寻找他汀类药物之外降低胆固醇的新方法

你好。

Hi.

我是伊拉·弗拉托，欢迎收听科学星期五。

It's Ira Flatow, and this is science Friday.

如果你已经预约了年度体检，你的医生很可能会要求你做一项胆固醇检测，也就是血脂检测。

If you've scheduled your yearly physical, one of the blood tests your doctor will probably order is a cholesterol test, that lipids panel.

对吧？

Right?

这项检测是一种窥视你动脉内部状况的方式。

The test is a kind of a way to peek inside your arteries.

它测量HDL（被认为是好的胆固醇）和LDL（不好的胆固醇），以判断你是否有心脏病或中风的风险。

It measures HDL, the presumed good stuff, and LDL, the bad stuff, to see if you might be at risk for a heart attack or a stroke.

如果你的医生对你的检测结果不满意，你可能会被建议加入数百万正在服用他汀类药物的美国人行列，或者你可能已经正在服用他汀类药物。

And if your doctor doesn't like your numbers, you may be asked to join the millions of Americans who are taking statins, or maybe you are already on a statin.

即使你吃了相当于自己体重那么多的燕麦，你的数值仍然很高。

And in spite of eating your body weight in oatmeal, your numbers are still high.

那现在该怎么办？

So what now?

你是否应该尝试目前市场上新的高胆固醇治疗方法？

Should you try one of the new treatments for high cholesterol that is on the market now?

如果你的医生能给你注射一针CRISPR疗法，直接改变你的基因，可能终生降低你的胆固醇水平，你会这么做吗？

And what if your doctor could give you one injection, a CRISPR treatment that actually changed your genes and lowered your numbers maybe for life, would you do that?

这正是我们今天这一小时要讨论的内容。

That's what we're gonna be talking about this hour.

让我介绍一下内哈·帕吉迪帕蒂，她是预防心脏病专家，也是北卡罗来纳州达勒姆杜克大学心血管代谢预防诊所的主任，以及基兰·穆萨努鲁，他是宾夕法尼亚大学费城的心脏病专家和转化研究教授。

So let me introduce Neha Pajidipati, who is a preventive cardiologist and director of the cardio metabolic prevention clinic at Duke University in Durham, North Carolina, and Kiran Musanuru, a cardiologist and professor of translational research at the University of Pennsylvania in Philadelphia.

感谢你们两位的参与。

Thank you both for joining me.

欢迎来到科学星期五。

Welcome to Science Friday.

非常感谢。

Thank you so much.

谢谢你们邀请我们。

Thanks for having us.

Neha，你如何决定谁需要治疗或谁需要开始服用他汀类药物？

Neha, how do you decide who needs treatment or who needs to start a statin?

是的。

Yeah.

这是个很好的问题，我们在门诊每天都被问到。

It's a great question and something we're asked in clinic every day.

幸运的是，各大专业协会——心脏病学、糖尿病学等——都制定了非常明确的指南，帮助我们确定谁需要他汀类药物，谁不需要。

And lucky for us, there are actually really clear guidelines, from all of the major professional societies, cardiology, diabetes, and others that help to guide us and help us figure out exactly who needs statins and who doesn't.

所以这并不是什么谜题。

So it's not a mystery.

它基于扎实的证据，我认为这对患者来说非常重要。

It's based on really good evidence, and I think that's something that's really important for patients to know.

因此，对于曾经有过心脏病发作或中风，或者过去需要放置支架的患者，他们绝对应该接受他汀类药物治疗，或者如果无法耐受他汀类药物，或者未能达到目标值，也应使用其他疗法，以将低密度脂蛋白胆固醇降至目标水平。

So, you know, for patients who have had a heart attack or stroke or who have needed, you know, for example, a stent placed in the past, they absolutely should be on statin therapy or some other therapy if they can't tolerate statin therapy or if they don't get to their goals in order to get their LDL cholesterol down to the goal.

