Medication-based versus target-based lipid management
在血脂管理中以药物为基础还是以目标为基础
Managing low-density lipoprotein: Philosophy or pragmatism?
Many clinicians feel strongly about the value of bringing patients’ low-density lipoprotein cholesterol (LDL-C) to the risk-appropriate safe zone, be it <100, 70, or 55 mg/dL, whereas others feel equally strongly about the value of using the right doses of medications proven to reduce risk of atherosclerotic cardiovascular disease (ASCVD), perhaps even death. On the surface, these views may seem at odds, but a closer examination reveals that they represent two sides of the same coin. Specifically, LDL-C goals are often reached with the use of maximum doses of evidence-based therapies and, similarly, the most effective medications mitigate atherosclerotic risk because they lower LDL-C, often to goal levels. The discrepancies arise, naturally, when the LDL-C goal is attained in the absence of optimized, guideline-directed medical therapy or, conversely, when the appropriate medications at the recommended doses fail to achieve LDL-C goals. Does a patient with coronary artery disease who achieves an LDL-C of 50 mg/dL via veganism, supplements, and a bile-acid binding resin not enjoy the same cardioprotection as another patient who achieves an identical LDL-C with a high-potency statin? Similarly, is a coronary patient who takes rosuvastatin 40 mg and ezetimibe 10 mg daily sufficiently protected even though their LDL-C continues to hover around 90 mg/dL? These are the questions created by a false dichotomy of views; that is, providing the appropriate medication and dose versus targeting the proper LDL-C goal.
A quick look at guidelines
The 2013 American Heart Association (AHA)/American College of Cardiology (ACC) guidelines for cholesterol management have ushered in the era of superstardom for select statin drugs, with the high-dose, high-potency duo (atorvastatin 40–80 mg and rosuvastatin 20–40 mg) taking center stage in the management of individuals at the highest ASCVD risk.1 This paradigm shift was countered by several sets of guidelines that reinforced the older notion that stressed calibration of therapeutic LDL-C goals according to baseline ASCVD risk, regardless of the therapeutic means used to get there.2-4 The proliferation of societal cholesterol recommendations reached a highpoint with the publication of the 2017 American Association of Clinical Endocrinologists(AACE) guidelines, which not only maintain that targeting LDL-C to goal continues to be the strategy to follow, but actually add to the risk stratification ladder by including an “Extreme Risk” category with a recommended LDL-C goal of <55 mg/dL.5 This sets the controversy around the use of proprotein covertase subtilisin/kexin type 9 (PCSK9) inhibitors, with doctors following practice guidelines that either endorse only statins or create a nearly mandatory opening for PCSK9 inhibitor use in the highest-risk patients. Once again, these positions are incompatible only on paper. If one looks at the meaning behind the recommendation for use of the high-potency statins, it is clear that the intent is to achieve at least a 50% LDL-C reduction, and that if this result is not achieved, then the use of additional LDL-lowering medications is sanctioned. Considering that approximately 25% of patients on high-dose, high-potency statin therapy will not achieve a 50% reduction in LDL-C, this should be the strongest and most direct connection point between the apparently irreconcilable differences between sets of guidelines.6
Little flexibility with our medication armamentarium
The LDL-lowering drugs can be classified into three groups according to effectiveness: (i) the statins, with mean LDL-C reductions in the range 35%–40%; (ii) the oral non-statin agents (ezetimibe, niacin, and bile acid sequestrants), with mean LDL-C reductions in the range 15%–20%; and (iii) the injectable non-statin agents (PCSK9 inhibitors), with mean LDL-C reductions in the range 55%–60%. In the patient who successfully takes the appropriate intensity of statin for the level of ASCVD risk, the need for additional drugs is a result of failure to achieve either a 50% reduction in LDL-C or an absolute LDL-C goal, depending on the particular guideline one follows. In the former case, the additional medication will be an oral agent, because this combination will, more often than not, result in LDL-C lowering of over 50%. However, in the latter case, the choice of the next drug will depend on the remaining distance to the absolute LDL-C goal. For example, a diabetic patient with coronary artery disease (CAD) started on atorvastatin 80 mg daily whose LDL-C drops by 40% (from 166 to 100 mg/dL) still requires a decrease of at least 17 mg/dL to achieve the targeted 50% reduction, which would be expected to occur after adding ezetimibe. Conversely, this patient could be classified as having extreme ASCVD risk with an LDL-C goal of ≤55 mg/dL, in which case an additional 45% drop is unlikely to be achieved with the addition of a second oral agent, but is well within the capabilities of the PCSK9 inhibitors.5
Often it is more than just LDL
