他汀类药物治疗慢性肝病有效性及安全性研究进展

正他汀类药物通过竞争性抑制内源性胆固醇合成限速酶(3-hydroxy-3-methyl-glutaryl-coenzyme A reductase,HMGCR),致胆固醇合成减少,从而刺激肝细胞膜表面的低密度脂蛋白(Low Density Lipoprotein,LDL)受体数量增加、活性增强,使LDL-胆固醇(low-density lipoprotein cholesterol,LDL-C)水平降低,可用于冠心病和卒中的预防及治疗。非酒精性脂肪肝病(Non-alcoholic fatty liver disease,     

大剂量阿托伐他汀对稳定型冠心病患者脑血管事件的作用

业已证实,应用他汀类药物降低低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)水平可降低稳定型冠心病患者的卒中风险。在一些观察性研究中,低胆固醇水平与出血性卒中的风险增加有关。以往尚未对治疗稳定型冠心病患者使其LDL-C水平显著低于100 mg/dL(2.59 mmol/L)的脑血管的益处进行过研究。为此,美国加利福尼亚大学的Waters等对治疗新目标(Treating to New Targets,TNT)研究中的脑血管事件进行了分析,TNT试验将10 001例冠心病患者随机分组接受10 mg/d或80 mg/d阿托伐他汀治疗并随访4.9年(中位数)。     

血脂指标与大动脉粥样硬化性卒中的联系

在卒中患者中,低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL)是降低血管危险的主要血脂目标,但一些新的数据表明,其他血脂指标可更好地预测血管性风险.     

他汀类药物在缺血性卒中预防中的作用

有效的预防是减轻卒中负担的最佳途径.他汀类药物降低低密度脂蛋白胆固醇可降低高危患者首次卒中和缺血性卒中或短暂性脑缺血发作患者复发性卒中风险.在卒中预防方面,他汀类药物治疗已成为继阿司匹林和降压治疗之后的最重要进展.文章对他汀类药物在卒中预防中的作用进行了综述.     

载脂蛋白A多态性和他汀类药物治疗颈动脉粥样硬化疗效的相关性

目的观察载脂蛋白A[apolipoprotein,Apo(a)]基因rs3798220多态性对他汀类药物治疗颈动脉粥样硬化患者疗效的影响。方法对2012年4月至2013年4月在广东省佛山市顺德第一人民医院心内科及高级诊疗区住院部已经确诊的103例患者进行基因分型,并对患者采用阿托伐他汀20 mg/d进行治疗,临床随访2年。检测治疗前、后患者的血浆脂蛋白。a[lipoprotein a,LP(a)]浓度及血清三酰甘油(triacylglycerol,TG),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)浓度。结果他汀类药物治疗能够显著降低颈动脉内膜中层厚度(IMT)、降低血清TC、TG、LDL-C浓度、升高血清HDL-C浓度,但是对血浆Lp(a)浓度没有显著影响。通过对他汀类药物治疗颈动脉粥样硬化患者的疗效进行分析发现,采用他汀类药物治疗时Apo(a)基因rs3798220的分型对颈动脉内膜中层厚度、TG、Lp(a)以及HDL-C的改善没有影响,对LDL-C有一定的影响,而对TC有显著影响。结论他汀类药物治疗颈动脉粥样硬化患者能够取得良好的效果。Apo(a)基因rs3798220多态性对他汀类药物治疗疗效有一定的影响,其能够成为他汀类药物治疗颈动脉粥样硬化患者效果的辅助判断,为颈动脉粥样硬化以及冠状动脉粥样硬化性心脏病(冠心病)患者的个体化医疗提供依据。     

他汀类药物对慢性肝脏疾病进展及预后的影响

慢性肝病严重时可进展为肝纤维化和肝硬化,进而引起门静脉高压,最终可能发展至肝细胞癌。近年来,越来越多的研究发现他汀类药物可以使非酒精性脂肪性肝病患者的肝脏组织学得到改善,延缓肝纤维化进展,降低失代偿事件以及肝细胞癌的发生风险。介绍了他汀类药物在慢性肝病患者中的应用进展,为慢性肝脏疾病的防治提供一定的依据。     

低密度脂蛋白胆固醇≥190mg/dL的患者使用降脂治疗的差异

正低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)≥190mg/dL(1mg/dL=0.026mmol/L)的患者存在动脉粥样硬化性心血管病高风险。治疗指南建议对这些患者进行强化治疗。Virani等利用美国心脏病学会国家心血管数据注册处-实践创新和临床登记处的数据,评估了2013年1月至2016年12月期间,接受他汀类药物、高强度他汀类药物、使LDL-C降     