因为我们知道，LDL胆固醇和LDL颗粒数量越低，对降低风险越好。

Because we know the lower, the better for LDL cholesterol and LDL particle number in terms of reducing your risk.

但当涉及到那些尚未发生过心梗或中风、而我们试图首次预防这类事件的患者时，我们会使用多种方法来评估他们的风险。

But then where it becomes a little more interesting is for patients who have not yet had a heart attack or stroke and you're trying to prevent that for the first time, we use a variety of different ways to assess that person's risk.

有时我们还会检查心脏动脉是否存在钙化或动脉粥样硬化，以帮助判断患者是否需要他汀类治疗以及治疗的强度。

And sometimes we actually look to see if there's any calcification or atherosclerosis in the heart arteries to help us decide whether or not that person needs statin therapy and how intense that therapy should be.

Neha，有模型吗？

Neha, is there a model?

我的意思是，我们是如何将一个人归入这些模型中的？

I mean, how does it work that that you fit into one of these models that we're we're looking at?

这是个很好的问题。

It's a great question.

传统上，我们一直使用风险评分。

So, traditionally, what we have done is we have used risk risk scores.

这些风险评分有助于估算您在未来十年内发生心梗或中风的风险。

So risk scores that help to estimate your risk of having a heart attack or stroke over the coming ten years.

这些模型效果还不错。

And they work pretty well.

它们并不一定能代表所有人，因为它们所依据的人群并不包括多样化的群体，但效果还是不错的。

They, don't necessarily represent all people because they're not based on populations that include, you know, diverse diverse people, but they work pretty well.

然而，这种方法也有一些缺点。

However, there are some downsides to this.

一是年轻人在接下来的十年内很少能达到高风险评分，因此不符合治疗标准。

One is that individuals who are younger rarely achieve that high risk score over the next ten years to then merit therapy.

但我们知道，动脉粥样硬化的病理过程并不会在一个人即将发生心梗或中风时才突然开始。

But we know that the disease process of atherosclerosis doesn't just start right before a person has a heart attack or stroke.

它也不是在60岁的人发生心梗时才突然开始的。

It doesn't just start before the 60 year old has their heart attack.

它早在几十年前就已经开始了。

It started decades before.

如果我们当时检查过他们是否有动脉粥样硬化，或许早就该更积极地干预，阻止这一过程了。

If we had looked to see if they have atherosclerosis, we might have started to, aggressively try to prevent that process much sooner.

但仅使用风险评分，我们常常会漏掉一些人，尤其是那些风险可能在30年或一生中都很高，但在未来十年内风险并不那么高的年轻个体。

But just using risk scores, we will often miss individuals, especially younger individuals whose risk might be high over 30 or over a lifetime, but isn't that high over the next ten years.

所以我认为这是我们在诊所里看到年轻个体时必须要考虑的一个非常重要的问题。

So I think this is something really important that we have to think about in the clinic when we see especially younger individuals.

Kiran，这在多大程度上取决于医生的判断？

Kiran, how much is it a call by the doctor?

我的意思是，感觉可能有的医生会说，好吧。

I mean, it feels like one doctor might say, okay.

你55岁了。

You're 55.

是时候开始服用他汀类药物了，而另一个人可能会说可以再等等。

Time to start a statin, while another might say it's okay to wait.

你可以尝试饮食控制和锻炼。

You can try diet and exercise.

对吧？

Right?

有官方指南吗？

Are there official guidelines?

患者该如何做出决定？

How are patients supposed to decide?

我的意思是，这些指南会考虑家族史或种族等因素吗？

I mean, do the guidelines take into account things like family history or ethnicity?

越来越多的指南会考虑这些因素。

Increasingly, they do.

因此，许多因素都会被纳入这些风险预测算法中。

And so a lot of factors can go into these risk prediction algorithms.

