/20 mg (n = 353) or 10/40 mg (n = 280) vs. separate co‐administration of ezetimibe 10 mg plus atorvastatin 20 mg (n = 346) or 40 mg (n = 280), respectively, in hypercholesterolemic patients. Percent changes from baseline in LDL‐C (primary endpoint) and other lipids (secondary endpoints) were assessed by analysis of covariance; triglycerides were evaluated by longitudinal‐data analysis. Expected differences between FDC and the corresponding co‐administered doses were predicted from a dose–response relationship model; sample size was estimated given the expected difference and equivalence margins (±4%). LDL‐C‐lowering equivalence was based on 97.5% expanded confidence intervals (CI) for the difference contained within the margins; equivalence margins for other lipids were not prespecified. Ezetimibe/atorvastatin FDC 10/20 mg was equivalent to co‐administered ezetimibe+atorvastatin 20 mg in reducing LDL‐C levels (54.0% vs. 53.8%) as was FDC 10/40 mg and ezetimibe+atorvastatin 40 mg (58.9% vs. 58.7%), as predicted by the model. Changes in other lipids were consistent with equivalence (97.5% expanded CIs <±3%, included 0); triglyceride changes varied more. All treatments were generally well tolerated. Hypercholesterolemic patients administered ezetimibe/atorvastatin 10/20 and 10/40 mg FDC had equivalent LDL‐C lowering. This FDC formulation proved to be an efficacious and generally well‐tolerated lipid‐lowering therapy.     

Efficacy, safety and LDL-C goal attainment of ezetimibe 10 mg-simvastatin 20 mg vs. placebo-simvastatin 20 mg in UK-based adults with coronary heart disease and hypercholesterolaemia

It is increasingly accepted that more intensive lipid‐lowering treatment is associated with greater cardiovascular risk reductions in patients with coronary heart disease (CHD), thus providing a rationale for more aggressive LDL‐cholesterol (LDL‐C) targets. Ezetimibe in combination with statin therapy provides an additional approach to lipid management by utilising the additive action of two different mechanisms of LDL‐C reduction. In this multicentre, randomised, double‐blind, placebo‐controlled study, a total of 98 men and 55 women with CHD and primary hypercholesterolaemia, naïve to statin therapy, were randomised to receive treatment for 6 weeks with either ezetimibe 10 mg–simvastatin 20 mg (n = 77) or placebo–simvastatin 20 mg (n = 75). At 6 weeks, ezetimibe 10 mg–simvastatin 20 mg provided a mean additional LDL‐C reduction of 14.6% (95% CI 10.1–19.1) compared with simvastatin monotherapy (p < 0.0001). Moreover, a higher proportion of patients on ezetimibe/simvastatin achieved the National Standard Framework LDL‐C standard (<3.0 mmol/l; 93% vs. 75%, p < 0.001) or the new Joint British Societies (JBS 2) goal of LDL‐C < 2.0 mmol/l (49.3% vs. 11.1%, p < 0.001). On logistic regression analysis, the odds ratio of achieving target LDL‐C with ezetimibe 10 mg–simvastatin 20 mg was 5.1 (95% CI 1.8–15.0) times higher than with simvastatin monotherapy (p = 0.003). Clinical chemistry profiles and proportions of adverse events were similar in both groups at baseline and follow‐up. In conclusion, ezetimibe 10 mg–simvastatin 20 mg is a practical, effective and safe option for the treatment of primary hypercholesterolaemia in CHD patients, and brings more patients to new aggressive cholesterol targets compared with simvastatin 20 mg monotherapy.     

Lipid‐altering efficacy of ezetimibe/simvastatin 10/20 mg compared with rosuvastatin 10 mg in high‐risk hypercholesterolaemic patients inadequately controlled with prior statin monotherapy – The IN‐CROSS study

