Ezetimibe reduces plaque inflammation in a rabbit model of atherosclerosis and inhibits monocyte migration in addition to its lipid-lowering effect

Background and purpose:

Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, might also suppress inflammatory components of atherogenesis. We have studied the effects of ezetimibe on two characteristics of atherosclerotic plaques (infiltrate and fibrosis) and on expression of inflammatory genes in a rabbit model of accelerated atherosclerosis.

Experimental approach:

Femoral atherosclerosis was induced by a combination of endothelial desiccation and atherogenic diet. Animals were randomized to ezetimibe (0.6 mg·kg⁻¹·day⁻¹), simvastatin (5 mg·kg⁻¹·day⁻¹), ezetimibe plus simvastatin or no treatment, still on atherogenic diet. A control group of rabbits received normolipidemic diet.

Key results:

Rabbits fed the normolipidemic diet showed normal plasma lipid levels. Either the normolipidemic diet or drug treatment reduced the intima/media ratio (normolipidemic diet: 22%, ezetimibe: 13%, simvastatin: 27%, ezetimibe + simvastatin: 28%), compared with rabbits with atherosclerosis. Ezetimibe also decreased macrophage content and monocyte chemoattractant protein-1 expression in atherosclerotic lesions. Furthermore, ezetimibe reduced the increased activity of nuclear factor κB in peripheral blood leucocytes and plasma C-reactive protein levels in rabbits with atherosclerosis. In THP-1 cells, ezetimibe decreased monocyte chemoattractant protein-1-induced monocyte migration. Importantly, the combination of ezetimibe with simvastatin was associated with a more significant reduction in plaque monocyte/macrophage content and some proinflammatory markers than observed with each drug alone.

Conclusions and implications:

Ezetimibe had beneficial effects both on atherosclerosis progression and plaque stabilization and showed additional anti-atherogenic benefits when combined with simvastatin. Its effect on monocyte migration provides a potentially beneficial action, in addition to its effects on lipids.     

阿托伐他汀对血脂及基质金属蛋白酶的影响

目的 研究较大剂量阿托伐他汀与小剂量阿托伐他汀联合依折麦布对冠心病患者血脂及血清基质金属蛋白酶(MMP)水平的影响。方法 选取冠状动脉狭窄50%~70%的冠心病患者(未植入支架)42例,随机分为较大剂量阿托伐他汀单药治疗组（20、40 mg）（阿托伐他汀组,n=19）和小剂量阿托伐他汀（5、10 mg）＋依折麦布（10 mg）治疗组（联合治疗组,n=23),检测并分析12周内的血脂指标、肝肾功能、肌酸激酶及血清MMP-2、MMP-9和MMP组织抑制因子-1(TIMP-1)水平的变化。结果 ①12周时阿托伐他汀组的低密度脂蛋白胆固醇（LDL-C）为（1.94±0.49） mmol/L,较治疗前下降37.82％;联合治疗组的LDL-C为（1.92±0.54） mmol/L,较治疗前下降38.26％;两组间治疗前及治疗12周时LDL-C比较差异无统计学意义（P>0.05）。②阿托伐他汀组血清MMP-2和MMP-9水平在12周时均较治疗前明显降低,TIMP-1则明显升高。结论 单用较大剂量阿托伐他汀以及联合使用小剂量阿托伐他汀+依折麦布的降脂效果相似,但联合治疗未能降低血清MMP-2、MMP-9和TIMP-1的水平。     

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.

依折麦布联合普伐他汀治疗高胆固醇血症患者的疗效

目的探索依折麦布联合普伐他汀治疗高胆固醇血症的临床疗效。方法选择符合高胆固醇血症的患者180例,男女各90例,在合理的饮食、生活习惯和体育运动下,分为三组,每组男女平衡：A组为单用依折麦布治疗组60例：B组为单用普伐他汀治疗组60例;C组为依折麦布联合普伐他汀治疗组60例。观察三组血清总胆固醇（total cholesterol,TC）、低密度脂蛋白胆固醇（low-density lipoprotein cholesterol, LDL-C）、高密度脂蛋白胆固醇（high—density lipoprotein cholesterol,HDL—C）、载脂蛋白B（apoprotein B,Apo—B）及三酰甘油（triacylglycerol,TG）等治疗前、后的变化,并记录不良反应。结果三组治疗后血清TC、LDL—C、Apo-B、TG浓度均能降低,血清HDL—C浓度均能升高,但以C组更明显（P〈0．05）;C组总有效率达91．7％,优于A、B组。结论依折麦布联合普伐他汀具有良好的药物协同效应,可有效调节胆固醇代谢,效果明显优于单独使用,可避免大剂量他汀类药物的不良反应。     

Effect of Ezetimibe on Insulin Sensitivity and Lipid Profile in Obese and Dyslipidaemic Patients

Summary Aim: To evaluate the effect of ezetimibe on insulin sensitivity and lipid profile in obese and dyslipidaemic patients. Methods: A randomized, 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 randomly 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.     