比如基本的指标：胆固醇水平，包括好胆固醇和坏胆固醇，血压，是否患有糖尿病，以及你的生活习惯。

So it's it's your basic metrics like cholesterol levels, whether it's the good cholesterol or bad cholesterol, things like blood pressure, things like whether you have diabetes or not, your actions.

比如你是吸烟者还是非吸烟者，现在越来越多地纳入家族史、祖先背景，甚至开始纳入遗传因素。

So if you're a smoker versus a nonsmoker, increasingly incorporating things like family history, your your ancestral background, and even starting to incorporate genetic factors.

但由于这些因素并不十分精确，它们主要针对人群进行估算。

But because these aren't the most precise things, they're really geared towards populations and their estimates.

因此，你可能有百分之十的几率在今后十年内发生心脏病发作。

And so you might have, say, a ten percent risk of having a heart attack in the next ten years.

但要做出决定有点困难。

But it's a little bit hard to decide.

这算是高风险吗？

Well, is that really high risk?

这是低风险吗？

Is that low risk?

我能接受这样的风险吗？

Am I comfortable with that risk?

因此，关于你能接受多高的风险、医生认为对你来说什么是明智的，这很大程度上取决于你和你的医生之间的个性化决策。

And so a lot of it becomes an individualized decision between you and your physician as to what level of risk you're comfortable with, what they feel, is advisable for you.

就像生活中许多事情一样，不同的人有不同的看法，医生也是如此。

And as is the case with many things in life, different people have different opinions, and that's true of physicians.

他们可能更保守一些，说：我们先别给你开药。

They might be a little bit more conservative and say, well, let's hold off giving you a medication.

让我们尝试一些生活方式的干预措施。

Let's try some lifestyle interventions.

让我们帮你减掉一些体重，更好地控制血压，更有效地管理糖尿病。

Let's try to have you lose some weight, get your blood pressure under better control, get better management of your diabetes.

其他人可能会更积极一些，说：看。

Others might be a little more aggressive and say, look.

我知道，我真的很想尽最大努力保护你，我觉得你应该开始服药。

You know, I I really want to protect you as best as I can, and I really think you should start on medication.

这是最好的处理方式。

That's the best course of action.

所以这里存在一定的灵活性，也有判断的空间。

So there there is some fluidity there, and there's there's room for judgment.

因此，你就能看到不同医生之间的意见差异。

And so that's why you can see differences of opinions between different doctors.

是的。

Mhmm.

基兰，我们知道他汀类药物是如何起作用的吗？为什么它们有效？

Kiran, do we know how statins work, why do they work?

我们对他汀类药物的作用机制有很清晰的理解。

We have a very good sense of how statins work.

它们的作用是抑制肝脏中胆固醇的生成。

What they do is they block the production of cholesterol in the liver.

实际上，人体内的胆固醇来源有多个。

So we actually have multiple sources of cholesterol in the body.

其中很多来自饮食，也就是你吃的食物。

A lot of it comes into the diet, the things that you eat.

但如果你从饮食中摄入的胆固醇不足，身体会有一个备用机制。

But if you don't bring in enough cholesterol in your diet, you have a backup mechanism.

你的肝脏可以完全从头合成胆固醇。

Your liver can actually synthesize cholesterol from scratch.

因此，这两种来源——饮食和肝脏从头合成胆固醇——共同构成了你体内所有的胆固醇。

And so between those two inputs, if you will, the diet and then the liver producing cholesterol from scratch, that's where you get all your body's cholesterol.

顺便说一下，胆固醇是很重要的。

And cholesterol is important, by the way.

它并不是那种应该被自动恐惧的东西。

It's it's not something that should automatically be feared.

它并不是有毒的物质。

It's not something that's that's toxic.

我们身体的所有细胞都需要胆固醇来保持完整。

All the cells in our body need cholesterol to be intact.

我们整个身体的健康在很大程度上依赖于胆固醇。

The integrity of our entire body relies very much on cholesterol.

胆固醇还有其他用途。

Cholesterol is used for other things.