Aims: To evaluate the efficacy of switching from a previous statin monotherapy to ezetimibe/simvastatin (EZE/SIMVA) 10/20 mg vs. rosuvastatin (ROSUVA) 10 mg. Methods: In this randomised, double‐blind study, 618 patients with documented hypercholesterolaemia [low‐density lipoprotein cholesterol (LDL‐C) ≥ 2.59 and ≤ 4.92 mmol/l] and with high cardiovascular risk who were taking a stable daily dose of one of several statin medications for ≥ 6 weeks prior to the study randomisation visit entered a 6‐week open‐label stabilisation/screening period during which they continued to receive their prestudy statin dose. Following stratification by study site and statin dose/potency, patients were randomised to EZE/SIMVA 10/20 mg (n = 314) or ROSUVA 10 mg (n = 304) for 6 weeks. Results: EZE/SIMVA produced greater reductions in LDL‐C (?27.7% vs. ?16.9%; p ≤ 0.001), total cholesterol (?17.5% vs. ?10.3%; p ≤ 0.001), non‐high‐density lipoprotein cholesterol (HDL‐C) (?23.4% vs. ?14.0%; p ≤ 0.001) and apolipoprotein B (?17.9% vs. ?9.8%; p ≤ 0.001) compared with ROSUVA, while both treatments were equally effective at increasing HDL‐C (2.1% vs. 3.0%; p = 0.433). More patients achieved LDL‐C levels < 2.59 mmol/l (73% vs. 56%), < 2.00 mmol/l (38% vs. 19%) and < 1.81 mmol/l (25% vs. 11%) with EZE/SIMVA than ROSUVA (p ≤ 0.001). A borderline significantly greater reduction in triglycerides (p = 0.056) was observed for EZE/SIMVA (?11.0%) vs. ROSUVA (?5.3%). There were no between‐group differences in the incidences of adverse events or liver transaminase and creatine kinase elevations. Conclusion: EZE/SIMVA 10/20 mg produced greater improvements in LDL‐C, total cholesterol, non‐HDL‐C and apoB with a similar safety profile as for ROSUVA 10 mg.     

Achieving lipid goals in real life: the Dutch DISCOVERY study

DISCOVERY Netherlands was an open‐label, randomised, multicentre study (D3560/L00003) designed to compare the effects of rosuvastatin with those of atorvastatin, simvastatin or pravastatin on low‐density lipoprotein cholesterol (LDL‐C) goal achievement in a primary care setting. Patients (n = 1215) with type IIa or type IIb hypercholesterolaemia and cardiovascular risk of >20% or a history of coronary heart or other atherosclerotic vascular disease were randomised to receive treatment with rosuvastatin 10 mg (n = 621), atorvastatin 10 mg (n = 189), simvastatin 20 mg (n = 194) or pravastatin 40 mg (n = 211) for 12 weeks. Significantly, more patients achieved 1998 and 2003 European LDL‐C goals with rosuvastatin than with other statins after 12 weeks (p < 0.001). Rosuvastatin reduced LDL‐C and total cholesterol levels significantly more than other statins, both in patients who were statin‐naïve and in patients who had received previous statin treatment (p < 0.05). All treatments were similarly well tolerated. In conclusion, greater reductions in LDL‐C were achieved with rosuvastatin compared with atorvastatin, simvastatin and pravastatin, enabling more patients to achieve European LDL‐C goals.     

Attainment of Canadian and European guidelines' lipid targets with atorvastatin plus ezetimibe vs. doubling the dose of atorvastatin

Background: Canadian and European treatment guidelines identify low‐density lipoprotein cholesterol (LDL‐C) as a primary treatment target for hypercholesterolaemia. Objectives: This post hoc analysis compared ezetimibe 10 mg (ezetimibe) added to atorvastatin vs. doubling the atorvastatin dose on achievement of the 2009 Canadian Cardiovascular Society (CCS) and the 2007 Joint European Prevention Guidelines primary and optional secondary lipid targets and high‐sensitivity C‐reactive protein (hs‐CRP) levels. Methods: After stabilisation on atorvastatin, hypercholesterolaemic patients at moderately high risk (MHR) for coronary heart disease (CHD) not at LDL‐C < 2.6 mmol/l were randomised to atorvastatin 20 mg vs. doubling their atorvastatin dose to 40 mg; and patients at high risk (HR) for CHD not at LDL‐C < 1.8 mmol/l were randomised to atorvastatin 40 mg plus ezetimibe vs. doubling their atorvastatin dose to 80 mg for 6 weeks. Results: When treated with atorvastatin plus ezetimibe, MHR and HR patients had greater attainment of LDL‐C, most lipids and lipoproteins and/or hs‐CRP targets compared with doubling their atorvastatin dose. More MHR and HR patients achieved dual targets of LDL‐C and: Apolipoprotein (Apo) B, total cholesterol (total‐C), total‐C/high‐density lipoprotein cholesterol (HDL‐C), non‐HDL‐C, triglycerides, Apo B/Apo A‐I or hs‐CRP with ezetimibe + atorvastatin treatment compared with doubling their atorvastatin dose. Conclusions: These results demonstrated greater achievement of single/dual treatment targets as set by Canadian and European treatment guidelines with ezetimibe added to atorvastatin 20 mg or 40 mg compared with doubling the atorvastatin dose to 40 mg or 80 mg in MHR and HR patients, respectively.     

