International Circulation: Are we entering a new phase of treatment with the PCSK9 inhibitors?
Dr Robinson: We are all quite excited about this new class of drugs， PCSK9 monoclonal antibodies. We block PCSK9， which means that LDL receptors continue functioning and taking cholesterol out of the circulation. Normally， PCSK9 breaks down these LDL receptors thus preventing the removal of LDL. It lowers LDL-cholesterol a further 60-65% on top of background statin therapy. So these are very powerful drugs. What this opens our minds to is that we know statins are very effective and we know they cut the risk of heart attack， stroke and death by 30-50%， but that means there are still a lot of people having heart attacks and strokes and dying while using statins. So if we can cut that another 50%， that would be exciting. The reason I say 50% is because now we have two trials ongoing， one of which I had published today in the New England Journal of Medicine and another I am involved in and reported on here with evolocumab showing very similar results with one year of follow-up. Both studies were performed for safety but we found that in both trials， there was about a 50% reduction in heart attacks， strokes and cardiovascular deaths within a year to a year-and-a-half of treatment. That was evident almost immediately after people started taking the drug. It certainly looks like we lower LDL a lot， but we also have the potential to reduce cardiovascular events dramatically as well. That is why we are all pretty excited about this new class of drugs.
International Circulation: So how do you see the next decade in lipid altering therapy?
Dr Robinson: There are two PCSK9 inhibitors， alirocumab and evolocumab， which have been filed for approval with the USFDA and we hope they will receive that approval which will allow them to be used for LDL-lowering. That is a huge unmet need in terms of people with familial (genetic) hypercholesterolemia and also people who are statin intolerant or at least intolerant to the dose that they should take. This will give them another option to prevent future heart attacks and stroke. In the long-term， we will wait for the results of the cardiovascular outcomes trials which are ongoing with these drugs. These are high-risk patients with cardiovascular disease and on maximum statin therapy， to whom we add alirocumab (about 18000 people with acute coronary syndromes) or evolocumab (27000 people) and see if these PSCK9 inhibitors on top of statins will further reduce the risk for cardiovascular events. If they do， that’s exciting. There has been some pushback because they are monoclonal antibodies which is quite high tech， but I think if we can have something that can cut the risk for heart attack and stroke so dramatically， it will be very important to get that to our patients.
《国际循环》：我们是否已进入应用PCSK9抑制剂治疗的一个全新阶段？调脂治疗的下一个十年，它有何前景？
Robinson教授：对这种PCSK9酶单克隆抗体新药，我们都非常兴奋。我们阻断可降解LDL受体的PCSK9酶，使LDL受体继续发挥作用，减少循环胆固醇。在他汀治疗基础上，它可使LDL胆固醇进一步降低60%~65％，是非常强效的药物。这使我们不禁想，他汀类药物非常有效，可使心脏病发作、卒中和死亡风险降低30%~50％，但这也意味着服用他汀的患者仍然有很多人会有心脏病发作、卒中以及死亡。因此，如果我们能够削减剩余的50%，那将是令人兴奋的。我之所以说50％是因为现在我们有两项正在进行的试验，其中一项在ACC.15期间发表于《新英格兰医学杂志》，另一项我参与并在会议上报道的是evolocumab的试验，1年随访显示出非常相似的结果。这两项研究旨在考察安全性，但我们发现，这两项试验中，治疗1年至1年半，心脏病发作、卒中和心血管死亡降低约50%。在患者开始服用这种药物后很快就出现了这种显而易见的效应。当然，LDL降低了很多，但降低心血管事件的潜力也令人注目。
目前已有两种向USFDA提出批准申请的PCSK9抑制剂，即alirocumab和evolocumab，我们希望他们能获得批准用于降低LDL。对家族性（遗传性）高胆固醇血症患者、他汀不耐受或至少对他们应该服用的剂量不耐受的患者而言，这是一个巨大的未得到满足的需求。这将给他们提供另一个选择以预防未来的心脏病发作和卒中。从长远来看，我们将等待正在进行的这些药物的心血管终点试验。这些都是高危心血管疾病患者，且在接受最大剂量的他汀类药物治疗，在此基础上添加alirocumab（约18000例急性冠脉综合征患者）或evolocumab（27000例），观察在他汀类药物基础上应用PSCK9抑制剂是否将进一步降低心血管事件风险。若结果的确如此则是令人兴奋的。已经有一些抵触情绪，因为他们是高科技单克隆抗体，但我认为，如果能有可以如此显著降低心脏病发作和卒中风险的药物，那么将其带给患者是非常重要的。
International Circulation: Could you talk about the management strategy for LDL-cholesterol levels <25mg/dl or <15 mg/dl?
Dr Robinson: We have looked at the pooled data from the alirocumab program and I reported on that here at the meeting. When you lower LDL another 65% on top of statins， you have a large number of people with LDL <25 and as low as 15， but there seem to be no signals there. There is no increase in adverse events at these very low LDL levels in the studies to-date. The long-term trials we are doing will give us a better feel for that， but there seems to be no increase in associated adverse events.
《国际循环》：您能否谈谈对LDL-C水平<25mg/dl or <15 mg/dl的管理策略？
Robinson教授：本次会议报道的来自alirocumab项目的汇总数据显示，在他汀类药物基础上将LDL再降低65％，则会有很多患者LDL<25 mg/dl，甚至低至15 mg/dl，但似乎没有任何征象出现。在该研究中这些非常低的LDL水平上，并无不良事件的增加。我们正在做的长期试验会让我们对此有更好的认识，但是相关不良事件似乎没有增加。
International Circulation: Now you have reported on the trial results for PCSK9 thus far， should we be expecting a revision of the guidelines?
Dr Robinson: The 2013 ACC/AHA Guidelines came out a year-and-a-half ago and changed the paradigm to maximizing statin therapy. We didn’t have any evidence for lower targets so they were not made recommendations. We just have evidence from IMPROVE-IT that adding ezetimibe gets LDL down by 20% and also modestly reduces cardiovascular events by 10%， so we have another drug we can add to statins for people who need more LDL-lowering. The guidelines state that they would prefer people to use non-statins only if they have been shown to reduce cardiovascular events because we had a string of trials with drugs that lowered LDL but didn’t reduce cardiovascular events. So that is the standard that is required. The fact that the preliminary studies suggest that there is cardiovascular risk reduction benefit with the PCSK9 inhibitors reassures us all that these drugs are going to do what we want them to do， which is to prevent heart attack and stroke.
《国际循环》：目前您报告了PCSK9试验结果，对指南修订会有哪些预期？
Robinson 教授：1年半前，2013年ACC/ AHA指南发布，使治疗模式变为最大化他汀类药物治疗。我们没有任何更低目标的证据，因此未做出推荐。我们只有来自IMPROVE-IT的证据，即添加依折麦布使LDL降低了20％，也使心血管事件小幅降低10%，现在对那些需要LDL降低更多的患者，我们有了另一种可以在他汀类药物基础上应用的药物。鉴于既往一系列试验显示，非他汀类药物降低LDL但并不减少心血管事件，因此指南指出，除非证明非他汀类药物可降低心血管事件，否则不推荐患者优选非他汀类药物。初步研究提示，PCSK9抑制剂有降低心血管疾病风险的益处，这令人欣慰，也正是我们想要的效果，即预防心脏并发作和卒中。