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.     

Ezetimibe and Rosuvastatin Combination Treatment Can Reduce the Dose of Rosuvastatin Without Compromising Its Lipid-lowering Efficacy

PurposeThe goal of this study was to compare the lipid-lowering efficacy of the combination of ezetimibe and low- or intermediate-intensity statin therapy versus that of high-intensity statin monotherapy.MethodsThis study is a post hoc analysis of an 8-week, randomized, double-blind, Phase III trial. Patients who had hypercholesterolemia and required lipid-lowering treatment were randomly assigned to 1 of 6 treatment groups: rosuvastatin 5 mg (R5, n = 68), rosuvastatin 10 mg (R10, n = 67), rosuvastatin 20 mg (R20, n = 69), and ezetimibe 10 mg combined with rosuvastatin 5 mg (R5 + E10, n = 67), rosuvastatin 10 mg (R10 + E10, n = 68), and rosuvastatin 20 mg (R20 + E10, n = 68) daily. The effects of coadministration of ezetimibe and a low dose of rosuvastatin on lipid parameters and the target achievement rate were compared between the R5 + E10 and R10 treatment groups, the R5 + E10 and R20 treatment groups, and the R10 + E10 and R20 treatment groups.FindingsReductions in total cholesterol, LDL-C, apolipoprotein B, the apolipoprotein B/A1 ratio, and non–HDL-C were not different between the R5 + E10 and R10 treatment groups (all, P > 0.017), the R5 + E10 and R20 treatment groups (all, P > 0.017), and the R10 + E10 and R20 treatment groups (all, P > 0.017). R5 + E10 treatment showed efficacy comparable to that of R10 or R20 in affording LDL levels <50% of the baseline level (R5 + E10 vs R10, 73.13% vs 62.69% [P = 0.1952]; R5 + E10 vs R20, 73.13% vs 73.91% [P = 0.9180]), LDL-C levels <70 mg/dL (R5 + E10 vs R10, 64.18% vs 55.22% [P = 0.2906]; R5 + E10 vs R20, 64.18% vs 62.32% [P = 0.8220]), and LDL-C levels <50% of the baseline level or <70 mg/dL (R5 + E10 vs R10, 77.61% vs 70.15% [P = 0.3255]; R5 + E10 vs R20, 77.61% vs 78.26% [P = 0.9273]). The R10 + E10 treatment group was better than the R20 treatment group in achieving the target LDL-C level <70 mg/dL (83.82% vs 62.32%; P = 0.0046), even among participants with a baseline LDL-C level >135 mg/dL (77.5% vs 48.8%, respectively; P = 0.0074).ImplicationsEzetimibe combined with low- or intermediate-intensity statin therapy has lipid-lowering efficacy comparable to or better than that of high-intensity rosuvastatin monotherapy. The results of the present study indicate that the combination treatment with ezetimibe is advantageous in that it permits dose reduction of rosuvastatin without compromising the lipid-lowering efficacy of rosuvastatin. ClinicalTrials.gov identifier: NCT02205606.     

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.

Combination Therapy of Rosuvastatin and Ezetimibe in Patients with High Cardiovascular Risk

Purpose

The aim of this study was to evaluate the efficacy and tolerability of rosuvastatin/ezetimibe combination therapy in Korean patients with high cardiovascular risk.

Efficacy and Safety of Ezetimibe and Rosuvastatin Combination Therapy Versus Those of Rosuvastatin Monotherapy in Patients With Primary Hypercholesterolemia

Purpose

The aim of this study was to evaluate the safety and efficacy of combination treatment of rosuvastatin with ezetimibe in patients with primary hypercholesterolemia.

Effects of ezetimibe/simvastatin on lipoprotein subfractions in patients with primary hypercholesterolemia: an exploratory analysis of archived samples using two commercially available techniques