Lipid-altering efficacy of ezetimibe/simvastatin 10/40 mg compared with doubling the statin dose in patients admitted to the hospital for a recent coronary event: the INFORCE study

Background: The aim of this study was to investigate the efficacy and safety profile of switching to ezetimibe/simvastatin (Eze/Simva) 10/40 mg compared with doubling the statin dose upon discharge in patients taking a statin and admitted to the hospital for the investigation of a coronary event. Design: This phase IV, multi‐centre, randomised, open‐label, active‐controlled, parallel group study enrolled 424 patients (aged ≥ 18 years) hospitalised for an acute coronary event and taking a stable dose of a statin (≥ 6 weeks) that could be doubled per the product label. Upon discharge from the hospital, patients were stratified by their statin dose/potency (high, medium and low) and randomised 1 : 1 to doubling of the statin dose (n = 211) or Eze/Simva 10/40 mg (n = 213) for 12 weeks. The primary efficacy variable was the absolute low‐density lipoprotein cholesterol (LDL‐C) value (mmol/l) at study end‐point. Results: Mean baseline LDL‐C for the two treatment groups were 2.48 and 2.31 mmol/l for the Eze/Simva and statin groups respectively. At study end‐point, least squares mean LDL‐C values were 1.74 mmol/l in the Eze/Simva group and 2.22 mmol/l in the statin group resulting in a significant between‐group difference of ?0.49 mmol/l (p ≤ 0.001). Eze/Simva 10/40 mg also produced significantly lower total cholesterol (?0.49 mmol/l), non‐high‐density lipoprotein cholesterol [(non‐HDL‐C); ?0.53 mmol/l] and apolipoprotein B (?0.14 mmol/l) values compared with doubling the statin dose (p ≤ 0.001 for all). Both treatments produced similar effects on triglycerides, C‐reactive protein and HDL‐C; the between treatment group differences were not significant (p ≥ 0.160). Significantly more patients achieved LDL‐C levels < 2.5 (< 100 mg/dl; 86% vs. 72%), < 2.0 (< 77 mg/dl; 70% vs. 42%) and < 1.8 mmol/l (< 70 mg/dl; 60% vs. 31%) with Eze/Simva than statin (all p ≤ 0.001). Eze/Simva was generally well tolerated, with a safety profile similar to statin. There were no differences in the incidences of liver transaminases ≥ 3 × upper limit of normal (ULN) or creatine kinase ≥ 10 × ULN between the groups. Conclusions: In patients taking a statin and admitted to the hospital for investigation of a coronary event, treatment with Eze/Simva 10/40 mg for 12 weeks produced greater improvements in lipids with a similar safety profile compared with doubling of the statin dose.     

Clinical Efficacy and Tolerability of Ezetimibe in Combination With Atorvastatin in Japanese Patients With Hypercholesterolemia—Ezetimibe Phase IV Randomized Controlled Trial in Patients With Hypercholesterolemia

ObjectiveThe purpose of this study was to compare the efficacy and tolerability of combination therapy of ezetimibe and atorvastatin in patients with high LDL cholesterol that had not reached the lipid management target value with 10 mg atorvastatin monotherapy, against increasing the dose to 20 mg atorvastatin or switching to 2.5 mg rosuvastatin.Design, setting, and participantsThis was an open-label, randomized, multicenter, 3-parallel-group comparison trial at 23 community hospitals and clinics in Japan (enrollment period March 2009 to May 2010) in 125 patients with high LDL cholesterol.InterventionsA total of 125 Japanese patients with high LDL cholesterol level were randomized to 1 of the following 3 treatment groups: the ezetimibe (10 mg/d) and atorvastatin (10 mg/d) group, the atorvastatin (20 mg/d) group, or the rosuvastatin (2.5 mg/d) group for 12 weeks after treatment with 10 mg atorvastatin alone for 4 weeks.Main outcome measurePercent change in LDL cholesterol level from baseline (4 weeks after treatment with 10 mg atorvastatin alone) until study completion.ResultsThe percent change in LDL cholesterol level from baseline until study completion was statistically greater for the combination of 10 mg ezetimibe + 10 mg atorvastatin compared with increasing atorvastatin to 20 mg (?25.8% vs ?15.1%; P < 0.0001). A similar result was observed for ezetimibe + atorvastatin compared with switching to 2.5 mgt rosuvastatin (?25.8% vs 0.8%; P < 0.0001). The proportion of patients who reached the target LDL cholesterol value with the combination of ezetimibe + atorvastatin was significantly higher than increasing atorvastatin and switching to rosuvastatin (78.7%, 41.3%, and 3.1%, respectively). Although 5 serious adverse experiences bearing no relation to the study medications were reported, there were no adverse reactions.ConclusionsThe combination of 10 mg ezetimibe +10 mg atorvastatin was more effective than increasing atorvastatin to 20 mg or switching to 2.5 mg rosuvastatin in patients with hypercholesterolemia whose LDL cholesterol levels had not reached the recommended target value with 10 mg atorvastatin monotherapy for 4 weeks. Ezetimibe coadministration with atorvastatin was well tolerated. ClinicalTrials.gov identifier: NCT00871351.     

