新型降脂药ezetimibe

流行病学调查已经证实，心血管疾病发病率和死亡率与总胆固醇及低密度脂蛋白水平的升高相一致，而与高密度脂蛋白水平的变化相反。大规模的临床研究亦证实，他汀类降脂药不仅能明显改善血脂紊乱，且能降低心血管疾病的发病率和死亡率。但对于血脂紊乱严重的病人单纯使用他汀类药物效果并不理想。ezetimibe属新一类的降脂药物，通过抑制胆固醇的吸收而达到其有效作用，可单用或与他汀类药物联合应用，以减少其药物副作用。本文对此新药的作用机制和临床研究予以综述。     

依折麦布联合他汀类药物降脂新进展

目前他汀类药物成为常用调脂药物,能有效降低低密度脂蛋白胆固醇（low-density lipoprotein cholesterol,LDL-C）水平,然而,他汀类药物单用时,并不能使所有冠心病患者的LDL-C降至目标值,因此,临床上需要考虑调脂药物联合用药。他汀类与贝特类药物联用时,肝脏毒性反应和肌病发生的危险性增大;而他汀类与烟酸类药物联用,患者的耐受性差,故上述联合用药方案难以广泛应用。     

Ezetirnibe／simvastatin降低LDL-胆固醇至目标水平

荷兰研究者报道，从单用辛伐他汀（simvastatin）（Ⅰ）或阿托伐他汀（atorvastatin）（Ⅱ）改为ezetimibe（Ⅲ）与（Ⅰ）联合使用比调高他汀类药物的用量能更有效地降低冠心病或2型糖尿病病人LDL-胆固醇至目标水平。     

关注他汀类药物应用的安全性

随着他汀药物使用范围的不断拓宽，其安全性也日益受到人们的关注。美国心脏学会(AHA)和英国心脏病学学会(ACC)挑战有关他汀类降胆固醇药物安全性的争论．明确地支持这类药物的安全性。他们指出，超过十年的医学研究已表明他汀类药物通过有效地降低血清胆固醇水平可延长生命和预防心脏病，他汀类药物控制病人胆固醇所获得的利益远超过这类药物所带来的副作用风险，这场争论引发于拜斯亭（cerivastatin，西立伐他汀)与31例服药者死亡有关而被迫从市场撤出。     

04019 他汀类药物在心衰治疗中的作用

美国耶鲁医学中心正在进行一项开拓性研究，评价他汀类药物在心力衰竭病人治疗中的作用。研究表明，他汀类药物可很有效地降低胆固醇的水平，而目前血管功能减退的心力衰竭患者并未使用他汀类药物治疗。     

新型胆固醇吸收抑制剂Ezetimibe的研究进展

Ezetimibe是一种新型选择性肠胆固醇吸收抑制剂，通过抑制肠上皮细胞的胆固醇吸收蛋白NPC1L1减少胆固醇、植物固醇的吸收以及胆汁胆固醇的再吸收，从而降低血浆固醇水平。Ezetimibe的作用与他汀类药物抑制胆固醇合成的机制互补，在降低血浆低密度脂蛋白胆固醇和总胆固醇水平的同时，升高高密度脂蛋白胆固醇水平，为高胆固醇血症的治疗、动脉粥样硬化和冠心病的防治提供了一种新的有效选择。     

降脂治疗新进展——新型胆固醇吸收抑制剂

Ezetimibe是一种新型选择性肠胆固醇吸收抑制通过抑制肠上皮细胞的胆固醇吸收蛋白NPCILI减少胆固醇、植物固醇的吸收以及胆汁胆固醇的再吸收，从而降低血浆固醇水平。Ezetimibe的作用与他汀类药物抑制胆固醇合成的机制互补，在降低血浆低密度脂蛋白胆固醇和总胆固醇水平的同时，升高高密度脂蛋白胆固醇水平，为高胆固醇血症的治疗、动脉粥样硬化和冠心病的防治提供了一种新的有效选择。     

他汀降胆固醇预防冠心病临床分析

目的 探讨他汀降胆固醇预防冠心病的临床效果.方法 对冠心病患者他汀类药物降胆固醇预防临床资料进行回顾性分析.结果 采用他汀类药物降脂治疗,以降低LDL-C,使其达到〈100 mg/dl（2.6 mmol/L）.TC、LDL、TG明显降低,及高密度脂蛋白升高.结论 他汀类药物能有效降低TC和LDL-C,还有延缓斑块进展,使斑块稳定和抗炎等调脂以外的作用.所有冠心病患者,无论其血脂水平如何,均应给予他汀类药物.     

