选择性胆固醇吸收抑制剂临床应用中国专家共识(2013版)

血脂异常与心血管疾病密切相关.过去10余年中,国内外先后完成了一系列里程碑式的血脂干预临床试验.这些研究结果有力证实,降低胆固醇水平显著降低心血管病患者其高危人群的心血管事件发生率,因而降胆固醇达标被视为防治心血管疾病的核心策略.确凿证据表明,他汀类药物在动脉粥样硬化性心血管疾病一、二级预防中具有重要地位,合理应用此类药物显著降低心血管疾病的发病率与病死率.临床实践中,许多患者接受他汀类药物治疗后其胆固醇水平仍不能达到目标值,另有一些患者不能耐受他汀类药物治疗,已成为提高血脂达标率的重要羁绊.此外,为使胆固醇达标,应用大剂量他汀类药物的安全性也正引起越来越多的关注.他汀类药物剂量加倍后其降胆固醇作用仅增加6％左右,但相关不良事件(特别是肝酶升高、肌病以及对糖代谢的影响)的风险与他汀类药物剂量相关,不良事件发生风险显著增加.     

依折麦布在他汀类药物致肝功能损害急性冠状动脉综合征患者中的应用

目的:探讨依折麦布在他汀类药物致肝功能损害的急性冠状动脉综合征(ACS)患者中应用的疗效及安全性。方法:连续入选因肝功能损害不耐受他汀类药物的ACS患者92例,停用他汀类药物后随机化分为对照组(46例)和依折麦布组(46例)。比较治疗两周后两组的血脂、肝功能及临床心血管事件。结果:治疗两周后,依折麦布组总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)水平显著低于对照组;两组心血管事件的发生无明显差异。结论:对于因肝功能损害需要暂时中断他汀类药物治疗的ACS患者,可应用依折麦布作为过渡期的调脂治疗。     

他汀类药物对急性冠脉综合征并肾功能不全患者脂代谢水平的影响

目的探讨他汀类药物对急性冠脉综合征(ACS)并肾功能不全患者脂代谢水平的影响。方法选取2013-02~2014-07该院收治的96例ACS并肾功能不全患者,随机抽签分为常规组40例和他汀类药物组56例。常规组采用阿司匹林、β受体阻滞剂、硝酸酯类和血管紧张素转换酶抑制剂等常规药物治疗,他汀类药物组在常规治疗基础上采用他汀类药物治疗。他汀类药物组再分为小剂量组和大剂量组各28例,小剂量组采用小剂量他汀类药物治疗,大剂量组采用大剂量他汀类药物治疗,治疗3个月。观察常规组和他汀类药物组、小剂量组和大剂量组的总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)等血脂指标变化。结果治疗前常规组和他汀类药物组血脂指标TC、TG、LDL-C、HDL-C比较差异无统计学意义(P0.05);治疗后他汀类药物组TC[(4.34±0.63)mmol/L]、TG[(1.56±0.52)mmol/L]、LDL-C[(2.43±0.62)mmol/L]分别较常规组[(5.21±0.75)mmol/L、(2.15±0.73)mmol/L、(2.91±0.81)mmol/L]明显降低,差异有统计学意义(P0.05)。他汀类药物大剂量组TC[(4.04±0.65)mmol/L]、TG[(1.24±0.57)mmol/L]较小剂量组[(4.65±0.68)mmol/L、(1.75±0.74)mmol/L]显著降低,差异有统计学意义(P0.05)。结论他汀类药物能有效降低ACS并肾功能不全患者脂代谢水平,且大剂量他汀类药物降脂效果更佳。     

干预前蛋白转换酶枯草溶菌素9靶点的新进展

<正>在前蛋白转换酶枯草溶菌素9(proprotein convertase subtilisin/kexin type 9,PCSK9)之前的时代,学者们认为胆固醇稳态完全依赖于严格的细胞内调节系统。他汀类药物通过拮抗胆固醇合成过程中的关键限速酶,降低肝脏胆固醇合成,成为目前调脂治疗的基石。但在临床实践中,有部分患者对他汀类药物不耐受,此外,任一种他汀类药物剂量倍增后,LDL-C进一步降低幅度仅为6%,即使联合使用胆固醇吸收抑制剂依折麦布,许多患者LDL-C水平仍然不能达标。     