它被用于合成各种激素，确保我们身体各个器官正常运作。

It's used for various hormones that ensure that our all the different organs in our body are working properly.

所以胆固醇是必不可少的。

So so cholesterol is essential.

只是你需要摄入适量的胆固醇。

It's just that you have to have the right amount of it.

你不需要太多。

You don't want too much.

太少也不行。

You don't want too little either.

因此，身体在肝脏中设有一个备用机制来合成胆固醇。

And so that's why the body has this backup mechanism of making it in the liver.

他汀类药物的作用是阻断肝脏合成胆固醇过程中关键的酶之一。

And what a statin does is it blocks one of the key enzymes that's involved in the liver producing its own cholesterol.

通过这样做，你可以降低整体的胆固醇水平。

And so by doing that, you reduce the overall level of cholesterol.

我听说胆固醇分子有不同的大小，可能会影响你的风险。

I've heard that there are different size cholesterol molecules, and they could affect your risk.

这是正确的吗？

Is that correct?

为了明确一点，胆固醇是一种单一的分子。

So to be clear, cholesterol is is a single molecule.

实际上只有一种胆固醇分子，但它在体内循环时，是通过一些更大的颗粒携带的，我们称之为脂质，或者如果你想要更专业的说法，就是脂蛋白。

There's only, like, one cholesterol molecule, but it is carried around the body in the bloodstream by these larger particles, what we call lipids or or lipoproteins, if you wanna use the technical term.

这些颗粒可以有不同的大小，而这实际上非常重要，因为它对疾病风险有重大影响。

And so those particles can have different sizes, and that's actually quite important because it has a big influence on on the risk of disease.

因此，携带胆固醇的较小颗粒，你可以想象它们比大颗粒更容易穿透动脉血管的壁。

So smaller particles that are carrying cholesterol around, you can imagine that they're able to penetrate into the walls of the arteries of the blood vessels more easily than larger particles.

我们确实认为，这些较小的颗粒因为能够进入动脉壁，更容易促进动脉斑块的形成，尤其是在为心脏肌肉供血的冠状动脉中，长期来看它们更具危害性。

And we do think that those smaller particles, because they're able to get in to those arterial walls, they're able to promote the growth of plaques in the arteries, particularly the coronary arteries, which are the arteries that feed the heart muscle, that they're more problematic over the long run.

同样，你需要这些颗粒。

Again, you need these particles.

你身体里的每个人都需要胆固醇。

You need cholesterol in everyone in your body.

但随着时间推移，如果它们偏离了正常路径，进入动脉壁，就可能引发一些不良后果，比如在错误的位置形成动脉粥样硬化或斑块。

But over time, you know, if they go off course and they end up in the arterial walls, they can cause, you know, undesirable things to happen, like like the formation of atherosclerosis or plaques in the wrong places.

更小的颗粒，所有证据都表明，由于它们体积更小，能够进入较大颗粒无法到达的部位，因此长期来看更具危害性。

And the smaller particles, you know, all the evidence suggests that the smaller particles, because they're they're smaller, they can, you know, divvy into places that the larger particles can't, are more problematic over time.

总体而言，它们会增加心血管疾病的风险。

And they on on the whole, they increase the risk of cardiovascular disease.

内亚，我知道有些人服用他汀类药物时会感到非常疼痛。

Neha, I know there are some people who find statins very painful.

对吧？

Right?

他们的肌肉会酸痛，这被列为一种副作用。

Their muscles ache, and that is listed as one of the side effects.

真的有人完全无法服用他汀类药物吗？

There are there some people who just can't take statins?

它们对这些人无效吗？

Do they do they not work?

还是说，他们有其他替代治疗方案？

Or are and are there other treatments available to them?

是的。

Yeah.

这些问题非常好。

These these are excellent questions.

是的，确实有一些人真正无法耐受他汀类药物治疗，因为这会导致明显的功能障碍甚至肌肉损伤。

And, yes, there are some people who truly cannot tolerate statin therapy because it causes significant dysfunction and even muscle damage.