How common is it for a patient to present with a pure hypercholesterolemia? The prevalence of this presentation has declined, whereas chronic excess adiposity has produced an epidemic of combined dyslipidemia, with elevated triglyceride (TG) and low high-density lipoprotein-cholesterol (HDL-C) levels.7 Ezetimibe and the potent PCSK9 inhibitors reduce TG levels only minimally, less so than the statins, and have essentially no effect on HDL-C concentrations.8 Therefore, it is necessary to examine the entire lipid panel, even after LDL-C goals are attained. For TG management, this means initiating proper oral therapy with prescription marine omega-3 polyunsaturated fatty acids (PUFA) and/or fibrates (and often both) when appropriate. In many instances, a provider will fail to target TG for two main reasons: (i) non-fasting laboratory results; and (ii) poor diabetes control. Regarding laboratory assessment, individuals with normal lipid metabolism are able to clear a high-fat meal with minimal elevation in TG levels, and usually the postprandial TG peak stays well below 200 mg/dL. It is therefore not good practice to disregard moderate hypertriglyceridemia (200–400 mg/dL) in non-fasting patients. Regarding diabetes, it is true that higher HbA1c levels correlate with higher TG levels, but it is not true that moderate hypertriglyceridemia will be always and completely responsive to glucose management when HbA1c is approaching the 7% mark. Of course, we are not quite at the stage of combatting elevated TG levels with the same zeal and aggressiveness as we do for LDL-C, but things may change soon. Clinical trials of fibrates have, at best, provided hints that subgroups of patients with combined dyslipidemia may derive cardiovascular benefit beyond that produced by statin monotherapy, but most experts would agree that peculiarities in study design are the main reason why the results were not more obviously positive in the overall populations under study.9 Currently, two large, appropriately designed trials of prescription omega-3 PUFA are in progress and will determine whether high-risk patients with residual elevations in TGs (200–500 mg/dL) despite optimized statin therapy will benefit from an intervention addressing their residual lipid risk.10, 11 Positive results from these studies are poised to change the landscape of lipid management in high-risk individuals.
High-density lipoprotein is a different story, and one that is beyond the scope of this short essay. It should suffice to mention that the medical community is as far away from having a therapeutic target in mind for HDL as we have ever been, but at the same time we continue to realize that low HDL-C is a powerful predictor of ASCVD risk.12 The competent physician no longer seeks to raise HDL-C pharmacologically because numerous randomized controlled trials reveal a strikingly consistent absence of benefit from this approach.13-17 Beyond HDL-C, lipoprotein(a) is climbing the ladder of clinical relevance and may, one day, position itself as an additional bad actor, along with LDL-C and TG, that conspires against arterial health.18, 19 Given the fact that universal lipid testing is largely endorsed to screen for familial hypercholesterolemia (FH), it stands to reason that universal lipoprotein(a) screening should be seriously considered because extreme elevations in this parameter are far more common than (and likely as dangerous as) FH.20
Residual risk and biology of the plaque
There is growing consensus that LDL is causal in the development of atherosclerosis.21 The recent trials of PCSK9 inhibitors have taught us that extreme, prolonged reductions in LDL-C concentrations (to median 30 mg/dL), although safe and effective, are associated with only limited benefit to the artery wall (<1% atheroma burden reduction) and moderate reduction (15%–20%) in the relative risk of ASCVD events.22, 23 In one large trial that lasted slightly over 2 years, the event rate for the primary endpoint was 14.6% in the group treated with statin only and 12.6% in the group receiving statin plus PCSK9 inhibitor.24 Very similar results were obtained in another trial, smaller in size but of longer duration.25 As far as LDL-C lowering is concerned, the jury is in and the addressable risk is considerably less than the residual risk. The reason is not immediately evident, but it is likely connected with the fact that an arterial plaque cannot be extinguished by removal of the offending factor. Without plasma LDL, the atheroma will stop growing, but the halting of progression apparently will not trigger regression or complete stabilization. There are other avenues that mitigate risk related to the plaque, such as treating diabetes with cardioprotective antiglycemic drugs, controlling blood pressure to more aggressive goals, managing platelets and coagulation, quenching inflammation, and treating other aspects of dyslipidemia.26-29 A debate on LDL-lowering drugs versus LDL-C targets is no longer reflective of the state of knowledge. What we know is that, for LDL-C, lowest is best, that the highest-risk individuals deserve to be taken to the lowest possible point regardless of cost, and that even with that, these patients will remain at high risk and face cardiovascular disease as the most likely cause for lost days from work, worsening quality of life, hospitalizations, and death.