A systematic review and meta‐analysis on the therapeutic equivalence of statins

Background: Statins are the most commonly prescribed agents for hypercholesterolemia because of their efficacy and tolerability. As the number of patients in need of statin therapy continues to increase, information regarding the relative efficacy and safety of statins is required for decision‐making. Objective: This study will use systematic review to compare the efficacy and safety profiles of different statins at different doses and determine the therapeutically equivalent doses of statins to achieve a specific level of low‐density lipoprotein cholesterol (LDL‐C) lowering effect. Methods: Publications of head‐to‐head randomized controlled trials (RCTs) of statins were retrieved from the Oregon state database (1966–2004), MEDLINE (2005‐April of 2006), EMBASE (2005‐April of 2006), and the Cochrane Controlled Trials Registry (up to the first quarter of 2006). The publications were evaluated with predetermined criteria by a reviewer before they were included in the review. The mean change in cholesterol level of each statin was calculated and weighted by number of subjects involved in each RCT. Where possible, meta‐analysis was performed to generate pooled estimates of the cholesterol lowering effect of statins and the difference between statins. Results: Seventy‐five studies reporting RCTs of head‐to‐head comparisons on statins were included. Most studies had similar baseline characteristics, except the rosuvastatin related studies. A daily dose of atorvastatin 10 mg, fluvastatin 80 mg, lovastatin 40–80 mg, and simvastatin 20 mg could decrease LDL‐C by 30–40%, and fluvastatin 40 mg, lovastatin 10–20 mg, pravastatin 20–40 mg, and simvastatin 10 mg could decrease LDL‐C by 20–30%. The only two statins that could reduce LDL‐C more than 40% were rosuvastatin and atorvastatin at a daily dose of 20 mg or higher. Meta‐analysis indicated a statistically significant but clinically minor difference (<7%) between statins in cholesterol lowering effect. Comparisons of coronary heart disease prevention and safety could not be made because of insufficient data. Conclusions: At comparable doses, statins are therapeutically equivalent in reducing LDL‐C.     

Comparison of the effects of simvastatin vs. rosuvastatin vs. simvastatin/ezetimibe on parameters of insulin resistance

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 randomly 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.     

Prevalence of low HDL cholesterol,and relationship between serum HDL and cardiovascular disease in elderly Spanish population: the PREV‐ICTUS study

Objective: To assess the prevalence of low serum high‐density lipoprotein cholesterol (HDL‐C) concentration and the relationship between HDL‐C and established cardiovascular disease (CVD) in an elderly Mediterranean population. Methods: Analysis of Prevención del Riesgo de Ictus, a population‐based study on Spanish subjects aged ≥ 60 years. Low HDL‐C was defined following the European guidelines for cardiovascular prevention [men: < 40 mg/dl (< 1.0 mmol/l); women: < 46 mg/dl (< 1.2 mmol/l)]. The relationship between low HDL‐C or HDL‐C concentration (in quintiles) and CVD was assessed through multivariate models that included cardiovascular risk factors, statins and subclinical organ damage. Results: On 6010 subjects (71.7 years, 53.5% women), low HDL‐C was present in 17.5% [95% confidence interval (CI): 16.5–18.5] and was more frequent in women [20.4% (19.0–21.8) vs. 14.1% (12.8–15.4) in men p < 0.001] and in patients with diabetes, CVD or statin therapy. Low HDL‐C was independently associated with CVD [adjusted odds ratio (OR): 1.46, 95% CI: 1.22–1.74, p < 0.001]. The prevalence of CVD was higher as HDL‐C concentration was lower (chi‐square trend < 0.001). Compared with the highest quintile [> 65 mg/dl (> 1.67 mmol/l)], adjusted OR for CVD were 1.39 (1.10–1.76), 1.41 (1.11–1.80), 1.49 (1.18–1.89) and 1.91 (1.52–2.39), respectively for those in the fourth [57–65 mg/dl (1.46–1.67 mmol/l)], third [51–56 mg/dl (1.31–1.45 mmol/l)], second [46–50 mg/dl (1.18–1.30 mmol/l)] and first [< 46 mg/dl (< 1.18 mmol/l)] quintiles of HDL‐C. This association was seen in males and females. Conclusions: A total of 17.5% of this Spanish population aged ≥ 60 years had low HDL‐C. We found a strong, independent and inverse association between HDL‐C concentrations and established CVD, even at ranges of HDL‐C considered as normal.     