他汀类药物和脑卒中防治

他汀类药物属于羟甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂，它不仅是一类有效的降胆固醇药物，而且也有卓越的心血管保护作用，广泛用于临床治疗。在他汀类药物问世之前，尽管通过控制饮食和使用非他汀类的降脂药物可以降低血浆总胆固醇(TC)，但不能减少脑卒中的发生率。虽然血浆TC水平和动脉粥样硬化(AS)性脑卒中的多种相关病理状态(例如颈动脉粥样硬化等)明显相关，     

降血脂药：ezetimibe

1 商品名Ezetrol, Zetia2 开发与上市厂商默克和先灵葆雅公司共同开发,2002年11月在德国首次上市,不久即在美国、英国和瑞士上市。3 适应证辅助治疗原发性 (杂合子家族性或非家族性) 高胆固醇血症 (与他汀类药物合用,用于治疗单用他汀类药物不能控制或不能耐受的患者),纯合子家族性高胆固醇血症及同源型谷固醇血症。5 药理作用本品为新型胆固醇吸收抑制剂,局部作用于小肠上皮细胞,选择性抑制肠道胆固醇及相关植物固醇的吸收,使到达肝脏的胆固醇减少,降低肝脏中胆固醇水平,同时增加胆固醇在血液中的清除率;本品主要作用于外源性胆固醇,…     

Role of Colesevelam in Combination Lipid-Lowering Therapy

Hyperlipidemia is associated with an increased risk of cardiovascular events; reducing low-density lipoprotein cholesterol (LDL-C), the primary target for cholesterol-lowering therapy, lowers the risk for such events. Although bile acid sequestrants were the first class of drugs to show a mortality benefit related to LDL-C lowering, statins are now considered first-line pharmacological therapy for reducing LDL-C levels because of their potency and their remarkable record of successful outcomes studies. Nevertheless, a substantial proportion of patients do not achieve LDL-C goals with statin monotherapy. In addition, because of adverse effects (primarily myopathy), some patients may be unwilling to use or unable to tolerate statin therapy at all or may not tolerate a full therapeutic statin dose. Also, statins may increase risk of new-onset diabetes in patients at high risk for diabetes. Thus, there remains a need for other lipid-lowering drugs to be used in combination with or in place of statins. The purpose of this article is to review available data from the literature on the use of colesevelam, a second-generation bile acid sequestrant, in combination with other lipid-lowering agents. Colesevelam has been studied in combination with statins, niacin, fibrates, and ezetimibe (including some three-drug combinations). An additive reduction in LDL-C was seen with all combinations. Other observed effects of colesevelam in combination with other lipid-lowering drugs include reductions in apolipoprotein (apo) B (with statins, fibrates, ezetimibe, statin plus niacin, or statin plus ezetimibe) and high-sensitivity C-reactive protein (with statins), and increases in apo A-I (with statins, ezetimibe, or statins plus niacin). Triglyceride levels remained relatively unchanged when colesevelam was combined with statins, fibrates, ezetimibe, or statin plus ezetimibe, and decreased with the triple combination of colesevelam, statin, and niacin. Colesevelam offset the negative glycemic effects of statins and niacin in subjects with insulin resistance or impaired glucose tolerance. Colesevelam was generally well tolerated when added to other lipid-lowering therapies in clinical trials, with gastrointestinal effects such as constipation being the predominant adverse events. Since colesevelam is not absorbed and works primarily in the intestine, it has a low potential for systemic metabolic drug–drug interactions with other drugs. Colesevelam has been shown to not interact with the lipid-lowering drugs lovastatin and fenofibrate; where interaction may be anticipated, separating dosing times by 4 h reduces the impact of any interaction. Available data confirms that colesevelam has additive cholesterol-lowering effects when used in combination with other lipid-lowering therapies. Furthermore, in some patient populations, the additional glucose-lowering effect of colesevelam may be beneficial in offsetting hyperglycemic effects of other lipid-lowering drugs.     

