贝特类调脂药物研究进展

贝特类药物又称苯氧芳酸类药物,是指包括吉非贝齐、氯贝特、非诺贝特、苯扎贝特和环丙贝特等在内的一类调脂药物。这类药物口服吸收快而完全,服药后1~2 h内即可检测到血浆中药物浓度,与血浆蛋白结合率高。贝特类药物     

他汀类和贝特类降脂药物联合使用增加横纹肌溶解的危险

美国研究者称，他汀类(statin)药物和贝特类(fibrate)(纤维酸衍生物)降脂药物联合使用比单独使用他汀类药物增加因横纹肌溶解的住院危险。阿托伐他汀(atorvastatin)(Ⅰ)、普伐他汀(pravastatin)(Ⅱ)、辛伐他汀(simvastatin)(Ⅲ)单药治疗发生横纹肌溶解的住院危险相似，     

贝特类调脂药物治疗2型糖尿病患者调脂的作用

英国前瞻性糖尿病研究（UKPDS）结果显示,75%的2型糖尿病患者死于心血管疾病,而低密度脂蛋白胆固醇（LDL-C）升高及高密度脂蛋白胆固醇（HDL-C）下降是导致死亡的第1、2位危险因素.有研究表明,低HDL-C及高三酰甘油（TG）水平是心血管事件剩余风险的主要危险因素,降低LDL-C同时升高HDL-C、降低TG可进一步减少患者心血管事件的发生.临床上对于2型糖尿病患者的调脂治疗,目前常用他汀类及贝特类药物.他汀类调脂药物在降低LDL-C等心血管事件一、二级预防中作用显著,但心血管事件剩余风险仍较高;而贝特类调脂药物不仅可明显降低心血管事件剩余风险还可有效改善胰岛功能及胰岛素抵抗.现将贝特类调脂药物治疗2型糖尿病患者调脂的作用综述如下.     

烟酸类调脂药物研究进展

烟酸具有确切而全面的调脂作用,并且随着剂型的改进重新受到关注。本文综述了烟酸独特的药理作用,对其调脂疗效及联合作用疗效、安全性进行了循证评价,肯定了其在防治心血管疾病中的重要地位。     

他汀类调脂药物的应用分析

目的:了解中山医科大学第一附属医院1996～2000年调脂药物的使用情况,着重分析他汀类药物的应用.方法:采用限定日剂量值(DDD)分析法,对5年中消耗的他汀类调脂药物的数据进行分析,统计其用药频率及日均用药费用及调脂药销售金额、品种变化.结果:1997年他汀类销售金额随整体调脂药物增长有较大增幅;从1998年起他汀类品种逐渐增加,辛伐他汀的总用药人次值(DDDs)一直位居首位,日均用药费用基本呈下降趋势.结论:该院他汀类药物的使用符合经济、适用原则,基本无一味追求新药、贵药现象.     

调脂药物注册临床试验的考虑

本文旨在介绍调脂药物注册临床试验的主要考虑.有效性主要在于对血脂参数的影响、血管的保护作用和对于死亡率及心血管事件的影响.安全性集中在肝脏、肌肉和长期的心血管事件的发生上.同时本文也对调脂药物在儿童中开展试验的要求进行了阐述.     

血脂异常首选他汀类调脂药物

研究显示，血清总胆固醇（TC）、低密度脂蛋白-胆固醇（LDL-C）升高是导致缺血性心脑血管病（包括冠心病和缺血性脑卒中）的独立危险因素。随着人们生活水平的提高，血脂异常者呈上升趋势，心血管病已成为我国城乡居民的第一位死亡原因，重视血脂检测和调脂治疗对于心血管病的预防及治疗具有非常重要的意义。     

他汀类调脂药物治疗不稳定型心绞痛疗效分析

目的探讨他汀类调脂药物治疗不稳定型心绞痛的临床疗效。方法将112例不稳定型心绞痛患者随机分为观察组和对照组各56例,2组均常规治疗,观察组加用辛伐他汀治疗。治疗后比较2组临床疗效。结果观察组总有效率为87.50%高于对照组的67.86%,差异有统计学意义(P<0.05)。结论他汀类药物能降低胆固醇,抗动脉粥样硬化,对不稳定型心绞痛有显著疗效。     