The evolution and revolution of the implantable cardioverter defibrillator

A low-density lipoprotein (LDL) cholesterol goal of less than 100 mg/dl is recommended for patients at moderate to high risk of cardiovascular disease with an optional LDL goal of less than 70 mg/dl for patients at a very high risk of cardiovascular disease. Most patients will require reductions in LDL of more than 50% in order to achieve these more aggressive goals. Only a few agents will lower LDL by at least 50%. This review will focus on the efficacy and safety ezetimibe/simvastatin coadministered as a therapy with enhanced LDL-lowering efficacy, while minimizing the adverse effects of statins in a wide range of patients. Ezetimibe 10 mg/simvastatin 80 mg lowers LDL by approximately 60% and has been demonstrated to be superior to the highest doses of atorvastatin and rosuvastatin for lowering LDL and raising high-density lipoprotein.     

Combination therapy with ezetimibe and simvastatin to achieve aggressive LDL reduction

A low-density lipoprotein (LDL) cholesterol goal of less than 100 mg/dl is recommended for patients at moderate to high risk of cardiovascular disease with an optional LDL goal of less than 70 mg/dl for patients at a very high risk of cardiovascular disease. Most patients will require reductions in LDL of more than 50% in order to achieve these more aggressive goals. Only a few agents will lower LDL by at least 50%. This review will focus on the efficacy and safety ezetimibe/simvastatin coadministered as a therapy with enhanced LDL-lowering efficacy, while minimizing the adverse effects of statins in a wide range of patients. Ezetimibe 10 mg/simvastatin 80 mg lowers LDL by approximately 60% and has been demonstrated to be superior to the highest doses of atorvastatin and rosuvastatin for lowering LDL and raising high-density lipoprotein.     

Effects of rosuvastatin versus atorvastatin, simvastatin, and pravastatin on non-high-density lipoprotein cholesterol, apolipoproteins, and lipid ratios in patients with hypercholesterolemia: additional results from the STELLAR trial

BACKGROUND: Non-high-density lipoprotein cholesterol (HDL-C), apolipoprotein (apo) B, and lipid and apolipoprotein ratios that include both atherogenic and antiatherogenic lipid components have been found to be strong predictors of coronary heart disease risk. OBJECTIVE: The goal of this study was to examine prospectively the effects of rosuvastatin, atorvastatin, simvastatin, and pravastatin across dose ranges on non-HDL-C, apo B, apo A-I, and total cholesterol (TC):HDL-C, low-density lipoprotein cholesterol (LDL-C):HDL-C, non-HDL-C:HDL-C, and apo B:apo A-I ratios in patients with hypercholesterolemia (LDL-C > or =160 mg/dL and <250 mg/dL and triglycerides <400 mg/dL) in the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial. METHODS: In this randomized, Multicenter, parallel-group, open-label trial (4522IL/0065), patients > or =18 years of age received rosuvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; or pravastatin 10, 20, or 40 mg for 6 weeks. Pairwise comparisons were prospectively planned and performed between rosuvastatin 10, 20, and 40 mg and milligram-equivalent or higher doses of comparators. RESULTS: A total of 2268 patients were randomized to the rosuvastatin 10- to 40-mg, atorvastatin, simvastatin, and pravastatin groups. Fifty-one percent of patients were women, the mean (SD) age was 57 (12) years, and 19% had a documented history of atherosclerotic disease. Over 6 weeks, rosuvastatin significantly reduced non-HDL-C, apo B, and all lipid and apolipoprotein ratios assessed, compared with milligram-equivalent doses of atorvastatin and milligram-equivalent or higher doses of simvastatin and pravastatin (all, P < 0.002). Rosuvastatin reduced non-HDL-C by 42.0% to 50.9% compared with 34.4% to 48.1% with atorvastatin, 26.0% to 41.8% with simvastatin, and 18.6% to 27.4% with pravastatin. Rosuvastatin reduced apo B by 36.7% to 45.3% compared with 29.4% to 42.9% with atorvastatin, 22.2% to 34.7% with simvastatin, and 14.7% to 23.0% with pravastatin. The highest increase in apo A-I (8.8%) was observed in the rosuvastatin 20-mg group, and this increase was significantly greater than in the atorvastatin 40-mg and 80-mg groups (both, P < 0.002). CONCLUSION: Rosuvastatin 10 to 40 mg was more efficacious in improving the lipid profile of patients with hypercholesterolemia than milligram-equivalent doses of atorvastatin and milligram-equivalent or higher doses of simvastatin and pravastatin.     