What's a doctor to do?
The best strategy is to avoid the trap of a false dichotomy. A good doctor should first know their patient and then lay out a plan leading to maximal benefits. In our field, this means accurate risk assessement for all the apparently disease-free subjects, because many are in the primary prevention bucket only because of lack of non-invasive imaging data. All patients in the high, very high, and extreme risk categories should be targeted with one or more drugs until the contribution of LDL to the global atherogenic burden is eliminated. Depending on baseline LDL-C and the patient's circumstances, this may mean using a high-dose, high-potency statin, a low-dose, high-potency statin, any dose of a lower-potency statin, or even no statin at all in patients with intractable statin intolerance or statin aversion. Against that background, one should consider adding a non-statin oral agent if a level of LDL-C < 55 mg/dL can be achieved with another 15%–20% drop, or a PCSK9 inhibitor if the low target needs a > 25% drop.30 There should be no real reason to use triple therapy, except that many payers are forcing patients to take statin plus a second oral agent before qualifying them for the more expensive injectable drugs.31 The situation is more fluid for people in the lower risk categories, where a 35%–40% reduction in LDL-C induced by statin monotherapy may indeed be all that is needed. An exception to this rule is for subjects with FH, where the lifelong exposure to extremely elevated LDL-C levels represent sufficient atherogenic potential to warrant the most aggressive preventive therapies, even among those apparently healthy and without comorbidities.32
Acknowledgement
SF is supported, in part, by National Institutes of Health – National Heart Lung and Blood Institute grant 5R01HL132985.
Disclosure
SF has received compensation for advisory activities from Amgen, Kowa, Aegerion, Akcea, and Amarin. MDS has received compensation for advisory activities from Amgen, Kastle, Novartis, and Regeneron.
管理低密度脂蛋白:是哲学还是实用主义?
