Laropiprant plus niacin for dyslipidemia and prevention of cardiovascular disease

Importance of the field: Prevention of cardiovascular disease has been only partially successful with the use of cholesterol-lowering drugs like statins. There is a residual risk remaining, which may be addressed by increasing protective high-density lipoprotein (HDL) cholesterol and apolipoprotein A1. The best drug available for that purpose is niacin. In addition to increasing HDL cholesterol and apolipoprotein A1, niacin decreases triglycerides, low-density lipoprotein (LDL)-cholesterol and lipoprotein(a) and has been named the broad-spectrum lipid drug.

Areas covered in this review: This review summarizes to what extent a new formulation of niacin may meet this request. The effects of niacin on lipoproteins, atherosclerosis and cardiovascular disease are described, from its first publication in 1955, and also its mechanism of action on lipoproteins and on flushing. The flushing inhibitor laropiprant is described as well as the antiflushing effect of this compound when added to extended-release niacin.

What the reader will gain: The reader will gain knowledge of the development of niacin as an antiatherosclerosis treatment and of the added value that laropiprant may offer this treatment principle; and also the present place of niacin/laropiprant in the armamentarium of cardiovascular preventive drugs.

Take home message: Niacin/laropiprant is a welcome means to address the residual risk in high-risk patients on statin therapy. However, the drug combination cannot completely eliminate niacin-induced side effects. Prescribing this treatment, therefore, will require careful provision of information and instruction to the patient.     

Niacin: a lipid polypill?

Niacin is one of the oldest yet also most diverse lipid lowering agents. As it not only lowers low-density-lipoprotein (LDL) cholesterol, triglycerides (TG) and lipoprotein(a) [Lp(a)] but also increases high-density-lipoprotein (HDL) cholesterol, it is useful for treating a wide variety of lipid disorders including mixed hyperlipidaemia, hypertriglyceridaemia and isolated low HDL cholesterol, as well as elevated Lp(a). Niacin, which exists in several different formulations, such as immediate release (IR), extended release (ER) and slow release (SR) niacin, has several modes of action: it modulates liver TG synthesis, which leads to increased intracellular apolipoprotein (apo) B degradation and increases TG lipolysis in adipose tissue. Recently, a specific niacin receptor has also been discovered. Several clinical outcome trials have demonstrated that niacin reduces coronary artery disease risk in combination with statins and two large mortality trials are currently underway looking at hard end-point reduction with niacin and statin compared to statin alone. Niacin's major adverse event (AE) is flushing, and this prevents many patients from either taking it or reaching target doses of this drug. Flushing incidence and intensity is reduced with ER-niacin and by co-administration of aspirin and a selective or non-selective prostaglandin inhibitor.     

他汀联合烟酸类药物的临床试验评价

在他汀治疗使低密度脂蛋白胆固醇(LDL-C)达标的后,对高密度脂蛋白胆固醇(HDL-C)降低的患者加用烟酸,可以升高HDL-C并降低甘油三酯,显著改善血脂谱。尽管小规模临床试验显示在他汀基础上联合烟酸可以延缓冠状动脉斑块或颈动脉内膜中层厚度的进展,但他汀联合烟酸的疗效至今仍然没有在大规模临床试验中得到证实。单纯升高HDL-C血浆水平而不关注HDL-C的清除是目前针对HDL-C干预治疗的问题所在,他汀联合烟酸的有效性和安全性有待于进一步证实。     

降脂药物联合应用新进展

降脂治疗是冠心病防治的基石,能显著降低心血管事件的发病风险。在他汀类基础上合理加用其他类降脂药物能进一步减少剩留的心血管风险,使高危患者获得最大的临床益处。本文系统地阐述了调脂药物联合应用的现状,并探讨了药物联合调脂治疗的安全性,进而分析了目前该领域的研究趋势和发展方向,为合理选用联合降脂治疗方案提供了新的依据。     

