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[GW-ICC]降脂治疗药物及靶点思辨
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 关键字:降脂治疗 PSCK 9 HDL-C 

  编者按:近年来,调脂治疗药物迅速发展。新型药物能否撼动传统他汀治疗的基石地位,如何评价新型药物的临床功效?在第二十六届长城国际心脏病学会议上,美国伊利诺伊CGH医学中心预防心脏病学主任Peter Paul Tóth做出了解答。

  International Circulation: I would like to ask two questions about cholesterol lowering therapy. The first one is, cholesterol lowering therapy is multiple mechanisms of intervention,PCSK9 inhibitors have become the shining star in the cholesterol lowering field. Numerous studies have shown that PSCK9 inhibitors can significantly reduce LDL-C levels. And what do you think about the efficacy of the PSCK9 inhibitors? And how do you think about its clinical application prospect?

  评价新型PCSK9药物降脂疗效

  Peter: Well, the PCSK 9 molecule antibodies are going to revolutionary as the cardiovascular medicine, of that I have no doubt. PCSK 9 can extremely application as an approach, and providing very substantial reduction in LDL cholesterol. Even against statins or statins process of MI background. And we are going to see a very significant number of people getting LDL below 40 or below 25. And this is going to be a range where we are going to dramatically reduce rates of disease progression. And based on the analysis from the ODYSSEY trail using alirocumab, I have seen long term alirocumab, these drug really do appear to provide significant incremental pass the reduce the cardiovascular events. Both of these studies were published in English Journal of Medicine side to side. And in just one year with very expanded primary compensative point, which included that the usual non-fatal MI, non-fatal stroke and death, but also in the hospital for acute coronary syndrome, for heart failure, and for revascularization. Alirocumab against the sustain background, and do the 50% of relative risk reduction in advanced in just one year. Similarily for alirocumab in one and half year, they observed incremental 48% relative risk reduction event. Now these results do need to be confirmed by larger trials, which include HDL-C outcomes. As well as four year, which are including 18000 and 28000 patients respectively, and we are expecting hear about those studies in 2017. But this is very dramatic breakthrough in the management of heightened LDL cholesterol, and I believe that the PSCK 9 molecule antibody inhibitors are very effective and are going to be taking LDL to a never been seen level.

  作为心血管药物,前蛋白转化酶枯草溶菌素9(PCSK9)实现了该领域另一个突破。该药可在他汀治疗基础上大幅降低低密度脂蛋白胆固醇(LDL-C)水平,研究显示患者LDL水平降至40 mg/dl甚至25 mg/dl,显著延缓心血管疾病进程。研究显示,长期服用Alirocumab可显著减少心血管事件。1年随访数据显示,患者非致死性心肌梗死、非致死性卒中以及死亡率显著降低,院内急性冠状动脉综合征、需血运重建的心力衰竭发生率均降低,晚期事件相对风险降低50%。1年半随访数据显示晚期事件风险降低48%。当然这些数据还需大规模试验进一步证实,也包括高密度脂蛋白胆固醇(HDL-C)在内的预后评估。近期一项大规模试验分别纳入1.8万例和2.8万例患者进行分析,结果将在2017年公布。这是加强LDL-C管理的重要进展。

  International Circulation: My next question is the HDL cholesterol is a biomarker of cardiovascular risk prediction, but there are lot of controversies in terms of the effect of intervention of HDL cholesterol on cardiovascular disease outcomes. In your opinion, is this necessary to intervene HDL cholesterol to cardiovascular disease?

  HDL-C暂不作为治疗靶点

  Peter: I think the short answer to that question is NO. Because we don’t have any perspective randomized clinical trial data with any drug showing that HDL reduce or cure cardiovascular events. But I think that there is still a possibility that new drugs are coming and do so; but obviously in the last three years, we have been probably found to be disappointed. We are disappointed with the niacinand AIM-HIGH, as well as HPS2-THRIVE. And we have seen EGP inhibitor class, we have seen ILLUMINATE trial with torcetrapib?deal out without cetrapib, and accelerate with either cetrapib or fail. But that doesn’t mean that raising HDL is not that of occasions. What is telling me is that goes mechanistic approaches to raising HDL. In very well controlled patients already on high dose of that drugs didn’t work. HDL is a very very complex with a protein of above 200 components of a lipidome where even the lipid constitutes the particle impacts functionality, and a number of micro RNAs also traveling along with the HDL. This make the HDL very complex poly-molecular assembly, and that is not easy to reveal. So there is a great deal of basic science that  we still have to do before we can really ask the question: is it time to abandon the HDL? I think the answer to that is no, because why we were put so much energy into constructing such complex level protein. If it does nothing, that will be very puzzling finding. So I think more need to be ongoing; but in 2015, HDL is not a treatment of heart yet.

  目前并没有大规模临床试验证实HDL-C水平与心血管事件的相关性,不论烟酸治疗、AIM-HIGH试验还是HPS2-THRIVE试验均未观察到阳性结果。但这并不能说明升高HDL-C不起作用,只是未找到确切机制。HDL-C组成非常复杂,由200多个脂质组构成,每个脂质颗粒都发挥相应功能,另有大量微小核糖核酸作为调节因子。只有阐明HDL-C作用的分子机制,临床才能提出是否干预HDL-C,在这之前还有很多基础研究需进行。至少在2015年,HDL-C不会成为调脂干预的靶点。

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