BACKGROUND: Cholesterol-rich lipoproteins, including low-density lipoprotein cholesterol (LDL-C), intermediate-density lipoprotein cholesterol (IDL-C), and very-low-density lipoprotein cholesterol (VLDL-C), are known to promote atherosclerosis. Ezetimibe/simvastatin (E/S) is an efficacious lipid-lowering treatment that inhibits both the intestinal absorption and biosynthesis of cholesterol. OBJECTIVE: The aim of the current analysis was to compare the effects of ezetimibe and simvastatin monotherapy and E/S treatment on lipoprotein subfractions and LDL particle size in patients with primary hypercholesterolemia. METHODS: This was an exploratory (hypothesis generating) analysis of archived plasma samples drawn from patients in a multicenter, randomized, double-blind, placebo-controlled, parallel-arm study. After a washout and diet/placebo run-in, patients with hypercholesterolemia (LDL-C, > or =145- < or =250 mg/dL; triglycerides, < or =350 mg/dL) were randomized equally to 1 of 10 daily treatments for 12 weeks: E/S (10/10, 10/20, 10/40, or 10/80 mg), simvastatin monotherapy (10, 20, 40, or 80 mg), ezetimibe monotherapy (10 mg), or placebo. A subset of patients had lipid subfraction measurements taken at baseline (week 0) and postrandomization (week 12). Plasma samples were used to quantify cholesterol associated with VLDL subfractions (VLDLI+2 and VLDL3), IDL, and 4 LDL subfractions (LDL1-4) via the Vertical Auto Profile II method. LDL-C particle size was determined using segmented gradient gel electrophoresis. The primary end point was median percent change in subfraction cholesterol for E/S versus ezetimibe or simvastatin monotherapy, pooled across doses. RESULTS: Of the 1528 patients randomized in the original study, 1397 (91%) had lipid subfraction measurements taken. E/S was associated with significant reductions in VLDL-CI+2, VLDL-C3, IDL-C, LDL-C1, LDL-C2, and LDL-C3 versus ezetimibe, simvastatin, and placebo. E/S resulted in near-additive reductions in VLDL-CI+2, VLDL-C3, IDL-C, LDL-C1, LDL-C2, and LDL-C3 versus ezetimibe and simvastatin monotherapy. Of the subfractions examined, with regard to E/S, the greatest reductions were observed in IDL-C and LDL-C1, LDL-C2, and LDL-C3. When compared with placebo, ezetimibe, simvastatin, and E/S did not shift the distribution of LDL particles toward a larger, more buoyant LDL subclass pattern. CONCLUSION: E/S was more effective than ezetimibe and simvastatin monotherapy in reducing atherogenic lipoprotein subfractions in these patients with primary hypercholesterolemia.     

Incremental cholesterol reduction with ezetimibe/simvastatin,atorvastatin and rosuvastatin in UK General Practice (IN‐PRACTICE): randomised controlled trial of achievement of Joint British Societies (JBS‐2) cholesterol targets

Aim: The aim of this study was to compare ezetimibe/simvastatin combination therapy with intensified statin monotherapy as alternative treatment strategies to achieve the Joint British Societies (JBS)‐2 and National Institute for Health and Clinical Excellence low‐density‐lipoprotein cholesterol (LDL‐C) target of < 2 mmol/l for secondary prevention or JBS‐2 LDL‐C target of < 2 mmol/l for primary prevention in high‐risk patients who have failed to reach target with simvastatin 40 mg. Methods: This is a prospective, double‐blind study conducted in 34 UK primary care centres; 1748 patients with established cardiovascular disease (CVD), diabetes or high risk of CVD who had been taking simvastatin 40 mg for ≥ 6 weeks were screened and 786 (45%) with fasting LDL‐C ≥ 2.0 mmol/l (and < 4.2 mmol/l) at screening and after a further 6‐week run‐in period on simvastatin 40 mg were randomised to ezetimibe/simvastatin 10/40 mg (as a combination tablet; n = 261), atorvastatin 40 mg (n = 263) or rosuvastatin 5 mg (n = 73) or 10 mg (n = 189) once daily for 6 weeks. Rosuvastatin dose was based on UK prescribing instructions. The primary outcome measure was the proportion of patients achieving LDL‐C < 2 mmol/l at the end of the study. Results: The percentage of patients (adjusted for baseline differences) achieving LDL‐C < 2 mmol/l was 69.4% with ezetimibe/simvastatin 10/40 mg, compared with 33.5% for atorvastatin 40 mg [odds ratio 4.5 (95% CI: 3.0–6.8); p < 0.001] and 14.3% for rosuvastatin 5 or 10 mg [odds ratio 13.6 (95% CI: 8.6–21.6); p < 0.001]. Similar results were observed for achievement of total cholesterol < 4.0 mmol/l. All study treatments were well tolerated. Conclusion: Approximately 45% of patients screened had not achieved LDL‐C < 2 mmol/l after ≥ 12 weeks of treatment with simvastatin 40 mg. In this group, treatment with ezetimibe/simvastatin 10/40 mg achieved target LDL‐C levels in a significantly higher proportion of patients during a 6‐week period than switching to either atorvastatin 40 mg or rosuvastatin 5–10 mg.     

