Lipid-altering efficacy of switching from atorvastatin 10 mg/day to ezetimibe/simvastatin 10/20 mg/day compared to doubling the dose of atorvastatin in hypercholesterolaemic patients with atherosclerosis or coronary heart disease

This randomised, double-blind study evaluated the efficacy and safety of ezetimibe/simvastatin (EZE/SIMVA) 10/20 mg tablet compared to doubling the atorvastatin (ATV) dose in hypercholesterolaemic patients with atherosclerotic or coronary heart disease (CHD). The study group included 435 male and female CHD patients (aged >or=18 years) who had not achieved their low-density lipoprotein cholesterol (LDL-C) goal of <2.50 mmol/l while on a stable dose of ATV 10 mg for >or=6 weeks. After a 1-week diet/stabilisation period, patients with LDL-C >or=2.50 mmol/l and 相似文献   

瑞舒伐他汀联合依折麦布治疗冠心病伴早期糖尿病肾病疗效观察

目的：本研究通过瑞舒伐他汀联合依折麦布治疗冠心病伴早期糖尿病肾病,以寻找冠心病伴早期糖尿病肾病更好的治疗方法,预防急性心血管事件及终末期肾病的发生。方法选择2013年7月至2014年1月河北省老年病医院明确诊断为血糖控制良好的稳定型心绞痛合并早期糖尿病肾病患者80例。男42例,女38例;年龄60岁以上,相互之间无血缘关系。随机分为治疗组和对照组,每组40例。对照组在常规治疗基础上加服瑞舒伐他汀10 mg/ d。治疗组在常规治疗基础上加服瑞舒伐他汀10 mg/ d 和依折麦布10 mg/ d。结果治疗12周后 LDL 在治疗组较对照组下降更明显（ P <0.01）。对照组心绞痛发作时间较治疗前明显缩短,心绞痛发作次数较治疗前明显减轻（ P <0.05）。治疗12周时,心绞痛发作次数在治疗组降低更加明显,2组差异有统计学意义（ P <0.05）;治疗组和对照组 UAER 水平较治疗前均有显著下降（ P <0.01）,治疗组 UAER 较对照组下降更为显著,差异有统计学意义（P <0.05）;2组治疗前后肌酐、肌酸激酶、丙氨酸氨基转移酶、天门冬氨酸氨基转移酶变化差异无统计学意义（ P >0.05）。结论联合应用瑞舒伐他汀和依折麦布治疗冠心病伴早期糖尿病肾病,可以明显减少心绞痛的发作次数和持续时间,促进心肌缺血改善的同时减少尿微量蛋白尿,可以更有效的降低 LDL 及 TC、提高血脂高达标率,没有增加不良反应事件,体现了良好的安全性。     

Evaluating the safety of Liptruzet (ezetimibe and atorvastatin): what are the potential benefits beyond low-density lipoprotein cholesterol-lowering effect?

Introduction: The combination of ezetimibe and atorvastatin (Liptruzet – referred to in this article as eze/ator), has recently been approved by the FDA for reducing low-density lipoprotein cholesterol (LDL-c) in patients with primary or mixed hyperlipidemia as in case of homozygous familial hypercholesterolemia. It helps block intestinal absorption of cholesterol and it inhibits the production of cholesterol in the liver.

Areas covered:The safety and effectiveness of the eze/ator combination as treatment of hyperlipidemia. Medline was searched for atorvastatin and/or ezetimibe.

Expert opinion:The combination of (eze/ator) is proven to be effective in lowering LDL-c. It is not only a safe and effective treatment of hyperlipidemia, but it also reduces inflammatory markers and atherosclerosis. It is not yet clear, however, whether the combination therapy can decrease the risk of diabetes associated with statin administration. Insulin sensitivity is improved by the single administration of ezetimibe, a finding that is documented by several clinical and animal studies. More specifically, ezetimibe has been shown to decrease insulin resistance associated with nonalcoholic fatty liver disease (NAFLD). The effects of combination therapy that have to be explored in future research and clinical trials include whether this combination can be used in the treatment of NAFLD, cholesterol gallstones and portal hypertension.     

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.

