高密度脂蛋白胆固醇增量药物研究进展

流行病学研究显示,高密度脂蛋白胆固醇（HDL-C）水平下降与心血管疾病的危险性增高密切相关。HDL-C已成为近10年来心血管疾病的一项重要治疗靶点。本文阐述HDL胆固醇的生物学效应,并就新近有关提高HDL-C水平的药物：静脉输注重组Apo A-1 Milano／磷酯复合物（ETC-216）以及胆固醇酯转移蛋白抑制剂（torcetrapib,JTT-705）等的开发进行简要讨论。     

胆固醇酯转移蛋白抑制剂开发

脂代谢异常是动脉粥样硬化和冠心病的重要危险因素,调脂药物通过调控脂质代谢,降低血脂水平,进而降低心血管疾病的发生。胆固醇酯转移蛋白(CETP)抑制剂可明显升高高密度脂蛋白-胆固醇,本文综述几种处于临床研究阶段的CETP抑制剂研究进展。     

调节高密度脂蛋白药物的研究进展

动脉粥样硬化性心血管疾病是引起患者死亡的一个主要原因。高密度脂蛋白(HDL)不仅具有抗动脉粥样硬化的作用,同时高密度脂蛋白胆固醇(HDL-C)水平与患心血管疾病的危险性呈负相关。因此,HDL成为抗动脉粥样硬化和冠心病药物的作用靶点。目前,临床上常用的调节血脂药物并非特异性地作用于HDL-C,对调节HDL作用较弱。研究和开发新的调节HDL的药物可从不同途径升高HDL-C水平或者改善HDL-C的功能,对预防和治疗心血管疾病具有重要意义。本文对调节或改善HDL的药物进行了综述。     

torcetrapib与动脉粥样硬化

动脉粥样硬化(AS)是引起心肌梗死、脑梗死及冠心病等心脑血管疾病死亡的主要原因。近来对胆固醇酯转移蛋白(CETP)的抑制作用已成为治疗AS的新靶点,torcetrapib是治疗AS和脂蛋白紊乱的新的CETP抑制剂。家兔实验表明,torcetrapib对CETP活性的抑制达70%~80%,且能使HDL-C水平增加50%~100%。临床试验表明,torcetrapib单独服用或伍用其他抑制剂,均能使HDL-C水平增加,LDL-C水平降低,达到AS的治疗目标。     

胆固醇酯转移蛋白抑制剂的开发及研究进展

胆固醇酯转移蛋白(CETP)抑制剂可升高血浆中高密度脂蛋白胆固醇(HDL-C)水平,同时降低低密度脂蛋白胆固醇(LDL-C)水平,为目前调脂药物的开发及研究重点,预期可改善心血管疾病的结局。目前尽管CETP抑制剂的研发已经取得重大进展,但寻找安全、有效的CETP抑制剂仍面临许多挑战。本文对目前CETP抑制剂的临床研究进展进行综述。     

降血脂药物国外研发的现状

高胆固醇和高脂蛋自血症是心血管疾病的主要危险因素，降低血浆胆固醇水平是治疗动脉粥样硬化疾病的有效方法川，因此，降血脂药物的研究与发展越来越受到人们的重视。降血脂药物根据其作用机制可分为：（1）影响脂质合成、代谢和清除的药物；（2）影响胆固醇和胆酸吸收的药物；（3）多烯脂肪酸类；（4）其他（酰基辅酶A胆固醇酰基转移酶抑制剂、微球体甘油三酯转移蛋自抑制剂、胆固醇酯转移蛋白抑制剂等）。     