调脂药物的合理应用

目的探讨调脂类药物的临床应用。方法通过查阅文献,介绍调脂类药物在临床上的重要性,特别是在心血管疾病方面的应用。结果调脂类药物在高胆固醇血症和动脉粥样硬化方面治疗效果显著。结论调脂类药物的应用日益受到重视。     

他汀类降脂药物在冠心病防治中的地位

已有的证据表明:冠心病的发病有若干危险因素起重要作用,主要的危险因素有高胆固醇血症、高血压、吸烟和糖尿病,低高密度脂蛋白血症、年龄等也是重要的危险因素,在以上各因素中高胆固醇血症最被重视。流行病学显示,随着血胆固醇的长期增高,冠心病事件的发生率增加;降低胆固醇可以减轻动脉粥样硬化,减少冠心病事件。他汀类药物作为强效降胆固醇药物,在冠心病的防治中具有重要的地位。1他汀类药物防治冠心病的作用机制临床试验表明,他汀类药物可降低胆固醇、减轻动脉粥样硬化、减少冠心病事件。其可能的作用机制包括:(1)他汀类药物通过竞争性…     

Strategies for the management of diabetic dyslipidaemia

Atherosclerosis, the complication most prominently associated with type 2 diabetes and cardiovascular disease, represents a major burden for both individuals and society. Mortality rates associated with cardiovascular disease among patients with type 2 diabetes are at least 3 times those in the general population, and although 'traditional' cardiovascular risk factors affect patients with this disorder as they do other individuals, they do not account for the excess risk attached to type 2 diabetes. There is a growing body of evidence to show that hyperglycaemia and dyslipidaemia are connected with this excess cardiovascular risk: hypertriglyceridaemia has been implicated in several prospective clinical studies, and available data suggest that low density lipoprotein (LDL)-cholesterol is more atherogenic in patients with type 2 diabetes than in other individuals. It is possible that this increased atherogenicity is associated with a preponderance of small, dense LDL particles that are more prone to oxidation and glycation than larger fractions and that may be involved in endothelial dysfunction. These findings lead to the recommendation of mandatory global risk assessment, accompanied by good glycaemic control, aggressive lowering of serum levels of LDL-cholesterol and maintenance of serum levels of triglyceride at the lowest possible level in patients with type 2 diabetes.     

Simvastatin plus ezetimibe: combination therapy for the management of dyslipidaemia

Hyperlipidaemia is a pivotal risk factor for the development of atherosclerotic disease. A large number of studies have demonstrated that the treatment of abnormalities in lipoprotein levels reduces the risk for myocardial infarction, peripheral vascular disease, carotid artery disease, stroke, and cardiovascular mortality. Despite the development of multiple drug classes to treat dyslipidaemias and the promulgation of clearly defined guidelines for the management of lipid disorders, dyslipidaemia tends to be undertreated in the majority of patients at risk for cardiovascular disease. A part of the reluctance to treat different lipoprotein fractions to goal levels is attributable to physician- and patient-related concerns over the increasing toxicity of available therapies, as their dosages are increased. The risks of hepatotoxicity, myalgia, and rhabdomyolysis are fairly well characterised in patients receiving statins, fibrates and niacin. Another issue affecting treatment success rates is the fact that many patients with complex dyslipidaemias are inadequately responsive to single-agent therapy. As the epidemics of obesity, metabolic syndrome and diabetes mellitus continue to worsen, physicians will encounter severe, mixed dyslipidaemias more frequently. Many of these patients will require combinations of drugs to address the various metabolic derangements causing changes in multiple lipoprotein fractions. Although the need for combination therapy is well-established in the management of disorders, such as hypertension and diabetes, it is less often used for the treatment of dyslipidaemias. The development of safe, cost-effective, and efficacious combination dyslipidaemic therapy is an important goal in cardiovascular medicine. Simvastatin plus ezetimibe has recently been combined as a fixed dose therapy, which offers clinicians the opportunity to simultaneously inhibit two key pathways in cholesterol metabolism: hepatic cholesterol biosynthesis and the absorption of cholesterol at the level of the proximal jejunum. This dual mechanism of inhibition substantially increases the capacity to decrease serum levels of atherogenic low-density lipoproteins and increase high-density lipoprotein, compared with that observed when either drug is used alone. This combination increases the likelihood of therapeutic success in patients with dyslipidaemia.     