载脂蛋白E基因多态性与他汀类药物降脂疗效的关系

正他汀类药物是羟甲基戊二酰基辅酶A (HMG-CoA)还原酶(胆固醇合成过程的限速酶)的抑制剂,通过降低胆固醇生物合成和激活低密度脂蛋白受体(LDLr)降低胆固醇,是心血管疾病一级和二级预防的重要药物。然而,他汀类药物治疗效果差异很大[1],许多患者不论如何增加他汀类药物剂量,仍无法达到血浆胆固醇目标水平。除了饮食运动、个体依从性、副作用等因素,个体之间的遗传差异是很重要的原因。研究发现,APOE的3种共显性等位基因ε2,ε3和ε4     

他汀类药物调脂外作用及临床应用

塞伐他汀、洛伐他汀、辛伐他汀、西伐他汀、氟伐他汀、普伐他汀等为一大类其英文词尾均为statin(他汀)的药物被统称为他汀类药物。他们能够竞争性抑制胆固醇合成代谢中关键性限速酶3-羟-3-甲基戊二酰辅酶A还原酶的作用,使肝内胆固醇合成减少,临床多用于高胆固醇血症的治疗,对冠     

他汀类药物导致肝损伤的诊断和监测

他汀类药物广泛应用于高脂血症治疗和冠心病的一、二级预防,其调脂和心血管保护作用明确。在临床应用中,他汀类药物所致肝酶异常屡见报道,尽管当前普遍认为他汀类药物应用安全可靠,轻中度的肝酶升高不是他汀类药物停用指征,而在真实世界中,他汀类药物所致肝酶异常严重影响着患者依从性,临床工作者制定临床决策时仍然充满困惑。因此,现归纳综述新近关于他汀类药物所致肝损伤的相关研究,以期对临床实践作为参考。     

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新型胆固醇吸收抑制剂依哲麦布(ezetimihe,EZ)可显著降低患者的低密度脂蛋白胆固醇(LDL-C),升高高密度脂蛋白胆固醇(HDL-C)水平,不良反应较少.EZ与他汀类药物联合应用,有良好的药物协同效应,可避免大剂量他汀潜在的不良反应.如果患者在单用最佳剂量他汀类治疗的情况下没有达标,那么EZ联合他汀类可以是一种合理的治疗.     

他汀类药物抗纤维化研究新进展

器官纤维化在临床上非常常见,危害严重,目前仍缺乏非常有效的治疗手段.已有研究证实,他汀类药物除抑制胆固醇合成外,还参与了某些酶的激活和细胞因子的表达、小G蛋白转录后修饰的抑制及氧化应激等.有关这些非降脂作用的研究表明,他汀类药物具有一定的抗纤维化作用.本文就他汀类药物与肺、心、肾、肝等器官纤维化研究的新进展进行扼要综述.     

86例急性冠脉综合征患者他汀类药物治疗对肝功能的影响病例分析

摘 要 目的：探讨他汀类药物治疗急性冠脉综合征对肝功能的影响及安全性。方法：收集2014年2月至2014年7月于我院心内科住院治疗的86例急性冠脉综合征患者病例资料,入院即刻给予常规剂量他汀类药物治疗,检测24h内、7天、15天的肝脏转氨酶,根据服用他汀类药物后7天后肝功能(丙氨酸氨基转移酶)正常与否分成两组:肝功能正常组与肝功能异常组;分析两组肝脏转氨酶变化趋势。结果：两组入院后7天、15天无肝脏转氨酶超过正常高限3倍以上的病例;两组肝脏天门冬氨酸氨基转移酶（AST）入院24小时内均数明显增高,入院后7天、15天降至正常范围内;肝功能异常组入院24小时内丙氨酸氨基转移酶(ALT)均数呈轻中度增高,入院后7天、15天呈轻度增高;肝功能正常组入院24小时内丙氨酸氨基转移酶(ALT)均数呈轻中度增高,入院后7天、15天降至正常;结论：部分患者服用他汀类药物后肝功能ALT轻度增高,AST降至正常范围,急性冠脉综合征患者服用常规剂量他汀是安全的。     