胆固醇酯转运蛋白抑制剂研究进展

胆固醇酯转移蛋白(CETP)是胆固醇逆转运(RCT)循环中协调脂质转运的重要蛋白。CETP调控胆固醇酯和甘油三酯在高密度脂蛋白、低密度脂蛋白和极低密度脂蛋白之间的转运,在高密度脂蛋白代谢中起核心作用。抑制CETP活性可以有效提高体内高密度脂蛋白水平(同时降低低密度脂蛋白水平)从而可以预防心血管疾病的发生,因此CETP是一个非常具有开发前景的潜在调血脂药物作用靶标。本文对新降脂靶点CETP及目前CETP抑制剂的最新研究现状进行综述。     

抗动脉粥样硬化药物研究进展

本文对近年来出现的抗动脉粥样硬化新药物靶标过氧化物酶体增殖活化受体激动剂、胆固醇酯转移蛋白抑制剂、输注载脂蛋白A-I、肝脏X受体激活剂和磷脂转移蛋白抑制剂等进行了综述。     

胆固醇酯转移蛋白质抑制药在冠心病防治中的应用

胆固醇酯转移蛋白抑制药是一种新型的调脂药物,具有升高高密度脂蛋白,促进胆固醇转运等作用,在抗动脉粥样硬化和冠心病预防中发挥重要作用。     

高密度脂蛋白升高药物的研发现状

高密度脂蛋白(HDL)在胆固醇逆向转运中所发挥的重要作用,使其在近年来开发动脉粥样硬化性心血管疾病药物中占据着主导性地位.按作用机制分类,开发中的HDL升高药物可分为以下7类:胆固醇酯转移蛋白(CETP)抑制剂、过氧化物酶体增殖因子激活受体(PPARs)激动剂、HDL模拟药物、肝X受体(LXR)激动剂、基因治疗、HDL去脂策略及其他.文中就处于开发阶段的HDL升高药物进行了综述.     

The potential for CETP inhibition to reduce cardiovascular disease risk

ABSTRACT

Background: Although reductions in cardiovascular risk can be achieved by lowering low-density lipoprotein cholesterol, treated patients remain at substantial risk. Epidemiological studies have established that higher levels of high-density lipoprotein cholesterol (HDL-C) are strongly associated with reduced cardiovascular risk, and therefore raising levels of HDL-C may be beneficial. The activity of cholesteryl ester transfer protein (CETP) appears to be inversely correlated with HDL-C levels and thus CETP is an attractive target for intervention to raise levels of HDL-C and potentially reduce residual cardiovascular risk.

Objectives: This paper reviews the evidence for an atheroprotective role of higher levels of HDL‐C, the function of CETP in cholesterol metabolism, and the concept of CETP inhibition as a potential new strategy for decreasing cardiovascular risk. An analysis of clinical studies of CETP inhibition was also performed.

Methods: MEDLINE (1966 to June 2006), EMBASE (1974 to June 2006), and cardiology conference proceedings were searched for clinical trials of CETP inhibition.

Results: Thirteen reports involving vaccine-based and pharmacological inhibition of CETP were found. Modest and inconsistent elevation of HDL‐C was observed with vaccine-based therapy, whereas HDL-C elevation with pharmacological inhibitors was greater and more consistent.

Conclusions: Elevation of HDL‐C via CETP inhibition appears to be a potentially promising approach to reduce cardiovascular disease. Preliminary studies suggest benefits of CETP inhibition on serum lipid levels, and ongoing studies should establish the effects on atherosclerosis and cardiovascular events.     

Cholesteryl ester transfer protein inhibitors

As well as hypercholesterolaemia, low levels of high-density lipoprotein cholesterol (HDL-C) are critical risk factors for atherosclerosis and coronary heart disease (CHD). Although fibrate, simvastatin and niacin can be used for the treatment of a low HDL-C level, their effects, however, are not wholly satisfactory. Thus, better drugs for the elevation of HDL-C are desired. Among the many methods that may be used to raise HDL-C levels, this review focuses on small molecule inhibitors of cholesteryl ester transfer protein (CETP) and summarises recent patent and journal data.     

High-density lipoprotein cholesterol targeting for novel drug discovery: where have we gone wrong?