但真正因出现显著肌病或肌肉损伤而无法耐受他汀的人数，与那些感到肌肉酸痛便认为是药物引起的人相比，可能只占极小比例。

But the number of people who truly can't tolerate statins because they have developed, you know, a significant myopathy or muscle damage is probably a tiny proportion in comparison to the number of people who feel achy and think that that is the statin medication.

这一点实际上已在多项临床试验中得到证实。

And this has actually been shown in a number of of trials.

确实存在一种被称为‘反安慰剂效应’的现象。

There is such a thing as as something that's called the nocebo effect.

安慰剂效应是指，我服用了一颗糖丸。

So the placebo effect is I take a sugar pill.

我认为它会让我感觉更好。

I think it's gonna make me feel better.

我觉得好多了，因为心理确实有很大的影响。

I feel better because the mind really is really influential.

反安慰剂效应正好相反。

The nocebo effect is the opposite.

我到处都看到说他汀类药物会导致肌肉酸痛。

I have read everywhere that statins are gonna cause muscle aches.

所有信息都告诉我，它们会引起肌肉酸痛。

Everything has told me that they're gonna cause muscle aches.

所以如果明天我感到酸痛，而我昨天才开始服用他汀类药物，那一定是药物引起的。

So if I feel achy tomorrow and I started a statin yesterday, it must be the statin medication.

事实上，是的，他汀类药物确实可能引起肌肉损伤。

The reality is that, yes, statins can cause muscle damage.

它们可能导致肌肉酸痛，但这种情况比人们随着年龄增长而自然出现的酸痛要少见得多。

They can cause muscle aches, but it's far less common than people just aching as we age.

你知道，当我们开始服用他汀类药物时，通常都是年纪较大的人，而随着年龄增长，肌肉酸痛是很常见的。

You know, as we get on statins, it tends to be people in their you know, as we age and muscle aches are common.

所以这是需要留意的一点。

So it is something to be aware of.

如果你开始服用他汀类药物后突然无法行走，那就是个问题。

If you start a statin medication and you suddenly cannot walk, that's a problem.

对吧？

Right?

但如果你开始服用他汀类药物，第二天只是右手指——你知道的，右手中指开始疼，那很可能不是药物引起的。

But if you start a statin medication and then your right finger, you know, your right index finger starts to hurt the next day, that's probably not the statin medication.

真正更可能由药物引起的肌肉酸痛通常发生在近端部位。

The types of muscle aches that are really more likely to be caused by the medication are proximal.

也就是你较大的肌群，比如大腿、臀部、肩膀。

They're kind of your large muscle groups, your thighs, your buttocks, your shoulders.

不会是远端部位，比如指尖，而且也从不会是单侧的。

It's not more distal like your fingertips, and it's never asymmetric.

如果只出现在一侧，那就不是药物引起的。

If it happens on one side, that's not the medication.

这种药物是全身性的。

The medication is systemic.

对于那些确实存在你问题第二部分的人来说，这一点也非常关键。

For the people who do have your the second part of your question is also really important.

对于那些确实无法耐受药物的人，无论是因为出现了真正的肌病，还是其他原因，他们就是不愿意服用。

For the people who do they truly cannot tolerate it, either because they had a real myopathy or for whatever reason, they just don't they're just not gonna take it.

对吧？

Right?

尽管我们可能认为他们可以服用，但如果他们根本不愿意吃，而药物又对他们无效，那强迫他们服用也没有意义。

As much as we might think that they can take it, if they're not gonna take it and it doesn't help them, then it doesn't help for me to force it.

对吧？

Right?

对于这些个体，可以考虑其他替代方案。

And and so for those individuals, there can be alternatives.

还有其他疗法可以帮助他们，这些疗法通常不会引起任何肌病、肌痛或肌肉酸痛。

And and there are other therapies that can be helpful that really don't have any of the myopathies or any of the myalgias and muscle aches associated with them.