瑞舒伐他汀联合依折麦布对老年急性脑梗的降脂效果与安全性研究

【目的】研究瑞舒伐他汀联合依折麦布对老年急性脑梗死血脂未达标患者的降脂效果和安全性。【方法】入选89例急性脑梗死患者,A 组46例给予瑞舒伐他汀（10 mg／d）联合依折麦布（10 mg／d）治疗,B 组43例给予瑞舒伐他汀（10 mg／d）治疗,治疗2周及12周后观察两组患者血脂水平及肝功能,肌酶变化并进行比较。【结果】治疗2周后两组患者低密度脂蛋白胆固醇（LDL‐C）平均下降比例分别为32．7％和17．3％;而治疗12周后平均下降比例分别为48．4％和27．2％,组间比较 A组下降较 B 组更早更快,差异有显著统计学意义（均 P ＜0．001）,且和 B 组相比肝功能,肌酶等无变化,治疗12周后 A 组达标率56．5％（26例）,B 达标率20．9％（9例）,差异有显著统计学意义（ P ＝0．002）。治疗12周后总胆固醇（TC）下降约45％和28％,与 B 组比较差异有显著统计学意义（ P ＝0．003）。治疗12周后三酰甘油（TG）下降,而高密度脂蛋白胆固醇（HDL‐C）升高,但与治疗前比较均无统计学意义。【结论】瑞舒伐他汀联合依折麦布对老年急性脑梗死患者不增加肝毒性和肌毒性且能使 LDL‐C 达标时间缩短,达标率升高。     

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.     

Effect of rosuvastatin monotherapy or in combination with fenofibrate or ω-3 fatty acids on lipoprotein subfraction profile in patients with mixed dyslipidaemia and metabolic syndrome

Background: Raised triglycerides (TG), decreased high‐density lipoprotein cholesterol (HDL‐C) levels and a predominance of small dense low density lipoproteins (sdLDL) are characteristics of the metabolic syndrome (MetS). Objective: To compare the effect of high‐dose rosuvastatin monotherapy with moderate dosing combined with fenofibrate or ω‐3 fatty acids on the lipoprotein subfraction profile in patients with mixed dyslipidaemia and MetS. Methods: We previously randomised patients with low‐density lipoprotein cholesterol (LDL‐C) > 160 and TG > 200 mg/dl to rosuvastatin monotherapy 40 mg/day (R group, n = 30) or rosuvastatin 10 mg/day combined with fenofibrate 200 mg/day (RF group, n = 30) or ω‐3 fatty acids 2 g/day (Rω group, n = 30). In the present study, only patients with MetS were included (24, 23 and 24 in the R, RF and Rω groups respectively). At baseline and after 12 weeks of treatment, the lipoprotein subfraction profile was determined by polyacrylamide 3% gel electrophoresis. Results: The mean LDL size was significantly increased in all groups. This change was more prominent with RF than with other treatments in parallel with its greater hypotriglyceridemic capacity (p < 0.05 compared with R and Rω). A decrease in insulin resistance by RF was also noted. Only RF significantly raised HDL‐C levels (by 7.7%, p < 0.05) by increasing the cholesterol of small HDL particles. The cholesterol of larger HDL subclasses was significantly increased by R and Rω. Conclusions: All regimens increased mean LDL size; RF was the most effective. A differential effect of treatments was noted on the HDL subfraction profile.     

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 Paradigm Shift in Dyslipidemia Management in Primary Care: A 12-Month Cohort Study