Statins: can the new generation make an impression?

Although large-scale statin trials have demonstrated significant reductions in cardiovascular risk, there are many patients who have a cardiovascular event despite receiving statin therapy. There is increasing evidence that larger reductions in low-density lipoprotein cholesterol (LDL-C) are associated with greater improvements in cardiovascular morbidity and mortality, which highlights the need for more efficacious statins. This article will review the lipid-altering effects of two new statins, rosuvastatin and pitavastatin. Rosuvastatin represents an advance in the pharmacological and clinical properties of other available agents. The large LDL-C reductions observed with rosuvastatin, even at the start dose of 10 mg and in patients switched from other statins to rosuvastatin 10 mg, should help to improve goal attainment, while reducing the need for dose titration. The ability of rosuvastatin to improve other elements of the lipid profile, such as high-density lipoprotein cholesterol (HDL-C), triglycerides and non-HDL-C, may be of utility in patients with diabetes and the metabolic syndrome. Increases in HDL-C, along with the greater efficacy of rosuvastatin for reducing LDL-C and non-HDL-C, may obviate the need for combination therapy. Results of a number of outcome studies with rosuvastatin are expected over the next 5 years, which will contribute to the evidence base for statin therapy and cardiovascular disease prevention.     

A safety look at currently available statins

In this mini-review, the evidence for safety and efficacy of currently available statins is discussed. Large-scale, long-term clinical studies have documented an outstanding efficacy and safety profile for statin monotherapy when used at pharmacological doses. Non-life-threatening side effects may occur in up to 15% of patients receiving one statin. Sporadic reports show possible adverse effects of statins on nervous system function including mood alterations. More serious side effects may also occur but at much lower rates. Significant elevations in the activity of serum aminotransferase and creatine kinase alone or in combination with muscle pain in statin-treated patients should be taken seriously; under these conditions, monitoring the statin dose or its discontinuation must be considered. Unlike monotherapy, combination therapy is more problematic. Particularly, combination of the statins with gemfibrozil results in higher rates of drug toxicity. Co-administration of statins with other drugs, especially those which may interfere with the cytochrome P450 system, should be considered carefully. Special attention must be paid to the tolerability of the statins in elderly and transplant patients. The safety of statins in children and adolescents has not yet been well-documented, thus, statin therapy is not routinely recommended in this group of hyperlipidaemic subjects. Future clinical studies and surveillance information will warrant long-term safety of each member of this class of lipid-lowering agents.     

A safety look at currently available statins

In this mini-review, the evidence for safety and efficacy of currently available statins is discussed. Large-scale, long-term clinical studies have documented an outstanding efficacy and safety profile for statin monotherapy when used at pharmacological doses. Non-life-threatening side effects may occur in up to 15% of patients receiving one statin. Sporadic reports show possible adverse effects of statins on nervous system function including mood alterations. More serious side effects may also occur but at much lower rates. Significant elevations in the activity of serum aminotransferase and creatine kinase alone or in combination with muscle pain in statin-treated patients should be taken seriously; under these conditions, monitoring the statin dose or its discontinuation must be considered. Unlike monotherapy, combination therapy is more problematic. Particularly, combination of the statins with gemfibrozil results in higher rates of drug toxicity. Co-administration of statins with other drugs, especially those which may interfere with the cytochrome P450 system, should be considered carefully. Special attention must be paid to the tolerability of the statins in elderly and transplant patients. The safety of statins in children and adolescents has not yet been well-documented, thus, statin therapy is not routinely recommended in this group of hyperlipidaemic subjects. Future clinical studies and surveillance information will warrant long-term safety of each member of this class of lipid-lowering agents.     

Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions

Patients with the metabolic syndrome and/or Type 2 diabetes mellitus continue to have a high risk of coronary heart disease (CHD) and progression of atherosclerotic lesions despite aggressive statin therapy. Although the National Cholesterol Education Programme Adult Treatment Panel III guidelines recommend the use of fibrates in combination with statins in patients at very high risk of CHD (e.g., patients at the low-density lipoprotein cholesterol target with high triglycerides and low high-density lipoprotein cholesterol, many physicians remain reluctant to use these combinations due to concerns of myotoxicity. Recently conducted metabolic and pharmacokinetic drug–drug interaction studies using gemfibrozil or fenofibrate in combination with five commonly used statins demonstrated a widely different drug interaction potential for these two fibrates. Gemfibrozil causes a 2- to 6-fold increase in statin area under the curve and increases the exposure to many recently approved drugs for the treatment of diabetes. Alternatively, fenofibrate does not adversely affect either the metabolism or pharmacokinetics of the statins studied. These pharmacokinetic differences appear to translate into less potential for interactions with fenofibrate/statin combination therapy compared to gemfibrozil/statin co-administration. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study in 10,000 patients with Type 2 diabetes mellitus is testing the efficacy and safety of fenofibrate/statin combination.     

Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions

Patients with the metabolic syndrome and/or Type 2 diabetes mellitus continue to have a high risk of coronary heart disease (CHD) and progression of atherosclerotic lesions despite aggressive statin therapy. Although the National Cholesterol Education Programme Adult Treatment Panel III guidelines recommend the use of fibrates in combination with statins in patients at very high risk of CHD (e.g., patients at the low-density lipoprotein cholesterol target with high triglycerides and low high-density lipoprotein cholesterol, many physicians remain reluctant to use these combinations due to concerns of myotoxicity. Recently conducted metabolic and pharmacokinetic drug-drug interaction studies using gemfibrozil or fenofibrate in combination with five commonly used statins demonstrated a widely different drug interaction potential for these two fibrates. Gemfibrozil causes a 2- to 6-fold increase in statin area under the curve and increases the exposure to many recently approved drugs for the treatment of diabetes. Alternatively, fenofibrate does not adversely affect either the metabolism or pharmacokinetics of the statins studied. These pharmacokinetic differences appear to translate into less potential for interactions with fenofibrate/statin combination therapy compared to gemfibrozil/statin co-administration. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study in 10,000 patients with Type 2 diabetes mellitus is testing the efficacy and safety of fenofibrate/statin combination.     

Statin therapy in the elderly: does it make good clinical and economic sense?

HMG-CoA reductase inhibitors (statins) have been established as the dominant treatment for coronary heart disease (CHD). This dominance is based on an impressive body of clinical trial evidence showing significant benefits in primary prevention of cardiovascular events in individuals at risk for CHD and in secondary prevention of such events in patients with CHD and high or normal plasma cholesterol levels. There is, however, significant room for improvement in the treatment of CHD with respect both to drug efficacy and to the disparity between evidence-based medicine and actual clinical practice particularly in relation to treatment strategies for the elderly. Current statins fall short of requirements for 'ideal' lipid-lowering treatment in several respects; 'super' statins and other agents currently in development may satisfy more of these requirements. Moreover, available therapies are not applied optimally, because of physician nonacceptance and/or patient noncompliance; thus, the majority of patients with CHD or its risk factors still have cholesterol levels that exceed guideline targets. There is also evidence that older patients with CHD, or at high risk of CHD, are undertreated - possibly because of concerns regarding the increased likelihood of adverse events or drug interactions or doubts regarding the cost effectiveness of statin therapy in this population. This group is of particular clinical relevance, since it is showing a proportionate rapid expansion in most national populations. To address their potential healthcare needs, the ongoing Pravastatin in the Elderly at Risk (PROSPER) study is assessing the effects of pravastatin in elderly patients (5804 men and women aged 70-82 years) who either have pre-existing vascular disease or are at significant risk for developing it, with the central hypothesis that statin therapy (pravastatin 40 mg/day) will diminish the risk of subsequent major vascular events compared with placebo. After a 3.2-year treatment period, a primary assessment will be made of the influence of statin treatment on major cardiovascular events (a combination of CHD death, nonfatal myocardial infarction, and fatal or nonfatal stroke). Optimal deployment of the currently available agents and of newer agents (no matter how well they satisfy requirements for ideal treatment) ultimately depends on the establishment of an evidence base and may require far-reaching educational programmes that change the way risk factor management is viewed by caregivers and patients alike.     