他汀类药物对卒中风险影响的Meta分析

随机对照试验的研究证据表明，高危心血管病患者服用羟甲基戊二酰辅酶A还原酶抑制剂（他汀类药物），可降低低密度脂蛋白胆固醇，继而降低缺血性卒中的发病率。而来自大型流行病学观察性研究的数据却表明，出血性卒中的风险与胆固醇水平呈负相关。     

卒中或短暂性脑缺血发作后大剂量阿托伐他汀治疗

他汀类药物可降低血管性疾病风险增高患者的卒中发病率,但能否降低新近卒中和短暂性脑缺血发作(transient ischemic attack,TIA)后的卒中风险仍不确定。强化降低胆固醇水平预防卒中(Stroke Prevention by nggressive Reduction in Cholesterol Levels,SPARCL)研究对4 731例脑血管病患者随机分组后给予阿托伐他汀(80 mg/d)或安慰剂双盲治疗。纳入标准为6个     

他汀类药物在心血管疾病中多重效应分析

在心血管疾病一级和二级预防中,他汀类药物(Statins)明显降低致命性和非致命性心血管疾病的事件.他汀类药物即3-羟基3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂,通过阻断HMG-CoA转变为胆固醇的前体甲羟戊酸,并反馈性激活肝脏低密度脂蛋白受体(LDLR),使得胆固醇的合成减少,清除增加,从而显著降低血清总胆固醇(TC)及低密度脂蛋白胆固醇(LDL-C)浓度,另外通过抑制肝细胞合成载脂蛋白B-100,从而降低三酰甘油,他汀类药物对心血管益处通常认为是降低LDL-C水平,随着他汀类药物临床应用的增多及基础研究的深入,人们发现他汀类药物产生的获益远大于降脂作用本身,并且观察到使用他汀在其降脂作用尚未显现时即可产生获益,提示他汀有独立于降脂作用之外的其他作用,称之为他汀类药物的多效性.     

Dyslipidemia in patients with nonalcoholic fatty liver disease

Patients with nonalcoholic fatty liver disease (NAFLD) often have dyslipidemia along with other features of metabolic syndrome such as obesity, diabetes mellitus, and hypertension. The dyslipidemia in NAFLD is characterized by increased serum triglycerides, increased small, dense low-density lipoprotein (LDL nontype A) particles, and low high-density lipoprotein (HDL) cholesterol. The pathogenesis of dyslipidemia in NAFLD is not well understood, but it is likely related to hepatic overproduction of the very low-density lipoprotein particles and dysregulated clearance of lipoproteins from the circulation. There is unequivocal evidence that cardiovascular disease is the most common cause of mortality in patients with NAFLD. Aggressive treatment of dyslipidemia plays a critical role in the overall management of patients with NAFLD. Statins are the first-line agents to treat high cholesterol and their dosage should be adjusted based on achieving therapeutic targets and tolerability. Although all statins appear to be effective in improving cholesterol levels in patients with NAFLD, there is more experience with atorvastatin in patients with NAFLD; furthermore, it is the only statin to date to show a reduced cardiovascular morbidity in patients with NAFLD. The risk for serious liver injury from statins is quite rare and patients with NAFLD are not at increased risk for statin hepatotoxicity. Omega-3 fatty acids are perhaps the first choice to treat hypertriglyceridemia because of their safety, tolerability, and efficacy in improving serum triglycerides, as well as their potential to improve liver disease.     

Nonalcoholic Fatty Liver Disease: Dyslipidemia,Risk for Cardiovascular Complications,and Treatment Strategy

Studies have shown that nonalcoholic fatty liver disease (NAFLD) is strongly associated with several metabolic disorders and diseases, such as obesity, type 2 diabetes mellitus, and dyslipidemia. In NAFLD, dyslipidemia is manifested as increased serum triglyceride and low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels, all of which are key risk factors for cardiovascular disease (CVD). CVD is a leading cause of mortality in NAFLD patients. Thus, implementation of an aggressive therapeutic strategy for dyslipidemia with hypolipidemic agents may mitigate the risk for CVD among NAFLD patients. Here, we provide a current review of literature regarding NAFLD, with particular emphasis on dyslipidemia and available treatment options.     

Lipid-lowering agents in the management of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is the most common chronic liver disease in developed countries and is associated not only with increased risk for liver disease-related complications but also with higher cardiovascular morbidity. Accordingly, lipid-lowering agents are frequently considered in these patients to reduce cardiovascular risk. However, there have been concerns regarding the safety of these agents in patients with chronic liver diseases. In the present review, we discuss the safety of lipid-lowering agents in patients with NAFLD as well as their effects on both cardiovascular and liver disease in this population. Accumulating data suggest that statins are safe in patients with NAFLD and that they reduce the increased cardiovascular morbidity of this population. However, it is still unclear whether statins are also useful as a treatment for NAFLD per se, since there are very limited and conflicting data on their effects on liver histology. There is also very scarce evidence regarding the safety and efficacy of other lipid-lowering agents in patients with NAFLD. Randomized controlled studies are needed to evaluate the role of lipid-lowering agents and particularly statins for the prevention of both cardiovascular and liver disease-related complications in this high-risk population.     