Ezetimibe/simvastatin vs atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia: the VYTAL study

OBJECTIVE: To compare the efficacy and safety of the recommended usual starting and next highest doses of ezetimibe/ simvastatin and atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia. PATIENTS AND METHODS: This double-blind, multicenter study (June 22 to December 7, 2005) consisted of adult patients randomized to the recommended usual starting (ezetimibe/simvastatin, 10/20 mg/d, vs atorvastatin, 10 or 20 mg/d) or next highest (ezetimibe/simvastatin, 10/40 mg/d, vs atorvastatin, 40 mg/d) doses. Efficacy end points included percent changes from baseline in low-density lipoprotein cholesterol (LDL-C) levels (primary) and proportion of patients attaining LDL-C levels less than 70 mg/dL (secondary). RESULTS: A total of 1229 patients participated in the study. Significantly greater mean reductions were found in LDL-C levels with ezetimibe/simvastatin, 10/20 mg/d (-53.6%; 95% confidence interval [CI], -55.4% to -51.8%), than with atorvastatin, 10 mg/d (-38.3%; 95% CI, -40.1% to -36.5%; P < .001) or 20 mg/d (-44.6%; 95% CI, -46.4% to -42.8%; P < .001), and with ezetimibe/simvastatin, 10/40 mg/d (-57.6%; 95% CI, -59.4% to -55.8%), vs atorvastatin, 40 mg/d (-50.9%; 95% CI, -52.7% to -49.1%; P < .001). Ezetimibe/simvastatin was also superior to atorvastatin in attainment of LDL-C levels less than 70 mg/dL (P < .001 for all dose comparisons). Significantly better improvements with ezetimibe/simvastatin than with atorvastatin (P < or = .001) were observed for total cholesterol, high-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol. Ezetimibe/ simvastatin, 10/20 mg/d, reduced high-sensitivity C-reactive protein and triglyceride levels significantly more than atorvastatin, 10 mg/d (P = .02), with comparable reductions at other doses. Incidences of clinical adverse events, including serious drug-related and prespecified gastrointestinal-, gallbladder-, and hepatitis-related allergic reactions or rash events, and laboratory adverse events, including repeated elevation of hepatic transaminases or creatine kinase levels, were similar for both treatments. CONCLUSION: Ezetimibe/simvastatin provided additional lipid-modifying benefits over atorvastatin monotherapy at the recommended usual starting and next highest doses in patients with type 2 diabetes. Both treatments were generally well tolerated.     

Efficacy and safety of ezetimibe/simvastatin association on non-diabetic and diabetic patients with polygenic hypercholesterolemia or combined hyperlipidemia and previously intolerant to standard statin treatment