许多临床医生都强烈认为要将患者的低密度脂蛋白胆固醇(LDL-C)降低到风险适度的安全区域, 达到< 100、70或者55 mg/dL的目标, 然而其他医生却同样强烈地认为患者应使用既往已经被证实可以降低动脉粥样硬化性心血管疾病(atherosclerotic cardiovascular disease,ASCVD)风险、甚至有可能减少死亡率药物的正确剂量。从表面上看, 这些观点似乎有分歧, 但更仔细地研究后发现, 这分别代表了同一个硬币的两面。具体来说,LDL-C目标往往是通过使用最大剂量的有循证医学证据的治疗药物来达到的, 同样, 最有效的药物可以降低动脉粥样硬化的风险, 因为这些药物可以降低LDL-C,并且通常都能够达到目标水平。在没有使用指南推荐、优化的药物进行治疗就能够达到LDL-C目标, 或者相反, 当推荐剂量的合适药物不能够达到LDL-C目标时, 自然就会产生分歧。如果一名冠心病患者通过素食、营养补充剂以及一种胆汁酸结合树脂治疗就达到了LDL-C 50 mg/dL目标, 而另外一名患者通过使用一种高效他汀类药物治疗后也达到了相同的LDL-C目标, 前者对心脏的保护作用难道就与后者不一样吗?同样, 如果一名冠心病患者每天服用40 mg瑞舒伐他汀与10 mg依折麦布联合治疗后LDL-C仍然徘徊在大约90 mg/dL左右, 那么这种治疗方法还有充分保护作用吗?这些问题都是由于错误地将概念一分为二所造成的;也就是说, 将提供合适剂量的药物与达到适当的LDL-C目标人为地对立起来了。
指南速览
自从2013年美国心脏协会(AHA)/美国心脏病学协会(ACC)公布了胆固醇管理指南以来, 他汀类药物成了这个时代的超级明星, 在最高风险的ASCVD患者管理中一切都要以高剂量、高效的他汀二重奏(阿托伐他汀40-80 mg与瑞舒伐他汀20-40 mg)治疗为中心1。然而, 有一些指南并不认同这种治疗模式的转变, 即仍然强调过去的观念:无论使用什么治疗方法, 一定要根据基线ASCVD风险设定LDL-C的治疗目标2-4。随着2017年美国临床内分泌学家协会指南的公布, 社会上的胆固醇推荐指南数量达到了极致, 这些指南不仅将LDL-C治疗达标作为一种策略延续下去, 而且将其纳入风险分层, 对“极端风险”的患者, 要将LDL-C目标控制到< 55 mg/dL5。这样一来, 使用前蛋白转化酶枯草溶菌素/可欣9型(proprotein covertase subtilisin/kexin type 9,PCSK9)抑制剂治疗引起许多争议, 临床医生因此遵循医疗指南, 在患者治疗中要么只使用他汀类药物, 要么在高危患者中几乎必需放开使用PCSK9抑制剂治疗。同样的, 这些争论只是在理论上不相容。如果我们看一下推荐使用高效他汀类药物的背后含义, 显然目标是使LDL-C达到至少50%的降幅, 并且如果这个目标不能够达到, 那么就要联用其他可以降低LDL的药物。考虑到大约有25%的患者使用高剂量、高效他汀类药物治疗后LDL-C仍然不能够达到至少50%的降幅, 这应该成为一系列指南中明显不相容差异的最强与最直接的连接点6。
我们的药物治疗库几乎没有灵活性
根据疗效可将降低LDL的药物分类为三组:(i)他汀类药物, 平均LDL-C降幅为35%-40%;(ii)口服非他汀类药物(依折麦布、烟酸与胆汁酸螯合剂),平均LDL-C降幅为15%-20%;以及(iii)注射用的非他汀类药物(PCSK9抑制剂),平均LDL-C降幅为55%-60%。对于根据ASCVD的风险水平已经成功服用适当强度他汀类药物进行治疗的患者而言, 因为LDL-C未能够达到50%的降幅或者未能够达到LDL-C的绝对目标值, 所以需要使用额外的药物联合治疗, 具体依赖于人们遵循的是哪一种特定的指南。在前一种情况下, 要另外加用一种口服药物, 因为这种联合治疗多半都会导致LDL-C下降超过50%。然而, 在后一种情况下, 下一个要选用何种药物将取决于距离LDL-C绝对目标值有多大。例如, 合并冠心病(CAD)的糖尿病患者开始每日使用80 mg的阿托伐他汀治疗后LDL-C降低了40%(从166下降至100 mg/dL),为了达到50%的降幅目标, 仍然需要进一步将LDL-C至少降低17 mg/dL,预计加用依折麦布治疗后会达到目标。反过来说, 该患者可被分类为具有ASCVD的极端风险,LDL-C的目标应该是≤ 55 mg/dL,在这种情况下, 加用第二种口服药物不太可能达到另外的45%降幅, 但是这却在PCSK9抑制剂的能力范围内5。
通常不仅仅只是要求LDL达标
只有单纯高胆固醇血症的患者有多常见?这种情况的患病率已经在下降, 然而慢性过度肥胖导致的混合性血脂异常却在日益流行, 同时会出现甘油三酯(TG)水平升高与高密度脂蛋白胆固醇(HDL-C)水平降低。依折麦布与高效PCSK9抑制剂只能轻度降低TG水平, 降幅比他汀类药物少得多, 并且基本上对HDL-C的浓度没有影响8。因此, 即使在达到了LDL-C目标之后, 还必须检查整个脂质谱。对于TG管理来说, 这意味着在适当的时候需要海洋ω-3多不饱和脂肪酸(PUFA)和/或贝特类(通常需要联用)药物进行适当的口服治疗。在许多情况下, 医护人员对TG达标的忽略有两个主要原因:(i)非空腹实验室结果;以及(ii)糖尿病控制不佳。