Niacin intake and risk of skin cancer in US women and men

A recent clinical trial found a protective role of niacinamide, a derivative of niacin, against skin cancer recurrence. However, there is no epidemiologic study to assess the association between niacin intake and risk of skin cancer [basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma]. We prospectively evaluated whether total, dietary and supplemental niacin intake was associated with skin cancer risk based on 72,308 women in the Nurses' Health Study (1984–2010) and 41,808 men in the Health Professionals Follow‐up Study (1986–2010). Niacin intake was assessed every 2 to 4 years during follow‐up and cumulative averaged intake. Cox proportional hazard models were used to compute the hazard ratios (HR) and 95% confidence intervals (CI) and cohort‐specific results were pooled using a random‐effects model. During the follow‐up, we documented 23,256 BCC, 2,530 SCC and 887 melanoma cases. Total niacin intake was inversely associated with SCC risk; the pooled HR for top vs. bottom quintiles was 0.84 (95% CI = 0.74–0.95; p_trend = 0.08). However, there were a marginally positive association between total niacin intake and BCC risk; the pooled HR for top versus bottom quintiles was 1.05 (95% CI = 1.01–1.10; p_trend < 0.01). Higher total niacin intake was also marginally positively associated with melanoma risk in men, but not in women. The results were similar in stratified analyses according to sun exposure related factors and by body location of melanoma and SCC. Our study supports a potential beneficial role of niacin intake in relation to SCC but not of BCC or melanoma.     

烟酸促进小鼠体内胆固醇逆转运

【目的】观察烟酸干预后小鼠血清脂质，血清、肝脏及粪便中^3H-胆固醇占注射总量的百分比，探讨烟酸对小鼠体内胆固醇逆转运的影响。【方法】14只C57BL／6小鼠随机分为两组，分别给予普通饲料、烟酸添加饲料喂养4周后，腹腔注射经ac-LDL及^3H-胆固醇处理过的小鼠巨噬细胞悬液，单独笼养24h后取血，酶法测定血清脂质；测定血清、肝脏和粪便中的^3H-胆固醇含量。【结果】与对照组比较，烟酸降低小鼠血清总胆固醇、低密度脂蛋白-胆固醇和血清甘油三酯水平，升高高密度脂蛋白-胆固醇14％；肝脏及粪便中的胆固醇流出分别增加19％和21％。【结论】烟酸能促进体内胆固醇逆转运，加速胆固醇由粪便清除，有益于动脉粥样硬化的防治。     

烟酸对动脉粥样硬化兔逆胆固醇转运的促进作用观察

目的 探讨烟酸促进动脉粥样硬化(AS)兔逆胆同醇转运(RCT)的作用及其可能机制.方法 健康雄性新两兰白兔12只,随机均分为对照组(给予单纯高脂饮食建立AS模型)及烟酸组[在高脂饮食基础上,每日给予口服烟酸400mg/(kg·d)3.6周后,取两组动物外周血单核细胞、腹腔巨噬细胞、腹部皮下脂肪细胞、肝细胞,流式细胞仪检测ATP结合盒转运子A1(ABCA1)表达量,液相闪烁计数法检测[~3H]胆固醇转出率;酶法和免疫方法检测兔血脂及主动脉组织、脂肪组织、肝组织的总胆固醇(TC)、非高密度脂蛋白胆同醇(NHDL-C)、高密度脂蛋白胆同醇(HDL-C)、载脂蛋白A1(apoA1)含量变化;Image-Pro Plus Version 6.0图像分析软件对比测定两组AS斑块面积.结果 与对照组相比,烟酸组TC、NHDL-C明显下降,HDL-C、apoA1明显上升(P<0.01),单核细胞、巨噬细胞、脂肪细胞的ABCA1表达量及胆同醇转出率均明显上升,而肝细胞ABCA1表达量、胆固醇转出率则明显下降(P<0.01),主动脉、脂肪组织、肝组织中胆固醇含量明显减少(P<0.01),AS斑块面积显著减小(P<0.05).结论 烟酸能明显改善血脂谱,增加外周细胞ABCA1表达量及胆固醇转出率,降低主动脉AS面积及组织中胆同醇含量.巨噬细胞ABCA1表达量可作为反映体内RCT水半的间接指标.     