Lowering low-density lipoprotein-cholesterol (LDL-C) is an effective strategy to reduce cardiovascular risk. However, a significant residual risk remains in statin-treated patients. High-density lipoprotein cholesterol (HDL-C) is a strong, independent and inverse predictor of cardiovascular risk in many epidemiologic studies and has, therefore, emerged as a potential novel therapeutic target for addressing this substantial residual risk. Nevertheless, the failure of cholesteryl ester transfer protein (CETP) inhibitors and niacin in clinical trials has generated considerable speculation about the beneficial effects of HDL. Experimental studies have identified several HDL cardioprotective functions, including enhancement of macrophage reverse cholesterol transport and endothelial function and its antioxidant, anti-inflammatory and anti-thrombotic properties. Furthermore, HDL is highly heterogeneous and the atheroprotective functions of the different HDL subpopulations are not completely understood. Current available data indicate that increased HDL-C levels do not always correlate with enhanced HDL functions and, therefore, should not be considered a biomarker of HDL functionality. The clinical application of the novel HDL-based therapeutic approaches requires the development of validated and reproducible measures of key HDL functions.     

Therapeutic implications of cholesteryl ester transfer protein inhibitors in hyperlipidemia and low high-density lipoprotein-cholesterolemia

Low levels of high-density lipoprotein cholesterol (HDL-C) in plasma are an independent coronary risk factor. Therapies that lower cholesteryl ester transfer protein (CETP) have preventative effects on aortic atherosclerosis in cholesterol-fed rabbits. CETP inhibitors are a new class of compounds that can increase HDL-C levels by up to 70%, according to data from phase I and II clinical trials. CETP inhibitors are therefore likely to be beneficial in patients with moderate hypercholesterolemia and HDL-C levels lower than 40 mg/dl. CETP inhibitors should, however, be viewed with caution as their effects on triglyceride metabolism are currently unknown.     

Pharmacological management of diabetic dyslipidemia

Introduction: Diabetes mellitus is associated with increased cardiovascular disease (CVD) risk.

Areas covered: Main goal of hypolipidemic treatment in diabetic patients is low-density lipoprotein cholesterol (LDL-C) lowering with the use of statins. Addition of ezetimibe is useful in diabetic patients who cannot achieve their LDL-C target. However, many diabetic patients have increased residual CVD risk, which is mainly attributed to high triglycerides and low high-density lipoprotein (HDL-C) values. The addition of fenofibrate targets these variables and possibly reduces residual CVD risk, but a possible beneficial effect has been shown only in a pre-specified subgroup analysis in patients with high triglycerides and low HDL-C values. The newer proprotein convertase subtilisin/kexin type 9 inhibitors lower substantially LDL-C levels, but data from specifically designed trials in diabetic patients are not currently available. Although the cholesterol ester transfer protein (CETP) inhibitors have shown harmful effects or lack of efficacy in completed clinical trials, the newer CETP inhibitors have promising effects on lipid profile and carbohydrate metabolism, but their effects on CVD risk and safety profile have not been assessed.

Expert commentary: Clinicians have a range of pharmacological options to reduce the CVD risk of diabetic patients.     

Investigational CETP antagonists for hyperlipidemia and atherosclerosis prevention