他汀类与非酒精性脂肪肝病患者的卒中预防

非酒精性脂肪肝病(non-alcoholic fatty liver disease,NAFLD)是慢性肝病中的一个重要类型,其发病率日益增高,是代谢综合征的肝脏表现,与心脑血管病的发生关系密切.对NAFLD患者的卒中预防十分重要.他汀类药物是最重要的一类降胆固醇药物,通过抑制羟甲基戊二酰辅酶A(hydroxy-methyl-glutaryl coenzyme A HMG-CoA)还原酶,减少胆固醇合成,上调肝脏低密度脂蛋白(low-density lipoprotein,LDL)受体,降低循环低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)水平,有效降低卒中风险.此外,他汀类的多效性以及对胆同醇相关细胞信号通路的影响,能减缓或防止NAFLD的进展.由于他汀类药物对肝脏有一定的不良作用,是否能应用于慢性肝病患者存在较大争议.现有证据显示,他汀类药物可在NAFLD患者中安全使用,通常无需监测肝酶,过分关注他汀类药物的肝毒性反而可能采取不恰当的停药,导致心血管事件风险的增高.为此,他汀类对NAFLD患者的有效性及安全性尚需进一步评估.     

Use and monitoring of "statin" lipid-lowering drugs compared with guidelines

BACKGROUND: In patients with high cholesterol, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (or "statins") have been shown to reduce overall mortality in primary and secondary prevention. The National Cholesterol Education Program expert panel's guidelines (Adult Treatment Panel II) recommend evaluation and treatment of high cholesterol based on stratification of patients according to cardiovascular risk. While evidence suggests that many patients are undertreated, comparatively few data are available regarding overtreatment. OBJECTIVES: To assess the appropriateness of statin therapy compared with national guidelines and to examine the appropriateness of monitoring for adverse effects. METHODS: For all patients at a tertiary medical center, electronic medical records were evaluated for presence or absence of statin use and for presence of established coronary heart disease or cardiac risk factors. Therapy was compared with the recommendations of the National Cholesterol Education Program guidelines. Our primary outcome measures included, for all patients taking statins, prevalence of appropriateness vs overuse, and for all patients with coronary heart disease, prevalence of appropriateness vs underuse. RESULTS: Overuse of statin therapy was found among 69% of patients undergoing primary prevention, and among 47% of patients undergoing secondary prevention. In addition, among patients with coronary heart disease who were not taking statins, 88% were undertreated. Monitoring of liver function varied widely, and did not correlate with the risk of adverse events secondary to statin use. CONCLUSIONS: Overtreatment and undertreatment for hyperlipidemia were frequent. Decision support may help physicians improve their performance compared with guidelines.     

Statins inhibit NK cell cytotoxicity by membrane raft depletion rather than inhibition of isoprenylation

To investigate the potential determinants of the pleiotropic effects of statins, we measured NK cell cytotoxicity in samples from normal subjects and patients, including patients receiving statin therapy. In a multivariate analysis, NK cell cytotoxicity was related to total plasma cholesterol concentration rather than statin use. In vitro, we investigated the role of lipid modification, specifically the effects on membrane rafts and raft-dependent signal transduction. We demonstrate that statins reduce NK cell cytotoxicity and that membrane cholesterol depletion by cyclodextrins has a similar effect. In contrast, isoprenyl transferase inhibitors had little or no effect on NK cell function. We hypothesise that the pleiotropic effects of statins reflect changes in membrane cholesterol and, specifically, the density of membrane rafts. Moreover, there is likely to be a relationship between membrane cholesterol, membrane rafts and cell function that may be involved in the pathogenesis of cardiovascular and metabolic diseases.     