Extended-release niacin with laropiprant: a review on efficacy,clinical effectiveness and safety

Mixed hyperlipidaemia is an important risk factor for the development of cardiovascular disease. The global management of mixed hyperlipidaemia is often more difficult than the treatment of pure hypercholesterolaemia in terms of goal attainments. Despite the significant clinical benefits provided by statins, many patients with mixed hyperlipidaemia do not achieve their recommended low-density and non-high-density lipoprotein cholesterol target goals with statin monotherapy. The combination of ezetimibe plus fenofibrate is a new alternative to improve the overall atherogenic lipid profile of patients with mixed hyperlipidaemia. However, the absence of comparative data with statin monotherapy and of long-term clinical studies suggests reservation of the combination of ezetimibe plus fenofibrate as a second-line therapy. Nevertheless, this combination therapy of ezetimibe plus fenofibrate seems particularly useful for patients with a poor response or intolerance to statin monotherapy.     

Ezetimibe plus fenofibrate: a new combination therapy for the management of mixed hyperlipidaemia?

Mixed hyperlipidaemia is an important risk factor for the development of cardiovascular disease. The global management of mixed hyperlipidaemia is often more difficult than the treatment of pure hypercholesterolaemia in terms of goal attainments. Despite the significant clinical benefits provided by statins, many patients with mixed hyperlipidaemia do not achieve their recommended low-density and non-high-density lipoprotein cholesterol target goals with statin monotherapy. The combination of ezetimibe plus fenofibrate is a new alternative to improve the overall atherogenic lipid profile of patients with mixed hyperlipidaemia. However, the absence of comparative data with statin monotherapy and of long-term clinical studies suggests reservation of the combination of ezetimibe plus fenofibrate as a second-line therapy. Nevertheless, this combination therapy of ezetimibe plus fenofibrate seems particularly useful for patients with a poor response or intolerance to statin monotherapy.     

Secondary prevention of coronary heart disease in elderly patients following myocardial infarction: are all HMG-CoA reductase inhibitors alike?

Cardiovascular disease remains the leading cause of mortality in elderly patients. While coronary heart disease (CHD) morbidity and mortality have decreased over the last 25 years, the percentage reduction in elderly patients is nearly 50% lower than that for the general adult population. Therefore, aggressive primary and secondary prevention of CHD is imperative for our society, and hyperlipidaemia remains the major modifiable risk factor in the elderly population. However, there appears to be a reluctance among practitioners to treat hyperlipidaemia in elderly patients, a bias that is particularly important given the absolute benefits of treating such patients. While many of the major clinical trials involving HMG-CoA reductase inhibitors (statins) in patients with CHD focused on younger individuals, subsequent subgroup analyses of elderly patients have shown consistent reductions in all-cause mortality, major CHD events and numbers of revascularization procedures. Intensive statin therapy in the setting of acute myocardial infarction (MI) has also been shown to reduce the risk of death, MI, unstable angina, revascularization and stroke in elderly patients. Furthermore, three recent articles that have evaluated intensive lipid-lowering in the elderly population have extended the known benefits of such therapy to elderly patients with acute coronary syndrome and stable CHD.Elderly patients often take multiple medications and are at significant risk of drug-drug interactions. Several available statin medications are metabolized by cytochrome P450 (CYP) 3A4 and can therefore interact with commonly used medications such as amiodarone, macrolide antibacterials, calcium channel antagonists, fibric acid derivatives and ciclosporin. These interactions can result in an increased frequency of statin-related hepatotoxicity and myopathy.There are currently six commercially available statin medications on the US market, three of which, lovastatin, simvastatin and pravastatin, are available in generic formulations, and are thus less expensive. Of the commercially available statins, rosuvastatin, atorvastatin and simvastatin have the highest potency. While rosuvastatin currently lacks clinical event data, atorvastatin has the most clinical event data for CHD and even stroke prevention. Although pravastatin has lower potency than other described statins, it also has the lowest risk of drug-drug interactions involving CYP.