INTRODUCTION: Reverse cholesterol transport (RCT) is a function of high-density lipoproteins (HDL) in humans and higher species. It is enabled by the cholesteryl ester transfer protein (CETP), a high molecular weight protein exchanging cholesteryl esters in HDL for triglycerides in very low-density lipoproteins (VLDL). Inhibition of CETP may provide a useful strategy to raise HDL, the protective lipoprotein fraction in plasma. AREAS COVERED: Evaluation based on clinical and experimental findings of the three drugs developed or in advanced development for CETP inhibition. EXPERT OPINION: Inhibition of CETP, both inherited and drug induced, at times leads to dramatic elevations of HDL-cholesterol (HDL-C) levels. Epidemiological data presently available do not, however, provide convincing evidence that reduced CETP levels or activity due to genetic factors and associated with HDL-C elevations, reduce cardiovascular risk. Indeed, the opposite may be true in some instances. All the three CETP inhibitors were the object of experimental and clinical evaluation. Large clinical trials with torcetrapib led to very negative findings, that is, raised cardiovascular morbidity and mortality in addition to raised risk of cancer and sepsis. Off-target effects of the drug, such as aldosterone retention and raised blood pressure, were believed to provide an explanation for these negative findings. The two newer agents, dalcetrapib and anacetrapib, do not exert off-target effects. The two drugs differ because anacetrapib has a more dramatic effect on HDL cholesterolemia (+139%) versus more moderate effects of dalcetrapib (+20-30%). Anacetrapib, however, may impair formation of pre-β HDL, that is, the primary particles in the process of cholesterol removal. The initial large trial with anacetrapib (DEFINE study) in coronary patients on statin treatment, appeared to confirm a remarkable HDL raising property, together with some reduction in vascular end points, in particular coronary procedures. The issue of other potentially harmful effects of CETP inhibition (sepsis and others) has yet to be clarified. Large clinical end-point trials, however, will be necessary to provide convincing evidence that, in addition to raising HDL-C, CETP inhibitors provide a valid additional treatment, for example, to statins in patients with coronary heart disease (CHD) or at high risk of CHD.     

On- and off-target pharmacology of torcetrapib: current understanding and implications for the structure activity relationships (SAR), discovery and development of cholesteryl ester-transfer protein (CETP) inhibitors

Lowering of serum low-density lipoprotein cholesterol (LDL-C) levels remains the primary aim of lipid management. Much progress has been made in reducing rates of cardiovascular disease morbidity and mortality, largely through increased awareness of lipid-lowering therapies and particularly through the use of high-efficacy LDL-C-lowering HMG-CoA reductase inhibitors (statins). While statins have been effective in reducing cardiovascular disease risk, many patients do not adequately achieve guideline-recommended LDL-C goals and may benefit from additional cholesterol management therapies. Low serum levels of high-density lipoprotein cholesterol (HDL-C) are considered another important determinant of cardiovascular disease risk, and increased serum HDL-C levels have been shown to be associated with reductions in the incidence of cardiovascular disease. One approach toward raising serum HDL-C levels is the inhibition of cholesteryl ester-transfer protein (CETP), a plasma protein that promotes the transfer of cholesteryl ester from HDL particles and other lipoprotein fractions to pro-atherogenic apolipoprotein B-containing lipoproteins. The inhibition of this protein raises HDL-C levels and also reduces LDL-C levels. The concept of raising HDL-C levels through pharmacological intervention of this target was validated in preclinical and clinical studies with torcetrapib, the first CETP inhibitor to be assessed in late-stage clinical trials. The large clinical outcomes trial, ILLUMINATE, was prematurely terminated due to other unexpected pharmacological effects of torcetrapib that led to an increased risk of cardiovascular events and deaths. Thus, the ultimate effect of CETP inhibition on cardiovascular disease outcomes remains to be determined. Other CETP inhibitors currently in development do not have the adverse effects of increased blood pressure and circulating levels of aldosterone shown to be structurally related to torcetrapib. Preclinical and pharmacology studies have shown that these CETP inhibitors are distinct compared with torcetrapib and lack the features related to its off-target pharmacology. These findings indicate that the off-target activities of torcetrapib are not necessarily class effects of CETP inhibitors. Recent clinical trials have shown that dalcetrapib, anacetrapib and evacetrapib, the most advanced of these compounds in development, effectively raise HDL-C levels and lower LDL-C in the absence of off-target activities. The results of these trials are encouraging within the limits of study size and duration and provide a rationale for conducting further studies, including large clinical outcomes trials to assess whether CETP inhibition can lead to cardioprotective effects. This review summarizes the data supporting the development of CETP inhibitors as HDL-C-raising therapy, including structure-activity relationships and preclinical and clinical pharmacology studies of known CETP inhibitors.     