Effect of statins on cholesterol crystallization and atherosclerotic plaque stabilization

Pleiotropic effects of statins have not been fully elucidated. Recently we demonstrated that cholesterol expands when crystallizing and may trigger plaque rupture. The present study evaluated the potential direct effects of statins in altering cholesterol crystallization as a possible mechanism for plaque stabilization independent of cholesterol lowering. Cholesterol powder was dissolved in oil with and without pravastatin, simvastatin, or atorvastatin (10 to 90 mg) and then allowed to crystallize to measure peak volume expansion (ΔVE) in graduated cylinders. Effect of ΔVE on fibrous membrane damage was also evaluated. Human coronary, carotid, and peripheral arterial plaques (65 plaques from 55 patients) were incubated with statin or saline solution using matched plaque segments to evaluate direct effects of statins on preformed crystals. Also, the effect of in vivo use of oral statins on crystal structure was examined by scanning electron microscopy and crystal content in plaques scored from 0 to +3. For all statins, ΔVE decreased significantly in a dose-dependent fashion (0.76 ± 0.1 vs 0 ml at 60 mg, p <0.001). By scanning electron microscopy crystal structure with statins had loss of pointed tip geometries, averting fibrous membrane damage. Cholesterol crystal density was markedly decreased and appeared dissolved in human plaques incubated with statins (+2.1 ± 1.1 vs +1.3 ± 1.0, p = 0.0001). Also, plaques from patients taking oral statins compared to controls had significantly more dissolving crystals (p = 0.03). In conclusion, statins decreased ΔVE by altering cholesterol crystallization and blunting sharp-tipped crystal structure and dissolving cholesterol crystals in human arteries in vivo and in vitro, providing plaque stabilization.     

Addition of statins to the standard treatment in patients with cirrhosis: Safety and efficacy

This review summarizes the safety and efficacy of statins in patients with cirrhosis. Due to concerns about the safety of statins in patients with impaired liver function, they have recently been investigated as a potential treatment option in cirrhosis. The most clinically significant adverse event is statin-related myopathy, and this may be related to the high serum statin concentrations in the setting of severely impaired liver function. Rhabdomyolysis is the most serious and potentially life-threatening manifestation. It has recently been demonstrated that the recommended dose of simvastatin in patients with decompensated cirrhosis would be 20 mg/d because higher values, such as 40 mg/d, are associated with many adverse events, especially muscle injury. Likewise, simvastatin should not be administered to patients with Model for End-stage Liver Disease score > 12 and/or Child-Pugh class C because of the high risk of severe muscle injury. Due to the pleiotropic effects, the focus on statins has shifted from being considered harmful to something useful. Through these effects, statins could prevent liver-related morbidity and mortality in cirrhotic patients. Observational studies in large populations of patients with cirrhosis have shown that treatment with statins to decrease high cholesterol levels was associated with a reduced risk of hepatic decompensation, hepatocellular carcinoma development and death. The few randomized controlled trials in patients with cirrhosis and portal hypertension showed that statins lower portal pressure, quite likely through a reduction in hepatic resistance. Another large randomized controlled trial in patients with variceal bleeding showed that simvastatin in addition to standard of care did not prevent rebleeding but improved survival rate. Despite these encouraging outcomes, the quality of the evidence regarding the use of statins is low or very low due to the observational characteristics of most of the studies involved. Therefore, it is advisable to perform further randomized controlled trials on a large series of patients with hard clinical endpoints, using different statin types and varying doses. The objectives would be to prevent liver-related morbidity and mortality rather than treating cirrhosis complications to take additional information that makes it possible to add statins to the standard of care of these patients.     

REVIEW: Efficacy and mechanisms of action of statins in the treatment of diabetic dyslipidemia

CONTEXT: The Adult Treatment Panel III recommends 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, as first-line lipid-altering therapy for all adult patients with diabetes mellitus. This is based on the well-characterized efficacy and safety profiles of this class of agents as well as several clinical trials demonstrating that statin treatment reduces the risk of cardiovascular events. EVIDENCE ACQUISITION: This review provides an overview of the effectiveness and mechanisms of action of statins in patients with diabetes mellitus using small efficacy trials and large clinical outcomes trials as well as studies of the effects of statins on apolipoprotein B (apoB) metabolism. EVIDENCE SYNTHESIS: The major findings presented are a review of mechanistic studies of selected subjects with diabetes mellitus and dyslipidemia and a compilation of results from large-scale clinical trials of patients with diabetes. CONCLUSIONS: Statins are highly efficacious as low-density lipoprotein cholesterol-lowering agents and have more modest effects on very low-density lipoprotein triglyceride and high-density lipoprotein cholesterol levels. The effects of statins on plasma lipids and lipoproteins result from their ability to both increase the efficiency with which very low-density lipoprotein and low-density lipoprotein are cleared from the circulation and reduce the production of apoB-containing lipoproteins by the liver. Additional investigations are needed to clarify the mechanisms by which statins reduce apoB secretion from the liver.     