Ezetimibe

Ezetimibe is a cholesterol absorption inhibitor that significantly lowers low- density lipoprotein cholesterol (LDL-C), and favourably affects triglyceride and high-density lipoprotein cholesterol blood levels in monotherapy and in combination with statins. Hepatic and extrahepatic (peripheral) cholesterol synthesis are well-known sources of cholesterol found in LDL-C. However, the emergence of ezetimibe has highlighted intestinal cholesterol absorption as an additional, important source of cholesterol in LDL-C, and has better illuminated how genetic factors, dietary content, pharmaceutical agents, and nuclear receptor activation (such as liver X receptors) all influence the relative contribution of these important cholesterol sources to LDL-C. In fact, investigations into ezetimibe have sometimes challenged existing scientific dogma, has prompted reconsideration of older data, and has helped create ‘new’ paradigms in cholesterol metabolism. Thus, ezetimibe's efficacy, excellent tolerability, and safety has not only expanded potential treatment options for dyslipidaemic patients, but also has promoted exploration of new frontiers of lipid research towards a better understanding of cholesterol metabolism.     

Effects of ezetimibe,either alone or in combination with atorvastatin,on serum visfatin levels: a pilot study

Introduction: Ezetimibe inhibits intestinal absorption of cholesterol and lowers circulating low-density lipoprotein cholesterol levels. Visfatin is a novel adipokine, which may be implicated in the atherosclerotic process. Objective: The aim of this study was to explore the possible association between ezetimibe administration and serum visfatin concentrations. Methods: Patients (n = 30) with primary dyslipidemia and another 30 who failed to reach their assigned low-density lipoprotein cholesterol target on atorvastatin therapy (20 mg/day) were included in the study. All participants were given ezetimibe at 10 mg/day for 12 weeks. Results: At baseline the visfatin levels correlated significantly with the total cholesterol (r = 0.61 and p < 0.01) and low-density lipoprotein cholesterol (r = 0.51 and p < 0.01) levels in the statin pretreatment group. Furthermore, in the statin group the post-treatment levels of visfatin and low-density lipoprotein cholesterol were significantly correlated (r = 0.57 and p < 0.01). The serum visfatin concentrations did not change significantly in either the monotherapy or statin pretreatment groups or in subgroups divided according to the baseline lipid variables. In both the ezetimibe monotherapy and ezetimibe plus atorvastatin groups the effect of ezetimibe on the lipid variables depended on the baseline lipid values. The low-density lipoprotein cholesterol:high density lipoprotein cholesterol ratio was consistently improved by ezetimibe in all groups or subgroups. Conclusions: Ezetimibe did not alter serum visfatin concentrations, either when administered as monotherapy or combined with a statin. Future studies investigating the effect of ezetimibe on visfatin levels need to include groups of patients with distinct lipid characteristics.     

Treatment of dyslipidaemia in HIV-infected persons

Accumulating evidence suggests that HIV-infected individuals have an increased risk of cardiovascular events. This risk seems to be at least partially mediated by dyslipidaemia, which is related to the use of highly active antiretroviral therapy (HAART). As HIV-infected individuals live longer due to HAART, their cardiovascular risk will invariably increase. Because HAART is likely to be used indefinitely, HAART-related dyslipidaemia has emerged as a major cardiovascular concern. This article summarises the evaluation of dyslipidaemia and cardiovascular risk in HIV-infected individuals, the potential pathophysiological and genetic mechanisms involved in HAART-related dyslipidaemia and the current treatment approaches. In general, dyslipidaemia is evaluated and treated as in HIV-negative persons. The first step is cardiovascular risk assessment and the determination of target lipid levels. A healthier lifestyle and, in particular, smoking cessation should be promoted. Lowering levels of low-density lipoprotein cholesterol (or, in the setting of significant hypertriglyceridaemia, non-high-density lipoprotein cholesterol) is the primary target of intervention. Switching HAART to a more lipid-favourable regimen should be considered if this does not jeopardise virological control. Many patients will need lipid-lowering drug therapy. Appropriate low-density lipoprotein cholesterol target levels may be more difficult to reach than in the HIV-negative population, and the potential for drug interactions when using lipid-lowering agents together with HAART needs to be considered. The identification of HAART strategies with no or minimal metabolic toxicity, and the identification of the safest and most efficacious lipid-lowering therapies for HIV-infected individuals with dyslipidaemia are important research goals.