Background and objective: One of the problems associated with reaching the low‐density lipoprotein cholesterol (LDL‐C) target during statin treatment is the emergence of laboratory or clinical side effects. The aim of our study was to evaluate the prevalence of statin‐associated adverse events in diabetic and non‐diabetic patients affected by polygenic hypercholesterolemia or combined hyperlipidemia and the efficacy and tolerability of treatment with ezetimibe/simvastatin 10/10 mg/day on the same subjects experiencing the adverse events. Methods: Consecutively enrolment of patients affected by polygenic hypercholesterolemia or combined hyperlipidemia with or without type 2 diabetes mellitus. Each Centre used any of the available statins on the basis of current clinical judgement and monitored enrolled patients for adverse events during the following 2 years. Those patients with moderate adverse events suspended the current statin therapy for 1 month (washout period), and then were shifted to treatment with ezetimibe/simvastatin 10/10 mg/day and again monitored for adverse events in the following 6 months. We assessed body mass index, glycated haemoglobin, fasting plasma glucose, total cholesterol, LDL‐C, high‐density lipoprotein cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, creatinine phosphokinase and monitored adverse events such as asthenia and myalgia. Results and discussion: All 1170 Caucasian patients affected by polygenic hypercholesterolemia obtained a significant reduction in LDL‐C during the observation period (P < 0·05), while those with combined hyperlipidemia also showed a reduction in TG plasma level (P < 0·05) and a significant increase in HDL‐C (P < 0·05). Patients affected by polygenic hypercholesterolemia experiencing adverse event under statin treatment obtained a significantly lower reduction than those tolerating the treatment (P < 0·001). The prevalence of adverse events under statin treatment was 4·9% in non‐diabetic patients with polygenic hypercholesterolemia, 8·6% in those with combined hyperlipidemia, 7·1% in diabetic patients with polygenic hypercholesterolemia and 7·6% in those with combined hyperlipidemia. Six months after the shift to treatment with ezetimibe/simvastatin 10/10 mg, all patients experienced a significant improvement in LDL‐C, TG and HDL‐C plasma level. No adverse event was registered during the ezetimibe/simvastatin 10/10 mg treatment period. It seems that previous side effects observed with statins did not re‐appear with the administration of ezetimibe/simvastatin 10/10 mg/day. Conclusions: The efficacy and adverse effect profile of the ezetimibe and simvastatin combination appear to be good for both diabetic and non‐diabetic patients, and in both conditions.     

The comparative effectiveness of rosuvastatin vs. other statins in patients with an increased risk of failure to reach NCEP ATP III goal

Background: Previous studies have demonstrated that failure to reach National Cholesterol Education Program (NCEP) target low‐density lipoprotein cholesterol (LDL‐C) goal increases the risk of cardiovascular events. Ability to meet goal may be impacted by the choice of statin therapy. Purpose: This study compares rosuvastatin to other statin therapies among patients presenting with risk factors associated with failure to reach NCEP goal. Methods: Retrospective analysis using medical and pharmacy claims linked to laboratory results from a national health plan encompassing private and MedicareAdvantage enrollees age ≥ 18 years and newly treated with statins from 1 August 2003 to 28 February 2005. Predictors of failure to reach goal were statin treatment group, age, gender, NCEP risk level, per cent reduction required to attain goal and days from index to LDL‐C measurement. Results: Of 11,814 eligible patients, 9.6% were initiated on rosuvastatin, 54.2% atorvastatin, 17.9% simvastatin, 7.1% pravastatin, 2.0% fluvastatin and 9.3% lovastatin. Independent predictors of failure to reach goal included ≥ 15% LDL‐C reduction required to reach goal, and high and moderate NCEP risk status. In the subset of patients at higher risk of failure to reach goal, rosuvastatin demonstrated a significantly lower rate of failure to achieve goal than atorvastatin, simvastatin, pravastatin, fluvastatin or lovastatin. Conclusions: Real‐world factors associated with high risk of failure to reach goal may be used in identifying patients more likely to succeed on rosuvastatin compared with other statins. Low‐risk patients needing < 15% LDL‐C reduction would be suitable candidates for initiation of most other statins, specifically simvastatin, which has recently become available in the generic form.     

Comparative effects of rosuvastatin and atorvastatin on glucose metabolism and adipokine levels in non-diabetic patients with dyslipidaemia: a prospective randomised open-label study

Aims: The impact of statins on glucose metabolism and adipokines remains controversial. We compared the effects of rosuvastatin and atorvastatin on glucose homeostasis, insulin sensitivity (IS), adiponectin and leptin levels as well as systemic inflammation in non‐diabetic patients with dyslipidaemia. Methods: Thirty‐six patients were randomly assigned to 10 mg/day of rosuvastatin (n = 18) or 20 mg/day of atorvastatin (n = 18) for 12 weeks. Total cholesterol (TC), low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), non‐HDL‐C, triglycerides (TG), fasting plasma glucose, insulin, homeostasis model assessment‐insulin resistance (HOMA‐IR), quantitative IS check index (QUICKI), adiponectin, leptin and high‐sensitivity C‐reactive protein (hsCRP) were measured at baseline and after 4 and 12 weeks. Results: Both statins significantly lowered TC, LDL‐C, non‐HDL‐C and TG compared with baseline. Only rosuvastatin caused a significant reduction in insulin and HOMA‐IR levels (?35%, p = 0.005 and ?33%, p = 0.011 respectively) and a significant increase in QUICKI (+11%, p = 0.003) at 12 weeks. In terms of adipokines and hsCRP, no difference was observed after 4 and 12 weeks of treatment with either statin. Conclusions: Rosuvastatin compared with atorvastatin resulted in significant improvements in IS indices. No significant changes in adiponectin, leptin or hsCRP levels were observed at 4 and 12 weeks of treatment with either statin.     