Long-term efficacy and safety of ezetimibe/simvastatin coadministered with extended-release niacin in hyperlipidaemic patients with diabetes or metabolic syndrome

Aims: To assess the efficacy and safety of ezetimibe/simvastatin (E/S) plus extended‐release niacin (N) in hyperlipidaemic patients with diabetes mellitus (DM), metabolic syndrome (MetS) without DM (MetS/non‐DM) or neither (non‐DM/non‐MetS). Methods: A subgroup analysis of a double‐blind, 64‐week trial of 1220 randomized patients who received E/S (10/20 mg) + N (to 2 g) or E/S (10/20 mg) for 64 weeks, or N (to 2 g) for 24 weeks then E/S (10/20 mg) + N (2 g) or E/S (10/20 mg) for 40 additional weeks. The evaluable populations of this analysis included n = 765 patients at 24 weeks and n = 574 at 64 weeks. Among those receiving N, only those who attained the 2‐g dose were included in the analysis. Results: E/S+N improved levels of low‐density lipoprotein cholesterol, other lipids and lipoprotein ratios compared with N and E/S at 24 weeks and E/S at 64 weeks. The combination increased high‐density lipoprotein cholesterol and apolipoprotein AI comparably to N and more than E/S. E/S+N reduced high‐sensitivity C‐reactive protein (hsCRP) levels more effectively than N and similarly to E/S. E/S+N was generally well tolerated. Discontinuations due to flushing with N and E/S+N were comparable and greater than E/S in all subgroups. Fasting glucose trended higher for N vs. E/S. Glucose elevations from baseline to 12 weeks were highest for patients with DM (24.9 mg/dl for N, 21.2 mg/dl for E/S+N, 17.5 mg/dl for E/S); fasting glucose then declined to pretreatment levels at 64 weeks in all subgroups. New‐onset DM was more frequent among MetS patients than those without MetS during the first 24 weeks and trended higher among those assigned to N‐containing regimens [n = 5(5.1%) for N, n = 2(1.7%) for E/S, n = 21(8.8%) for E/S+N]; during 24–64 weeks, diabetes was diagnosed in five additional patients in the E/S (cumulative incidence of 5.9%) and one in the E/S+N (cumulative incidence of 9.2%) groups. Treatment‐incident elevations in uric acid levels were increased among subjects assigned to N‐containing regimens, but there were no effects on symptomatic gout. Conclusion: Combination E/S+N is a safe treatment option for hyperlipidaemic patients including those with DM and MetS, but requires monitoring of glucose and potentially uric acid levels.     

Safety review of combination drugs for hyperlipidemia

Introduction: Despite statin monotherapy, many high-risk patients are not at recommended low-density lipoprotein cholesterol goals. Moreover, these patients are also likely to exhibit an atherogenic dyslipidemia characterized by decreased high-density lipoprotein cholesterol and elevated triglycerides. As a consequence, combination lipid-altering drug therapies are frequently required to improve the lipid profile. The long-term safety and tolerability of these combination therapies are key determinants for good compliance and cardiovascular benefits.

Areas covered: This review summarizes the safety data published on combination drugs for the treatment of hyperlipidemia by examining the various combinations with a statin and also the other combination therapies used when statin treatment is not tolerated. The reader will gain insight into the incidence and severity of the major adverse events expected with combination therapies and the recommendations on the use of these combined treatments. A specific focus is made on muscle-related side effects.

Expert opinion: The existing data suggest that ezetimibe, bile acid sequestrants and ω-3 fatty acids appear unlikely to increase the risk of adverse events, particularly myopathy, when used in combination with a statin, even with a high-dose statin. Although the combination of niacin or fenofibrate with moderate-dose statins appears to be safe, prescribing a combination of these drugs with high-dose statins needs caution and requires giving careful information to the patient.     

Ezetimibe effectively lowers LDL-cholesterol in cardiac allograft recipients on stable statin therapy