Diabetic dyslipidaemia: insights for optimizing patient management

BACKGROUND: Lipid abnormalities in people with diabetes are likely to play an important role in the development of atherogenesis. These lipid disorders include potentially atherogenic quantitative (increased triglyceride levels and decreased high-density lipoprotein-cholesterol [HDL-C] levels) and qualitative abnormalities of lipoproteins (changes in lipoprotein size, increase in triglyceride content of low-density lipoprotein (LDL) and HDL, glycation of apoproteins and increased susceptibility of LDL to oxidation). Guidelines from the two main diabetes organizations, the International Diabetes Federation and the American Diabetes Association, recommend the aggressive management of diabetic dyslipidaemia to reduce the risk of cardiovascular disease (CVD). Statins are the first choice pharmacological therapy to address diabetic dyslipidaemia due to their effectiveness at lowering LDL-C levels in patients with diabetes. Fibrates (peroxisome proliferator-activated receptor [PPAR]alpha ligands) target another aspect of dyslipidaemia by lower ing triglycerides (to a greater extent than statins) and raising HDL-C levels, especially when baseline levels are low. The PPARgamma agonist, pioglitazone appears to affect lipid metabolism by decreasing plasma triglycerides, increasing HDL-C and decreasing the number of small, dense atherogenic LDL particles. SCOPE: This paper provides a review of the current literature (based on searches of MEDLINE and EMBASE from 1985 to 2005, inclusive) supporting the recommendations for the management of dyslipidaemia among patients with type 2 diabetes, including new strategies involving drug combinations that achieve good glycaemic and lipidaemic control that could potentially reduce the morbidity and mortality associated with type 2 diabetes.     

Micronised fenofibrate: an updated review of its clinical efficacy in the management of dyslipidaemia

Micronised fenofibrate is a synthetic phenoxy-isobutyric acid derivative (fibric acid derivative) indicated for the treatment of dyslipidaemia. Recently, a new tablet formulation of micronised fenofibrate has become available with greater bioavailability than the older capsule formulation. The micronised fenofibrate 160mg tablet is bioequivalent to the 200mg capsule. The lipid-modifying profile of micronised fenofibrate 160mg (tablet) or 200mg (capsule) once daily is characterised by a decrease in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels, a marked reduction in plasma triglyceride (TG) levels and an increase in high-density lipoprotein cholesterol (HDL-C) levels. Micronised fenofibrate 200mg (capsule) once daily produced greater improvements in TG and, generally, in HDL-C levels than the hydroxymethylglutaryl coenzyme A reductase inhibitors simvastatin 10 or 20 mg/day, pravastatin 20 mg/day or atorvastatin 10 or 40 mg/day. Combination therapy with micronised fenofibrate 200mg (capsule) once daily plus fluvastatin 20 or 40 mg/day or atorvastatin 40 mg/day was associated with greater reductions from baseline than micronised fenofibrate alone in TC and LDL-C levels. Similar or greater changes in HDL-C and TG levels were seen in combination therapy, compared with monotherapy, recipients. Micronised fenofibrate 200mg (capsule) once daily was associated with significantly greater improvements from baseline in TC, LDL-C, HDL-C and TG levels than placebo in patients with type 2 diabetes mellitus enrolled in the double-blind, randomised Diabetes Atherosclerosis Intervention Study (DAIS) [> or =3 years follow-up]. Moreover, angiography showed micronised fenofibrate was associated with significantly less progression of coronary atherosclerosis than placebo. Micronised fenofibrate has also shown efficacy in patients with metabolic syndrome, patients with HIV infection and protease inhibitor-induced hypertriglyceridaemia and patients with dyslipidaemia secondary to heart transplantation. Micronised fenofibrate was generally well tolerated in clinical trials. The results of a large (n = 9884) 12-week study indicated that gastrointestinal disorders are the most frequent adverse events associated with micronised fenofibrate therapy. Elevations in serum transaminase and creatine phosphokinase levels have been reported rarely with micronised fenofibrate. In conclusion, micronised fenofibrate improves lipid levels in patients with primary dyslipidaemia; the drug has particular efficacy with regards to reducing TG levels and raising HDL-C levels. Micronised fenofibrate is also effective in diabetic dyslipidaemia; as well as improving lipid levels, the drug reduced progression of coronary atherosclerosis in patients with type 2 diabetes mellitus. The results of large ongoing studies (e.g. FIELD with approximately 10 000 patients) will clarify whether the beneficial lipid-modifying effects of micronised fenofibrate result in a reduction in cardiovascular morbidity and mortality.     