就实验室评估而言, 血脂代谢正常的个体能够清除高脂饮食的影响, 他们的TG水平只会轻度升高, 餐后TG峰值通常都低于200 mg/dL。因此, 不应忽视非空腹患者的中度高甘油三酯血症(200-400 mg/dL)。就糖尿病患者而言, 确实是高HbA1c水平与高TG水平相关, 但是, 当HbA1c接近7%标准时, 中度高甘油三酯血症一直都可以完全反映血糖控制的观念是不正确的。当然, 对于升高的TG水平, 目前我们还没有达到像应付LDL-C水平的热切与积极的阶段, 但是事情可能会很快改变。贝特类药物的临床试验结果提示混合性血脂异常的亚组患者联合治疗后所产生的心血管益处超过了单用他汀类药物, 但是大多数专家却认为, 研究设计的特殊性是导致为什么总研究人群中的阳性结果没有更显著的主要原因9。目前已经有两项设计得当的使用ω-3多不饱和脂肪酸处方药物治疗的试验正在进行中, 目的是在已经使用他汀类药物进行优化治疗但是残余TGs仍然较高(200-500 mg/dL)的高危患者中, 调查对残余血脂风险进行干预治疗是否有益10,11。若这些研究有阳性的结果, 那么将有望改变高危人群的血脂管理策略。
关于高密度脂蛋白的论述有所不同, 这超出了本篇短文的范围。应该提到的是, 针对HDL治疗目标医学界目前还像往常一样有很长的路要走, 但是与此同时我们也意识到了低HDL-C是ASCVD风险的强有力预测因子12。称职的医生再也不去寻求升高HDL-C的药物, 因为许多随机对照试验结果表明, 这种治疗方法惊人地一致性显示缺乏效益13-17。在HDL-C以外, 脂蛋白(a)正在不断地被证实具有临床相关性, 并且与LDL-C以及TG一样, 今后有可能会被定义为另外一种影响动脉健康的危险因素18,19。鉴于实际上普遍的血脂检测主要是用来筛查家族性高胆固醇血症(FH),因此我们有理由认真考虑普遍筛查脂蛋白(a),因为这个参数的极度升高远比FH更常见(并且有可能一样危险)20。
残余风险与斑块生物学
LDL是发生动脉粥样硬化的病因, 越来越多的人已经对此达成了共识21。最近有关PCSK9抑制剂的试验结果告诉我们, 长期将LDL-C的浓度极度降低(降至中位数为30 mg/dL)虽然安全并且有效, 但是导致的动脉壁获益很有限(减少的动脉粥样硬化负荷< 1%),并且ASCVD事件的相对风险也只有中度的下降(15%-20%)22,23。在一项持续时间略超过2年的大型试验中, 发现在只使用他汀类药物治疗的患者组中主要终点事件的发生率为14.6%,而在使用他汀类药物联合PCSK9抑制剂治疗的患者组中发生率为12.6%24。在另外一项试验中也获得了非常相似的结果, 这项研究的规模较小, 但是持续时间更长25。就LDL-C下降而言, 经过评判后发现, 可降低的风险远远小于残余风险。原因并不是立即显而易见的, 但是很可能与动脉斑块不能通过去除有害因素就可以消失的事实有关。没有血浆LDL,动脉粥样斑块就会停止生长, 但是停止进展并不会导致斑块消失或者完全稳定。还有其他方法可以减少与斑块有关的风险, 例如使用具有心脏保护作用的降糖药物来治疗糖尿病, 将血压控制到更积极的目标水平, 管理血小板与凝血, 消除炎症, 治疗其他方面的血脂异常26-29。关于降低LDL的药物与LDL-C目标的相关争论也不再是人们对相关问题认识水平的反映。就我们所知, 对于LDL-C来说, 越低越好, 具有最高风险的患者应该不计成本地尽可能地将LDL-C降低到最低点, 即使如此, 这些患者仍将处于高风险之中, 面临的心血管疾病将最有可能是他们损失工作的时间、生活质量变差、住院以及死亡的主要原因。
医生该怎么办?
最佳策略就是要避免踏入错误的二分法陷阱。一名好医生应该首先要了解患者, 然后制定出一个计划, 使患者利益最大化。在我们这个领域, 这意味着要对所有没有明显疾病的人进行精确的风险评估, 许多患者只是因为缺乏无创性的影像数据而处于一级预防状态。所有处于高、非常高、极高风险类别的患者都应该使用一种或者多种药物以达到治疗目标, 直到LDL导致动脉粥样硬化对所有负担被消除。要根据基线LDL-C以及患者的实际情况选择用药, 这可能意味着患者可能要选择使用一种高剂量、高效他汀类药物或是一种低剂量、高效他汀类药物, 或者是任何剂量的低效他汀类药物, 或者在难以处理的不耐受/不喜欢他汀类药物的患者中, 甚至根本就不使用他汀类药物。在这样的背景下, 如果LDL-C在< 55 mg/dL的水平下要求另外再降低15%-20%,那么应该考虑加用一种非他汀类口服药物, 如果要求更低的目标需要另外再降低>25%,那么应该考虑加用PCSK9抑制剂30。目前应该还没有真正需要使用三联治疗的理由, 除非在给患者使用更昂贵的注射药物之前, 有许多付款人要求患者使用他汀类药物加上第二种口服药物治疗31。在较低风险类别的人群中, 用药情况比较轻松, 单用他汀类药物治疗后可使LDL-C下降35%-40%,的确这样可能就足够了。这条原则有一个例外, 那就是合并FH的受试者, 他们终身暴露在极度升高的LDL-C水平下, 这意味着发生动脉粥样硬化的可能性极大, 因此需要对他们进行最积极的预防性治疗, 即使是那些明显健康并且没有合并症的人也需要预防性治疗32。