The role of cholesterol and statins in stroke

Flawed observational studies find weak associations between high cholesterol and ischemic stroke, and low cholesterol and hemorrhagic stroke. Low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides each appear to have individual effects on stroke risk and type. Statins decrease the risk of cerebral infarction in patients with coronary disease, diabetes, hypertension, and hypercholesterolemia. They also significantly decrease the risk of ischemic stroke in patients with recent cerebrovascular disease, while potentially increasing the risk of intracerebral hemorrhage. Lower achieved cholesterol values are associated with greater reductions in stroke risk. Besides their cholesterol-lowering properties, statins are also pleiotropic agents with various neuroprotective mechanisms. Neurologic disability and infarct size are decreased in patients administered statins during stroke. Mortality and neurologic deterioration are higher in patients with statin cessation during acute ischemic stroke. Cholesterol is a modifiable risk factor for stroke, and statins are excellent agents for prophylaxis and acute therapy.     

Is there a role of lipid-lowering therapies in the management of fatty liver disease?

Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations. It is highly prevalent in non-alcoholic fatty liver disease (NAFLD) and contributes to the increased cardiovascular risk associated with this condition. Alongside insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis (NASH) development and progression. It has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk individuals. This evidence highlights the importance of effective lipid modulation in NAFLD. In this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NASH are critically discussed. Preclinical and clinical evidence suggests that statins reduce hepatic steatosis, inflammation and fibrosis in patients with NAFLD/NASH. Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities, steatosis/fibrosis scores, and imaging evidence of steatosis as surrogates. Also, relevant histologic benefits were noted in small biopsy studies. Atorvastatin and rosuvastatin showed greater benefits, whereas data for other statins are scarce and sometimes conflicting. Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis. However, no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been shown. Preclinical studies showed that fibrates through peroxisome proliferator-activated receptor (PPAR)α activation may have a role in NAFLD prevention and management. Nevertheless, no relevant benefits have been noted in human studies. Species-related differences in PPARα expression and its activation responsiveness may help explain this discrepancy. Omega-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies, but their benefits on hepatic inflammation and fibrosis have not been established. Promising preliminary data for the highly purified eicosapentaenoic acid require further confirmation. Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD, though this needs to be established by future prospective studies.     

瘦素受体基因Gln223Arg多态性与非酒精性脂肪性肝病的关系

目的 探讨瘦素受体基因多态性与非酒精性脂肪肝患者临床表型间的关系.方法 以非酒精性脂肪肝患者和正常对照人群为研究对象,应用聚合酶链反应及限制性片段长度多态性方法(PCR-RFLP),对167例中国人(包括85例非酒精性脂肪肝患者和82例正常对照)的瘦素受体基因Gln223Arg进行研究,同时进行临床参数的检测.结果 (1)非酒精性脂肪肝患者和正常对照组人群中Gln223Arg基因型频率和等位基因频率差异无显著性(P>0.05).(2)非酒精性脂肪肝男性患者中AA AG基因型者TC、BMI高于GG基因型(P<0.05).(3)进一步用Logistic回归分析发现:在非酒精性脂肪肝男性患者中该基因变异与TC相关(P=0.019).结论 非酒精性脂肪肝男性患者瘦素受体基因Gln223Arg多态性与TC水平相关.瘦素受体基因Gln223Arg可能参与非酒精性脂肪肝的脂质代谢.     

The use of statins alone,or in combination with pioglitazone and other drugs,for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement

Non-alcoholic fatty liver disease (NAFLD), the most common liver disease, is characterized by accumulation of fat (> 5% of the liver tissue), in the absence of alcohol abuse or other chronic liver diseases. It is closely related to the epidemic of obesity, metabolic syndrome or type 2 diabetes mellitus (T2DM). NAFLD can cause liver inflammation and progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis or hepatocellular cancer (HCC). Nevertheless, cardiovascular disease (CVD) is the most common cause of death in NAFLD/NASH patients. Current guidelines suggest the use of pioglitazone both in patients with T2DM and in those without.The use of statins, though considered safe by the guidelines, have very limited use; only 10% in high CVD risk patients are on statins by tertiary centers in the US. There are data from several animal studies, 5 post hoc analyses of prospective long-term survival studies, and 5 rather small biopsy proven NASH studies, one at baseline and on at the end of the study. All these studies provide data for biochemical and histological improvement of NAFLD/NASH with statins and in the clinical studies large reductions in CVD events in comparison with those also on statins and normal liver. Ezetimibe was also reported to improve NAFLD.Drugs currently in clinical trials seem to have potential for slowing down the evolution of NAFLD and for reducing liver- and CVD-related morbidity and mortality, but it will take time before they are ready to be used in everyday clinical practice. The suggestion of this Expert Panel is that, pending forthcoming randomized clinical trials, physicians should consider using a PPARgamma agonist, such as pioglitazone, or, statin use in those with NAFLD/NASH at high CVD or HCC risk, alone and/or preferably in combination with each other or with ezetimibe, for the primary or secondary prevention of CVD, and the avoidance of cirrhosis, liver transplantation or HCC, bearing in mind that CVD is the main cause of death in NAFLD/NASH patients.     