Citicoline/Coenzyme Q10/Vitamin B3 Fixed Combination Exerts Synergistic Protective Effects on Neuronal Cells Exposed to Oxidative Stress

Background: The present study aimed to investigate the rationale and efficacy of using a citicoline, coenzyme Q10 (CAVAQ10) and vitamin B3 fixed combination in combating inflammation and oxidation in neuronal cells exposed to oxidative stress. Methods: HypoE22 cells and isolated hypothalamic specimens were selected as in vitro models to conduct the experiments. The efficacy of citicoline, CAVAQ10, and vitamin B3, with their fixed combination, were assayed after the exposure of hypothalamic cells to hydrogen peroxide (concentration range 1 nM–10 µM), in order to evaluate the biocompatibility of treatments. The activity of neuroprotective and pro-inflammatory factors, namely, brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα), involved in the neuronal cell damage in neurodegenerative diseases, were assayed in isolated hypothalamus. Results: Neither citicoline, CAVAQ10, nor vitamin B3 significantly altered hypothalamic cell viability, thus suggesting the biocompatibility of single ingredients and fixed combination in the concentration range considered for the study. In the same condition, citicoline and CAVAQ10 were also effective in reducing the gene expression of monoaminoxidase-B, involved in dopamine degradation. However, only citicoline demonstrated an ability to reduce dopamine levels. Conversely, all compounds were effective in reducing the gene expression of IL-6, and TNFα, and in inducing the gene expression of BDNF, with the co-administration of citicoline/CAVAQ10/vitamin B3 being generally more effective than single ingredients. Conclusions: The present findings support the beneficial and synergistic effects of citicoline, CAVAQ10, and vitamin B3 in fixed combination in reducing inflammation and oxidation, and in stimulating neurotrophin production in neuronal cells.     

Design and Rationale of the ARBITER 6 Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol)-6-HDL and LDL Treatment Strategies in Atherosclerosis (HALTS)

Background Recent evidence on the use of statin therapy indicates the potential for ultra-low levels of LDL-C to provide greater protection from recurrent coronary heart disease events. Guidelines for the treatment of lipid disorders were revised to indicate that an LDL-C treatment goal of 70 mg/dl was optional (NCEP ATPIII). In these same guidelines, low levels of HDL-C are also suggested but not specifically proscribed as a target of therapy. Recently ARBITER 2 (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 2) has provided the first evidence of the potential of raising HDL-C with extended release niacin when added to statin monotherapy in secondary prevention. However, whether this approach would be superior to a strategy in which lower concentrations of LDL-C are targeted is unknown. Materials and methods ARBITER 6-HALTS ( HDL and LDL Treatment Strategies) will be a randomized, parallel group, open-label study comparing HDL-C and LDL-C focused strategies of lipid treatments for their effects on atherosclerosis. Up to 400 subjects will be assigned to either intensified LDL-C lowering therapy with ezetimibe or HDL-C raising therapy with extended-release niacin. The primary endpoint is the mean change in the intima-media thickness of the common carotid artery after 14 months. Secondary endpoints include the change in lipid values and lipid subfractions, drug discontinuation due to adverse effects, change in quality of life, and a composite endpoint consisting of all major adverse cardiovascular events. Conclusion ARBITER 6-HALTS will guide clinicians on whether a lipid treatment strategy of raising HDL-C or further LDL-C reduction is superior in the secondary prevention of coronary heart disease. The opinions or assertions herein are the private views of the authors and are not to be construed as reflecting the views of the Department of the Army or the Department of Defense.