PurposeLDL-lowering therapy is beneficial to reduce the risk of cardiovascular disease (CVD). Higher statin doses lower LDL-C levels and prevent CVD; however, they increase adverse events, such as muscle-related adverse events and new-onset diabetes mellitus (DM). Ezetimibe combined with statin therapy improves LDL-C–lowering levels and tolerability in patients with established CVD. We aimed to analyze the efficacy and safety of a fixed-dose rosuvastatin and ezetimibe (R+E) combination therapy in intermediate-risk patients with hypercholesterolemia and no DM after 12 months of visiting a primary physician.MethodsThis multicenter, open-label, single-arm, prospective observational study involved 5717 patients from 258 primary health care centers in Korea enrolled between 2016 and 2018. Patients had no DM or previous CVD but had cardiovascular risk factors and were taking a statin or a fixed-dose combination of E (10 mg) + R (5, 10, or 20 mg). We analyzed 700 patients using propensity score matching.FindingsA fixed-dose R+E combination therapy significantly reduced LDL-C in 5/10 mg R+E (29.35%), 10/10 mg R+E (36.19%), and 20/10 mg R+E (41.83%) compared with statin monotherapy (19.09%) at 12-month follow-up (P = 0.017). Compared with statin monotherapy, HDL-C levels increased in 5/10 mg R+E (mean change at 12 months; P = 0.004), and triglyceride levels decreased in 10/10 mg R+E (mean change at 12 months; P = 0.033). The fixed-dose R+E combination therapy was associated with fewer adverse events and a neutral effect on glucose deterioration compared with statin monotherapy at 12 months of follow-up.ImplicationsIn a possible paradigm shift, a fixed-dose R+E combination therapy may be beneficial for primary cardiovascular prevention with potent LDL-lowering efficacy and tolerability; however, further large prospective studies are needed.     

Effect of 1PC111, a Fixed-dose Combination of Pitavastatin and Ezetimibe,Versus Pitavastatin or Ezetimibe Monotherapy on Lipid Profiles in Patients With Hypercholesterolemia or Mixed Dyslipidemia: A Randomized,Double-blind,Multicenter, Phase III Study

PurposeThis study aimed to show that the efficacy of 1PC111 is superior to that of either ezetimibe or pitavastatin alone (monotherapy) for the treatment of hypercholesterolemia.MethodsThis was a multicenter, randomized, double-blind, Phase III study. Patients with hypercholesterolemia or mixed dyslipidemia were randomized to receive 1PC111 (which was a fixed-dose combination of pitavastatin 2 mg and ezetimibe 10 mg), pitavastatin 2 mg, or ezetimibe 10 mg daily for 12 weeks. The primary end point was the difference in the percent change in LDL-C from baseline to week 12 between the 1PC111 and each monotherapy group. The secondary end points were the percent change in other lipid profiles from baseline to each visit. All patients were assessed for adverse events until end of study.FindingsA total of 388 patients were randomly assigned to the 1PC111 (n = 128), pitavastatin (n = 132), or ezetimibe (n = 128) group. Generally, baseline characteristics were similar among the 3 groups. A statistically significant decrease in the LDL-C level at week 12 was observed in the 1PC111 group (–50.50% [14.9%]) compared with either the pitavastatin (–36.11% [11.4%]; P < 0.001) or ezetimibe (–19.85% [12.4%]; P < 0.001) group. Also, there was a statistically significant difference between 1PC111 and each monotherapy group in the reduction in total cholesterol, non–HDL-C, and apolipoprotein B levels. Moreover, there was a trend toward more efficient lowering of LDL-C levels in elderly patients (age ≥65 years) than in younger patients (age <65 years) by 1PC111 treatment. In patients given a class I recommendation for atherosclerotic cardiovascular disease prevention, the percentage of patients achieving the LDL-C target of <100 mg/dL at week 12 was significantly higher in the 1PC111 group than in both monotherapy groups (P < 0.001). Overall, the incidence of adverse events was similar among 3 groups.Implications1PC111 was more effective in improving lipid profiles and achieving the LDL-C goal than pitavastatin or ezetimibe alone for hypercholesterolemia treatment. Furthermore, 1PC111 may provide more benefit in treating elderly patients. ClinicalTrials.gov identifier: NCT04643093.     