Pitavastatin: a review of its use in the management of hypercholesterolaemia or mixed dyslipidaemia

Pitavastatin (Livazo?, Livalo?), an inhibitor of HMG-CoA reductase (statin), is indicated for the reduction of elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels, in adult patients with primary hypercholesterolaemia and mixed dyslipidaemia, when response to diet and other non-pharmacological measures is inadequate. Pitavastatin has a favourable pharmacological profile following oral administration, including its long half-life (up to 12 hours), selective uptake into hepatocytes and minimal metabolism by cytochrome P450 (CYP) enzymes. This latter property decreases the likelihood of drug-drug interactions with agents that are metabolized by, inhibit or induce CYP enzymes. Pitavastatin improved the lipid profile (including LDL-C, TC and high-density lipoprotein cholesterol levels) in patients with hypercholesterolaemia and mixed dyslipidaemia, according to large, pivotal phase III studies of up to 60 weeks' duration. In these trials, pitavastatin for 12 weeks was noninferior to simvastatin and atorvastatin in terms of the improvement from baseline in LDL-C levels. In similarly designed trials, pitavastatin improved lipid profiles and was noninferior to simvastatin in patients with high cardiovascular risk and demonstrated significantly greater LDL-C reduction than pravastatin in elderly patients. Furthermore, in patients with type 2 diabetes mellitus, although noninferiority criteria for the comparison with atorvastatin were not met in terms of the improvement from baseline in LDL-C levels, pitavastatin was associated with some improvements in the lipid profile. Pitavastatin also demonstrated substantial lipid-modifying effects in exclusively Asian populations in well designed clinical trials. Pitavastatin was generally well tolerated in clinical trials of up to 60 weeks' duration, with a tolerability profile generally similar to that of atorvastatin and simvastatin. Therefore, pitavastatin appears to be an attractive alternative for the treatment of patients with primary hyperlipidaemia or mixed dyslipidaemia who have not responded adequately to diet and other non-pharmacological measures, and may present a useful treatment option in patients requiring polypharmacy, such as those at high risk of cardiovascular disease. Further studies evaluating the effects of pitavastatin on clinical endpoints, such as cardiovascular morbidity and mortality, are required to confirm the longer-term benefits of pitavastatin.     

Fenofibrate,simvastatin and their combination in the management of dyslipidaemia in type 2 diabetic patients

ABSTRACT

Objective: To evaluate the efficacy of fenofibrate, simvastatin or their combination in type 2 diabetic patients with combined dyslipidaemia.

Research design and methods: 241 patients, who had never previously taken lipid-lowering medications, received fenofibrate 145?mg/day, or simvastatin 40?mg/day, or fenofibrate 145?mg/day?+?simvastatin 40?mg/day?combination for 12 months. We evaluated lipids, glycaemic, haemostatic, and inflammatory variables at baseline, and after 6 and 12 months.