Targeting cAMP in chronic lymphocytic leukemia: a pathway-dependent approach for the treatment of leukemia and lymphoma

Background: CETP has an established role in the transport of cholesterol from the peripheral tissues to the liver for elimination. The fact that CETP was recognized as a target for raising high-density lipoprotein cholesterol (HDL-C) levels has led to research on CETP inhibitors to protect against atherosclerosis. Objective: To review the role of CETP as a pivotal target for atherosclerosis and cardiovascular diseases and the effect of its overexpression or inhibition on lipid metabolism. Methods: A review of literature on the role of CETP in cholesterol metabolism and on recent developments on CETP inhibitors. Results/conclusions: Animal and human studies have provided evidence supporting both the pro- and antiatherogenic roles of CETP. Clinical trials with CETP inhibitors remain under serious consideration. Further studies are necessary for understanding of the role of CETP in lipid metabolism and the development of novel therapies involving a combination of strategies for treatment of atherosclerosis and cardiovascular disease.     

Daratumumab granted breakthrough drug status

Statins effectively lower plasma low-density lipoprotein cholesterol (LDL-C) levels and reduce the risk of vascular events. However, this benefit might be improved by dealing with other vascular risk factors such as high-density lipoprotein cholesterol (HDL-C). It follows that there has been an interest in drugs that raise plasma HDL-C levels. Among these drugs are the cholesteryl ester transfer protein (CETP) inhibitors. The first CETP inhibitor to be evaluated in an event-based trial was torcetrapib. This drug can considerably elevate serum HDL-C levels (e.g., by 72%). However, a recently published trial (ILLUMINATE) showed that torcetrapib used in combination with atorvastatin was associated with significantly more vascular events and deaths than atorvastatin alone. This finding resulted in the discontinuation of the torcetrapib development programme. The cause(s) of the adverse outcome remain speculative. It has been suggested that a significant rise in systolic blood pressure and possibly the quality of the HDL produced may be relevant. Despite this disappointing outcome it seems to be too early to close the book on CETP inhibitors because two other members of this class are being evaluated. These drugs (JTT-705 and anacetrapib) may be devoid of the adverse effect on systolic blood pressure. Eventually only appropriately designed, event-based trials, will settle the issue of whether CETP inhibitors are clinically useful.     

Anacetrapib, a cholesteryl ester transfer protein inhibitor

INTRODUCTION: Inhibition of cholesteryl ester transfer protein (CETP) has the ability to increase high-density lipoprotein (HDL)-cholesterol levels and potentially reduce cardiovascular risk. The first CETP inhibitor, torcetrapib, was discontinued due to off-target effects resulting in increased mortality. However, anacetrapib does not appear to exhibit these effects and is being developed as a selective inhibitor of CETP to be orally administered for the treatment of primary hypercholesterolemia and mixed hyperlipidemia. AREAS COVERED: Areas covered are: mode of action, preclinical development and clinical trials of anacetrapib, a CETP inhibitor. The article provides an understanding of the pharmacokinetic and pharmacodynamic characteristics of anacetrapib and insight into its clinical efficacy and safety. In clinical trials, anacetrapib produced dose-dependent elevations in HDL-cholesterol and reductions in low-density lipoprotein (LDL)-cholesterol. Furthermore, anacetrapib has been shown to increase apolipoprotein (apo) A-I and decrease apoB levels. EXPERT OPINION: Anacetrapib is a potent, reversible CETP inhibitor that is not only able to increase HDL-cholesterol, but also further decrease LDL-cholesterol when taken in combination with a statin. Safety and tolerability studies reported to date are promising. The results from Phase III trials investigating the efficacy of anacetrapib for the prevention of major coronary events in patients with atherosclerotic cardiovascular disorders are awaited with interest.