Switching from statin monotherapy to ezetimibe/simvastatin or rosuvastatin modifies the relationships between apolipoprotein B, LDL cholesterol, and non-HDL cholesterol in patients at high risk of coronary disease

ObjectiveTo evaluate relationships between apolipoprotein B (Apo B), LDL cholesterol (LDL-C), and non-HDL-C in high-risk patients treated with lipid-lowering therapy.Design and methodsThis post-hoc analysis calculated LDL-C and non-HDL-C levels corresponding to an Apo B of 0.9 g/L following treatment with 1) statin monotherapy (baseline) and 2) ezetimibe/simvastatin 10/20 mg or rosuvastatin 10 mg (study end). The percentages of patients reaching LDL-C, non-HDL-C, and Apo B targets were calculated at study end.ResultsAfter switching to ezetimibe/simvastatin or rosuvastatin, the LDL-C and non-HDL-C corresponding to Apo B = 0.9 g/L were closer to the more aggressive LDL-C and non-HDL-C goals (1.81 and 2.59 mmol/L, respectively). Only slightly > 50% of the patients who reached minimum recommended LDL-C or non-HDL-C at study end also had an Apo B level < 0.9 g/L with both treatments.ConclusionThe use of Apo B for monitoring the efficacy of lipid-altering therapy would likely lead to more stringent criteria for lipid lowering.     

A Phase III,Multicenter, Randomized,Double-blind,Active Comparator Clinical Trial to Compare the Efficacy and Safety of Combination Therapy With Ezetimibe and Rosuvastatin Versus Rosuvastatin Monotherapy in Patients With Hypercholesterolemia: I-ROSETTE (Ildong Rosuvastatin & Ezetimibe for Hypercholesterolemia) Randomized Controlled Trial

Purpose

Combination therapy with ezetimibe and statins is recommended in cases of statin intolerance or insufficiency. The objective of this study was to compare the efficacy and safety of combination therapy with ezetimibe and rosuvastatin versus those of rosuvastatin monotherapy in patients with hypercholesterolemia.

Effects of simvastatin, atorvastatin, ezetimibe, and ezetimibe + simvastatin combination on the inflammatory process and on the liver metabolic changes of arthritic rats

In this study, simvastatin, atorvastatin, ezetimibe, and ezetimibe + simvastatin combination were administered to arthritic rats, first to determine their effects on the inflammatory response, employing a low‐dose adjuvant‐induced arthritis model in rats. Arthritis was induced by the subcutaneous injection of a suspension of Mycobacterium tuberculosis (100 μg) in mineral oil [complete Freund’s adjuvant used (CFA)] into the plantar surface of the hind paws. Simvastatin_40mg/kg, atorvastatin_10mg/kg, ezetimibe_10mg/kg, ezetimibe_10mg/kg + simvastatin_{20mg/kg or 40mg/kg} were given intragastrically and the treatment began on the day of CFA injection and continued daily up to the 28th day after arthritis induction. The ezetimibe + simvastatin combination was more effective in reducing the inflammatory response in arthritic rats than in atorvastatin, simvastatin, or ezetimibe monotherapy. The observed effect seems to be cholesterol‐independent as there were no changes in plasma cholesterol levels. In spite of the benefits on joint lesions, treatment with ezetimibe + simvastatin combination caused a marked increment in liver, kidneys, spleen size, and plasma transaminases activities. Therefore, animals treated with the ezetimibe_10mg/kg + simvastatin_40mg/kg combination were also submitted to liver perfusion experiments. In this regard, ezetimibe + simvastatin did not improve the liver metabolic alterations seen in control arthritic rats, on the contrary, a worsening was observed in liver production of glucose from alanine, as well as in oxygen uptake. All of these metabolic changes appear to be induced by treatment with ezetimibe + simvastatin combination, as the same metabolic effects were observed in normal and treated arthritic animals.