Rosuvastatin 5 and 10 mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies

BACKGROUND: Patients with high levels of low-density lipoprotein cholesterol (LDL-C) might not tolerate 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") because of adverse effects (AEs) and might not respond well enough to nonstatin lipid-lowering therapies (LLTs) to meet LDL-C goals. OBJECTIVE: The purpose of this study was to assess the acceptability, effectiveness, and safety profile of rosuvastatin 5 and 10 mg/d in consecutively referred patients with primary high LDL-C who were unable to tolerate other statins because of myalgia and, subsequently in some cases, unable to reach LDL-C goals with nonstatin LLT. METHODS: This prospective, open-label pilot study was conducted in consecutively referred male and female patients aged 38 to 80 years with primary high LDL-C (mean, 177 mg/dL) at The Cholesterol Center, Jewish Hospital, Cincinnati, Ohio. Patients were instructed in the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) therapeutic lifestyle changes diet. Rosuvastatin 5 mg/d was administered to patients categorized by NCEP ATP III risk stratification as moderately high risk, and rosuvastatin 10 mg/d was administered to patients categorized as high or very high risk. End points included acceptability (assessed using patient-initiated discontinuation of rosuvastatin), effectiveness (absolute and percentage reductions in LDL-C and triglycerides), and safety profile (aspartate and alanine aminotransferases [AST and ALT, respectively] >3 times the laboratory upper limit of normal [xULN] or elevations in creatine kinase [CK]>10xULN). RESULTS: A total of 61 patients were enrolled (41 women, 20 men; mean [SD] age, 60 [10] years; 5-mg/d dose, 25 patients; 10-mg/d dose, 36 patients). Myalgia, a predominant AE, had caused 50 patients to previously discontinue treatment with atorvastatin; 30, simvastatin; 19, pravastatin; 5, fluvastatin; 2, ezetimibe/simvastatin; and 1, lovastatin. Eighteen patients subsequently failed to reach LDL-C goals with nonstatin LLT(s) alone (colesevelam, 10 patients; ezetimibe, 8; niacin extended release, 2; and fenofibrate, 1). After a median treatment duration of 16 weeks, rosuvastatin 5 mg/d+diet was associated with a mean (SD) decrease from baseline in LDL-C of 75 (34) mg/dL (mean [SD] %Delta, -42% [18%]) (P<0.001 vs baseline). After a median treatment duration of 44 weeks, rosuvastatin 10 mg/d+diet was associated with a mean (SD) decrease from baseline in LDL-C of 79 (49) mg/dL (mean [SD] %Delta, -42% [24%]) (P<0.001 vs baseline). Of the 61 patients, 1 receiving the 10-mg/d dose discontinued rosuvastatin treatment because of unilateral muscular pain after 4 weeks; no AST or ALT levels were >3xULN, and no CK levels were >10xULN. CONCLUSION: In these 61 hypercholesterolemic patients unable to tolerate other statins and, subsequently in some cases, unable to meet LDL-C goals while receiving nonstatin LIT monotherapy, these preliminary observations suggest that rosuvastatin at doses of 5 and 10 mg/d+diet was well tolerated, effective, and had a good safety profile.     

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.     

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.     

Effects of fluvastatin extended-release (80 mg) alone and in combination with ezetimibe (10 mg) on low-density lipoprotein cholesterol and inflammatory parameters in patients with primary hypercholesterolemia: a 12-week, multicenter, randomized, open-label, parallel-group study

Background: Combining lipid-lowering agents with complementary mechanisms of action can provide greater cholesterol reductions than using either agent alone, improving achievement of target low-density lipoprotein cholesterol (LDL-C) levels. Objectives: The aim of this study was to assess the effects of fluvastatin extended-release (XL) 80 mg/d administered alone or combined with ezetimibe 10 mg/d on plasma lipid levels and inflammatory parameters in patients with primary hypercholesterolemia. The tol-erability of both regimens was also evaluated. Methods: In this multicenter, randomized, open-label, parallel-group study, patients with hypercholesterolemia were randomized in a 1:1 ratio to receive fluvastatin XL 80 mg/d alone or in combination with ezetimibe 10 mg/d for 12 weeks. The primary end point was the percentage change from baseline to week 12 in LDL-C level with fluvastatin XL + ezetimibe combination therapy compared with fluvastatin XL alone. Plasma concentrations of inflammatory biomarkers were measured at baseline and week 12. Proportions of patients who achieved National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) LDL-C goals were calculated. Tolerability was assessed by the monitoring and recording of all adverse events (AEs) and laboratory values. Results: A total of 82 patients were enrolled (mean [SD] age, 50.0 [12.0] years; 44% male; 100% white; mean [SD] weight, 73.5 [14.9] kg; combination group, 38 patients; monotherapy group, 44). Fluvastatin XL + ezetimibe and fluvastatin XL monotherapy were associated with significant decreases from baseline in mean LDL-C level (by 49.9% and 35.2%, respectively; between-group difference, P < 0.001). Fluvastatin XL + ezetimibe was associated with significantly greater reductions from baseline than fluvastatin XL monotherapy in total cholesterol (38.2% vs 27.5% P < 0.001), triglycerides (21% vs 3.8% P = 0.02) and apolipoprotein B (34.8% vs 22.5% P < 0.001). NCEP ATP III LDL-C goals were achieved by 87% of patients receiving fluvastatin XL + ezetimibe and 67% of patients receiving fluvastatin XL monotherapy (between-group difference, P = 0.042). The combination was associated with significantly lowered high-sensitivity C-reactive protein (hs-CRP) levels in patients with high baseline hs-CRP (>2 mg/L; P < 0.02), >1 cardiovascular risk factor (P < 0.05), or hypertension (P = 0.015); both regimens were associated with significantly reduced plasma levels of interleukin-1B. No significant between-group differences in the incidences of AEs were found. Most AEs were mild or moderate in intensity. Headache was the most common AE, occurring in 5/44 (11.4%) patients in the fluvastatin XL group and 2/38 (5.3%) patients in the fluvastatin XL + ezetimibe group. One serious AE (convulsive crisis) occurred in a patient receiving fluvastatin XL + ezetimibe, but was not suspected to be related to study medication. Conclusion: Fluvastatin XL in combination with ezetimibe was found to be well-tolerated and effective, allowing the majority (87%) of these patients with primary hypercholesterolemia to achieve current treatment goals, and reduced hs-CRP levels in patients at higher cardiovascular risk.     