这可能是被称为PCSK9抑制剂的一种药物。

That could be something called PCSK nine inhibitors.

有一种单克隆抗体，每两周注射一次，可以自行注射。

There are monoclonal antibodies that you can take every two weeks that you can self inject.

还有一种我们称为siRNA的药物，叫做依洛尤单抗，每六个月服用一次。

There are, there is an, what we call an siRNA, medication called inclisiran that can be taken every six months.

这是一种皮下注射药物，每六个月注射一次，同样靶向PCSK9分子。

It's a subcutaneous injection that you can take every six months that also targets that that molecule, the PCSK nine.

此外，还有一些其他口服疗法也可以使用。

And then there are another other oral therapies as well that could be utilized.

但真正来说，对所有人而言，一线治疗药物始终是他汀类药物，除非有明确的禁忌症。

But truly, the first line therapy for everybody really is a a statin medication unless there's some clear contraindication.

我们回来后，如果你能终身接种高胆固醇疫苗，你会怎么做？

When we come back, what if you could be vaccinated against high cholesterol for life?

你会愿意吗？

Would you do it?

我们会了解更多。

We'll find out more.

请继续关注我们。

Stay with us.

当所有人都服用这些GLP-1药物时，它们会影响胆固醇水平吗？

With everybody taking these GLP one medications, do they affect cholesterol levels?

我们是否应该对此感到担忧？

Are they something we should be worried about?

所以没什么好担心的。

So not much to worry about.

这些药物在各种被研究的人群中都非常有效。

These are these medications are incredibly effective in various populations where they've been studied.

它们常常能预防心脏病发作、中风、心力衰竭、肾病以及其他问题。

They, you know, have often prevented, heart attacks and strokes and heart failure and kidney disease and and other things.

但就对血脂的影响而言，只要体重有显著下降，血脂就会有一定程度的改善。

But in terms of the effects on lipids, anytime you have a significant amount of weight loss, you will have some positive effect on lipids.

因此，在GLP-1受体激动剂及类似疗法的各项试验中，我们观察到。

And so what we do see across the GLP one receptor agonist and and GLP one receptor agonist like therapies.

在这些试验中，您确实会看到低密度脂蛋白胆固醇（即我们常说的‘坏’胆固醇）略有下降。

Across those trials, you do see a little bit of a reduction in the LDL cholesterol, which is the quote unquote bad cholesterol that we worry so much about.

您也会看到高密度脂蛋白胆固醇（即‘好’胆固醇）略有上升。

You do see a little bit of an increase in the good cholesterol HDL.

您的甘油三酯水平会有更明显的下降，这与减重和血糖改善密切相关，但这些变化都不算巨大。

You see a bit more of a decrease with your triglycerides that's very much related to, weight loss and improvements in sugars, but none of it is that massive.

所以，如果您看这些疗法带来的低密度脂蛋白胆固醇降低幅度——通常比安慰剂组仅低几个百分点——这固然很好，

So if you look at the amount of LDL cholesterol lowering that you get, which is often kind of a few percentage points lower than baseline with these therapies than somebody who's on placebo, that probably can't I mean, it's great.

它不会有害，但无法解释GLP-1受体激动剂对心脏健康所带来的显著益处。

It can't hurt, but it cannot explain the degree of benefit that we see for heart health with GLP one receptor agonist.

基兰，很多年前我医生给我开他汀类药物时，他是位心脏病专家兼血液病专家，他说：‘你看他汀类药物，真正的益处其实不在于降低胆固醇，而在于减少血管内的炎症。’

Kieran, when my doctor started me on statins many years ago, he said to me and he was a he was a cardiologist, a hematologist, and he said, you know, I look at statins, and I find that the real benefit is not lowering your cholesterol, but it is preventing or lowering inflammation in your blood vessels.

你对这个说法有了解吗？

Do you know anything about this?

这有道理吗？

Does that make any sense?