Results: After 12 months total cholesterol (TC), LDL cholesterol (LDL-C) and triglycerides (Tg) decreased while HDL cholesterol (HDL-C) increased in all groups, even if the values obtained with fenofibrate?+?simvastatin were the best. At the end of the study apolipoprotein A-1 (Apo A-1) increased with fenofibrate?+?simvastatin, while apolipoprotein B (Apo B) decreased in all groups compared to baseline. Plasminogen activator inhibitor-1 (PAI-1) and high-sensitivity C reactive protein (hs-CRP) decreased after 12 months compared to baseline with simvastatin, and with fenofibrate?+?simvastatin even if the value obtained with fenofibrate–simvastatin was the lowest. After 12 months, fibrinogen (Fg) decreased compared to baseline with fenofibrate?+?simvastatin.

Limitations: This study has some limitations. The first one is the relatively small sample of studied patients. The second one is the lack of an advanced lipid proteins evaluation, such as lipoprotein subfraction changes in the different treatment regimen. Finally, we have not selected patients that could show the best response to fibrate (i.e.: hypertriglyceridemics) or statins (i.e.: hypercholesterolemics) monotherapy, so the effect of these drugs administered alone may have been partly attenuated.

Conclusions: Fenofibrate?+?simvastatin association improved lipid parameters, prothrombotic and inflammatory factors, and appeared to have a good tolerability profile over 12 months of therapy.     

Modulators of dyslipidaemia

Coronary heart disease (CHD) is the leading cause of morbidity and mortality in most developed nations and atherosclerotic cardiovascular disease accounts for approximately one-half of all deaths due to CHD. Dyslipidaemias, which include various combinations of hypercholesterolaemia, hypertriglyceridaemia and hypoalphalipoproteinaemia, are major risk factors for atherosclerotic CHD. Current therapy largely treats hypercholesterolaemia, as reflected in the sales of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (HMGR-Is, statins) which account for a worldwide market share of 88%. The fibrates, which account for 9% of worldwide market share, effectively treat hypertriglyceridaemia but have inconsistent effects on hypercholesterolaemia and hypoalphalipoproteinaemia. Niacin, although an effective treatment for dyslipidaemias, suffers from a poor side-effect profile and therefore poor compliance. Moreover, niacin is not recommended for diabetics, a population in which atherosclerotic cardiovascular disease due largely to dyslipidaemia is the most common cause of death. Although additional strategies to reduce hypercholesterolaemia are still under pursuit (e.g., cholesterol absorption inhibitors, acyl-CoA:cholesterol acyltransferase [ACAT] inhibitors, squalene synthetase [SQS] inhibitors), attention has shifted to therapeutic strategies that affect hypertriglyceridaemia and/or hypoalphalipoproteinaemia in addition to hypercholesterolaemia (e.g., very low-density lipoprotein [VLDL] assembly/secretion inhibitors, thyromimetics, oestrogen agonists, peroxisome proliferator activated receptor [PPAR] activators, cholesterol ester transfer protein [CETP] inhibitors, apolipoprotein A1 [apoA1] production stimulators, lipoprotein lipase [LPL] activators) and these strategies are being aggressively pursued. The status of current efforts in these emerging therapeutic areas is described below.     

Treatment of dyslipidaemia in childhood

Importance of the field: Atherosclerosis, the condition underlying cardiovascular disease (CVD), often begins in childhood. A disturbance in lipoprotein metabolism is one of the major modifiable risk factors for the development of atherosclerosis and ensuing CVD. Therefore, strategies to prevent CVD should be implemented at an early age, especially in populations at high risk.

Areas covered in this review: We discuss the current treatment options for a number of primary and secondary dyslipidaemias. A literature search was done using PubMed, and references from 1973 to 2009 are cited.

What the reader will gain: The reader will gain a comprehensive review on pharmacological and non-pharmacological treatment options for primary and secondary dyslipidaemia in childhood.

Take home message: Dyslipidaemia may require early diagnosis and management, especially when it is familial with elevated cholesterol levels from birth onwards. If target goals for low-density lipoprotein reduction cannot be reached with lifestyle modification, drug therapy can be considered.