We investigated tolerability and efficacy of ezetimibe treatment (10 mg/d) in 25 heart allograft recipients already on stable statin therapy. Total cholesterol (TC), low-density cholesterol (LDL-C), high-density cholesterol (HDL-C), triglycerides (TG), immunosuppressant drug levels, laboratory and clinical parameters were assessed before, four months and one yr after initiation of ezetimibe treatment. Mean equivalent statin dose was 53.5 +/- 12.3 mg of pravastatin, remaining unchanged throughout the study period. Ezetimibe was generally well tolerated, only two patients (8%) discontinued ezetimibe due to stomach pain or headache. Mean TC decreased from 231.8 +/- 6.4 mg/dL before therapy to 202.2 +/- 8.8 mg/dL after four months and 192.9 +/- 7.0 mg/dL after one yr (p < 0.001). Mean LDL-C decreased from 143.1 +/- 5.4 mg/dL to 121.4 +/- 7.9 mg/dL (month 4; p < 0.05) and 107.1 +/- 5.6 mg/dL (one yr; p < 0.001). TG decreased from 182 +/- 14.3 mg/dL to 173.3 +/- 17.5 mg/dL after one yr (p < 0.05), whereas HDL-C was unchanged. Initial LDL-C and cardiac diagnosis before transplantation were identified as predictors of absolute LDL-C reduction. Immunosuppressant drug doses and blood concentrations were unchanged as well as other laboratory and clinical parameters. Ezetimibe appears safe and effective for further reduction of TC and LDL-C in heart allograft recipients already on stable statin therapy. Extent of pre-treatment LDL-C and cardiac disorder prior to transplantation appear to correlate with the efficacy of ezetimibe therapy.     

Lack of clinically relevant drug-drug interactions when dalcetrapib is co-administered with ezetimibe

AIMS

Dalcetrapib, which targets cholesteryl ester transfer protein activity, is in development for prevention of cardiovascular events. Because dalcetrapib will likely be prescribed with other lipid-modifying therapies such as ezetimibe, a study was performed to investigate potential pharmacokinetic interactions between dalcetrapib and ezetimibe. Lipids changes and tolerability were secondary endpoints.

METHODS

Co-administration of dalcetrapib 900 mg (higher than the phase III dose) with ezetimibe was investigated in a three period, three treatment crossover study in healthy males: 7 days of dalcetrapib, 7 days of dalcetrapib plus ezetimibe, 7 days of ezetimibe alone. A full pharmacokinetic profile was performed on day 7 of each treatment.

RESULTS

Co-administration of dalcetrapib with ezetimibe was associated with minimal changes in dalcetrapib exposure compared with dalcetrapib alone. Least squares mean ratio (LSMR) (90% confidence interval) was 93.6 (87.1, 100.7) for AUC(0,24 h) and 99.0 (85.2, 115.0) for C_max. Ezetimibe exposure was reduced with co-administration of ezetimibe with dalcetrapib compared with ezetimibe alone: LSMR 80.3 (74.6, 86.4) for AUC(0,24 h) and 88.9 (80.9, 99.9) for C_max for total ezetimibe. High-density lipoprotein cholesterol increases associated with co-administration of dalcetrapib with ezetimibe (+29.8%) were comparable with those with dalcetrapib alone (+25.6%), while the reduction in low-density lipoprotein cholesterol with co-administration (−35.9%) was greater than with ezetimibe alone (−20.9%). Dalcetrapib was generally well tolerated when administered alone and when co-administered with ezetimibe.

CONCLUSION

Co-administration of dalcetrapib with ezetimibe was not associated with clinically significant changes in pharmacokinetic parameters or tolerability and did not diminish the lipid effects of either drug.     

尼曼-匹克C1型类似蛋白1介导依泽替米贝对RAW264.7细胞脂质蓄积的抑制作用

目的观察肠道胆固醇吸收抑制剂依泽替米贝(ezetimibe)对RAW264.7细胞源性荷脂细胞脂质蓄积的影响并对其机制进行初步探讨。方法采用油红O染色、高效液相色谱法检测细胞内脂滴数量和细胞内脂质含量,Western blot对NPC1L1(Niemann-Pick type C1Like-1)进行定性和半定量检测。结果RAW264.7细胞中有NPC1L1蛋白表达。不同浓度(0、0.003、0.01和0.03mol.L-1)依泽替米贝预先孵育RAW264.7细胞24h或最佳浓度(0.03mol.L-1)预先孵育不同时间(0、6、12和24h)后,换50mg.L-1oxLDL继续孵育24h,结果显示不同浓度ezetimibe预先孵育后,细胞内脂滴数量与面积随着浓度的增加而逐渐减少;Ezetimibe预先孵育可减少细胞内脂质蓄积,并呈浓度和时间依赖性。其中0.03mol.L-1ezetimibe预先孵育24h组作用最明显,CE百分比较oxLDL单独孵育组减少了约47%±0.1%。结论小鼠源性巨噬细胞RAW264.7中存在NPC1L1蛋白表达;依泽替米贝能够减少RAW264.7细胞中NPC1L1蛋白表达;依泽替米贝抑制RAW264.7细胞中脂质蓄积。