Nonlipid-lowering effects of statins

Optional statement Statins have been shown to effectively reduce cardiovascular events in patients with hypercholesterolemia, diabetes, and coronary disease, and after an acute coronary syndrome in several large-scale clinical trials. Interestingly, numerous studies have suggested that statins exert potentially important effects independent of lipid lowering (ie, improve endothelial function, reduce oxidant stress), and have direct antiinflammatory, antithrombotic, and plaque-stabilizing effects. These beneficial effects may contribute to cardiovascular protection by statin therapy beyond low-density lipoprotein (LDL) cholesterol lowering. Therefore, it remains unclear at present to what extent the beneficial cardiovascular effects of statin treatment are dependent on LDL cholesterol lowering (ie, whether the same effect would be achieved by other modes of lipid lowering). Consequently, statins should be used as a first-line therapy for lipid lowering. Importantly, the observation of LDL cholesterol-independent effects of statins has stimulated clinical studies testing a wider use of statin treatment for diseases that are not thought to be related to increased LDL cholesterol levels, such as in patients with chronic heart failure (in particular dilated cardiomyopathy) and even in inflammatory diseases such as rheumatoid arthritis and multiple sclerosis.     

HYPOLIPEMIC AGENTS FOR STROKE PREVENTION

An important issue for stroke prevention is identification and treatment of risk factors such as hypercholesterolemia. The four reasons to test hypolipidemic agents in stroke prevention are: (i) a statistical link between elevated low-density lipoprotein cholesterol (LDL-c) or decreased high-density lipoprotein cholesterol (HDL-c) and ischemic stroke; (ii) a reduction in vascular risk in randomized trials in patients with coronary heart disease; (iii) evidence of a decreased plaque progression under statins, (iv) pooled analyses of primary and secondary prevention trials showing that reduction of total serum cholesterol reduces the incidence of stroke, especially with the highest rate of cholesterol reduction, and in patients with the highest risk of stroke (i.e., with statins in secondary prevention trials), and (v) prophylactic neuroprotection induced by hypolipidemic agents in animal models of cerebral ischemia. Data provided by trials conducted in subjects with coronary heart disease and in asymptomatic individuals should now be confirmed in stroke patient.     

Role of selective peroxisome proliferator‐activated receptor modulators in managing cardiometabolic disease: tale of a roller‐coaster

Atherogenic dyslipidaemia is a hypertriglyceridaemic phenotype, associated with increased plasma concentrations of small, dense low‐density lipoprotein (sdLDL) particles, triglyceride‐rich lipoproteins (TRLs) and non‐high‐density lipoprotein cholesterol (non‐HDL‐C), and low HDL particles. Atherogenic dyslipidaemia commonly accompanies several metabolic disorders including type 2 diabetes, metabolic syndrome, non‐alcoholic fatty liver disease (NAFLD) and obesity, and increases the risk of cardiovascular disease (CVD). Statins significantly lower plasma LDL‐cholesterol and CVD risk, but their efficacy in correcting hypertriglyceridaemia is limited. Untreated hypertriglyceridaemia may partly account for residual risk of CVD in patients on statin treatment. Activators of peroxisome proliferator‐activated receptor (PPAR) α are more effective in correcting TRL and HDL metabolism than statins. A dual PPARα/δ agonist (GFT‐505) may have additional benefits on hepatic insulin sensitivity, steatosis and fibrosis. Selective PPAR modulators (SPPARMs) have the potential of increasing therapeutic specificity, while reducing unwanted off‐target effects. This review provides a summary of findings from randomized controlled trials of the efficacy of fenofibrate (as the most widely used PPARα agonist) and novel selective PPARα (ABT‐335 and k‐877), PPARα/δ (GFT‐505), PPARδ (MBX‐8025 and GW501516) and PPARγ (INT131) agonists in the treatment of atherogenic dyslipidaemia and NAFLD.