Rationale for intensive statin treatment in high-risk patients

Intensive lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is now an established regimen for patients at high risk for cardiovascular events, regardless of baseline low-density lipoprotein cholesterol levels. Treatment with statins to reduce low-density lipoprotein cholesterol levels significantly below 100 mg/dL has been shown to further reduce the risk of cardiovascular morbidity and mortality in high-risk patients and has provided the necessary data for an update to the National Cholesterol Education Program's Third Adult Treatment Panel (ATP III) guidelines. Intensive statin therapy is also well tolerated, with no increased risk of noncardiovascular adverse events and a low incidence of clinically significant liver or muscle enzyme abnormalities. Results of recent clinical and surrogate end point trials confirm that intensive lowering of low-density lipoprotein cholesterol is beneficial and safe in a majority of high-risk patients.     

Statins: potential new indications in inflammatory conditions

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are potent cholesterol-lowering drugs. In addition to their cholesterol-lowering properties, statins exert a number of so-called 'pleiotropic', vasculoprotective actions that include improvement of endothelial function, increased nitric oxide (NO) bioavailability, antioxidant properties, stabilisation of atherosclerotic plaques, regulation of progenitor cells, inhibition of inflammatory responses and immunomodulatory actions. Pleiotropic actions of statins may have potential clinical impact in vascular disease beyond cholesterol lowering. The ongoing Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), for example, tests the effects of statins in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol (LDL-C) and elevated high-sensitivity C-reactive protein (hs-CRP). Additionally, previous studies have shown that although cholesterol is not an established stroke risk factor, statin therapy is associated with a reduction in the incidence of strokes. It is known that sudden withdrawal of statin treatment may acutely impair vascular function and increase morbidity and mortality in patients with vascular disease. Furthermore, the anti-inflammatory effects of statins may have clinical impact in a number of non-vascular conditions including multiple sclerosis and rheumatoid arthritis.     

The Use of Statins in Patients With Chronic Liver Disease and Cirrhosis

Purpose of review

Statins are drugs developed to treat hypercholesterolemia. Its use in patients with liver disease has been limited because one of its potential and most feared side effects is hepatotoxicity. However, there is robust evidence that supports the safety of statins in this population in the absence of severe liver dysfunction. In this review, we will summarize the efficacy and safety of statins in cirrhosis.

Recent findings

Statins are effective in the treatment of dyslipidemia in patients with liver disease, because of their pleiotropic properties. These properties are independent of their effect on cholesterol levels, such as improving endothelial dysfunction or having antioxidant, antifibrotic, anti-inflammatory, antiproliferative, antiangiogenic, proapoptotic, or immunomodulation properties. Statins have been studied in other areas such as in treatment of portal hypertension, prevention of hepatocellular carcinoma, and/or protection against ischemia/reperfusion injury.

Summary

Approved indications for statins in patients with cirrhosis are those of the general population, including dyslipidemia and increased cardiovascular risk. Compensated cirrhosis is not a contraindication. In patients with decompensated cirrhosis, statins should be prescribed with extreme caution at low doses, and with frequent monitoring of creatinine phosphokinase levels in order to detect adverse events in a timely fashion.

     

他汀类药物治疗慢性心力衰竭的疗效及预后影响研究

目的:评价他汀类药物对慢性心力衰竭(CHF)患者疗效和预后的影响。方法:自2010年1月起共入选了我院、卢湾区中心医院及闵行区中心医院确诊的240例纽约心功能分级Ⅱ~Ⅳ级慢性收缩性心力衰竭患者[左心室射血分数(LVEF)≤45%],按照患者是否用他汀类药物治疗分为治疗组和对照组,每组各120例,比较2组患者治疗前后血脂、血清氨基末端脑钠肽前体(NT-proBNP)、炎症因子高敏C反应蛋白(hs-CRP)、肿瘤坏死因子α(TNF-α)的变化,以及心脏超声监测心腔大小及LVEF变化。观察2组患者的生存率及终点事件发生率。结果:与对照组相比,治疗组血脂水平及血清NT-proBNP、hs-CRP、TNF-α水平降低(P