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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.     

Efficacy and safety of ezetimibe coadministered with statins: randomised, placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia

We assessed pooled safety and lipid-regulating efficacy data from four similarly designed trials of ezetimibe coadministered with statins in 2382 patients with primary hypercholesterolemia. Patients were randomised to one of the following double-blind treatments for 12 weeks: placebo; ezetimibe 10 mg; statin; or statin + ezetimibe. Statin doses tested were 10, 20, 40 mg/day (atorvastatin, simvastatin, pravastatin or lovastatin) or 80 mg/day (atorvastatin, simvastatin). Treatment with ezetimibe + statin led to significantly greater reductions in low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and increases in HDL-C, compared to statin alone. At each statin dose, treatment with ezetimibe + statin led to a greater LDL-C reduction compared to the next highest statin monotherapy dose. Ezetimibe + statin had a safety profile similar to statin monotherapy. Coadministration of ezetimibe + statin offers a well-tolerated, highly efficacious new treatment strategy for patients with hypercholesterolemia.     

Rosuvastatin in the management of hyperlipidemia

BACKGROUND: Rosuvastatin is a new statin indicated to reduce elevated levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides and to increase levels of high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia, mixed dyslipidemia, and homozygous familial hypercholesterolemia. OBJECTIVE: The purpose of this article was to review the pharmacology, clinical efficacy, and tolerability of rosuvastatin as monotherapy and combination therapy for patients with hyperlipidemia. METHODS: A literature review was conducted using the search term rosuvastatin to identify English-language peer-reviewed articles and abstracts in the MEDLINE and Current Contents databases (both 1966 to March 2004). Citations from available articles were reviewed for additional references, and selected information from the manufacturer was discussed. RESULTS: Rosuvastatin 10 to 40 mg/d reduced LDL-C by 43% to 63% (P < 0.05). Compared with other statins, rosuvastatin had the highest dose-to-dose potency in lowering LDL-C (reduction of 60% vs 50% with atorvastatin, 40% with simvastatin, 30% with pravastatin or lovastatin, and 20% with fluvastatin) and better efficacy in raising HDL-C (increase of approximately 10% vs approximately 5% with other statins; P < 0.05). Rosuvastatin enabled significantly more patients to achieve the National Cholesterol Education Program (NCEP) goals for LDL-C with lower doses (P < 0.05). Rosuvastatin was well tolerated. Incidences of myopathy and liver function test abnormalities were rare and comparable to those of other statins. Because it is not metabolized by the cytochrome P-450 enzymes, rosuvastatin had fewer clinically significant drug interactions compared with other statins. Studies to assess the effect of rosuvastatin on cardiovascular outcomes are ongoing. CONCLUSIONS: Clinical studies continue to demonstrate that achieving optimal levels of LDL-C is an important goal in reducing cardiovascular events. Recent evidence suggests the need for an even lower LDL-C goal than that being recommended by the NCEP Based on the studies included in this review, rosuvastatin may help patients achieve optimal goals early with lower dosages, thus reducing the need for dose titration or combination therapy.