是的。

Yeah.

几十年来，一直有关于所谓‘多效性作用’的讨论，这意味着它在体内具有多种效应。

There's been a long running discussion going back decades now over so called what would the technical terms pleiotropic effects, meaning it has more than one effect in the body.

毫无疑问，它能降低胆固醇，降低胆固醇确实有益。

And so it's indisputable that it reduces cholesterol, there's benefit from reducing cholesterol.

因此，真正的问题是，它是否还能通过减少体内的炎症来带来额外的益处？

And so the real question is, does it have added benefits on top of that by reducing some of the inflammation in the body?

目前尚无定论。

And the jury is still sort of out.

我们并不确定炎症所起的作用有多大，也不确定他汀类药物减少炎症的效果是相对更大还是更小。

You know, we don't we don't know for sure how big a role the inflammation is playing and whether the statins effects on reducing inflammation are having, you know, relatively larger or smaller effect.

但不可否认的是，他汀类药物确实能降低心脏病的风险。

I mean, but what is incontrovertible is that statins will reduce the risk of heart disease.

从某种意义上说，具体的机制其实并没有那么重要。

And in a sense, it doesn't really matter that much what the mechanism is.

它们在一次又一次的临床试验中已被反复证实。

They've been proven in clinical trial after clinical trial over and over and over again.

几十年来，许多研究累计涉及数十万患者，这些研究都表明他汀类药物能降低心脏病风险。

Many studies with collectively hundreds of thousands of patients in these trials over several decades now, they reduce the risk of heart disease.

因此，降低坏胆固醇是其中非常关键的一部分。

And so a big part of it is absolutely lowering of the bad cholesterol.

可能还有像抗炎这样的额外益处，但你知道，最终的结果是一样的。

There might be extra benefits like inflammation, but, you know, the consequence is the same.

你正在获得对心脏病的保护。

You're you're getting protection against heart disease.

如果你患心脏病的风险降低了，研究是否也表明这能降低死亡率？

If you do have a lower risk of heart disease, do the studies also show it reduces mortality deaths?

当然可以。

Oh, absolutely.

因此，我们知道，如果能够降低心脏病发作和其他类型心血管疾病的发生率，就能延长预期寿命。

So we know that if you can reduce the incidence of heart attacks and other types of cardiovascular disease, that it will improve life expectancy.

这种关系非常明确。

That's a very, very clear relationship.

值得注意的是，作为一名心脏病专家，我一遍又一遍地对任何愿意听的人说：心血管疾病已成为全球首要死因，不仅在美国，不仅在高收入国家，甚至在中等收入国家，如今在低收入国家，心血管疾病导致的死亡已超过我们通常认为的全球健康问题，比如传染病等。

And it is worth noting, and as a cardiologist, I say this over and over again to anyone who will listen, cardiovascular disease has become the leading cause of death worldwide, not just in The United States, not just in high income countries, but even in middle income countries and even now low income countries, cardiovascular disease has become the leading cause of death more than the things we typically think of as global health problems, like infectious diseases and so forth.

你可能难以置信，但它确实是全球首要死因，而且这一趋势还在恶化。

Believe it or not, it is the leading cause of death, and it is just the trend is getting worse.

因此，我们越能有效应对心血管疾病，对全球整个人口就越有利。

And so the more we can do to address cardiovascular disease, the better it will be for the entire population worldwide.

作为心脏病专家，我们的理想是：无论人们身在何处，都能控制这种风险，让心血管疾病不再成为首要死因，因为人们通过推迟心脏病发作和中风几十年，可能不再因此死亡，或至少不会像以往那样早早离世，从而提升预期寿命。

And what we'd like to be able to do, I think our aspirations as cardiologists, is to get a handle on it wherever people are, reduce that risk, and and make it so that it's no longer the leading cause of death because people are pushing off heart attacks and strokes by decades and maybe not dying of them or at least not dying as young as they otherwise would have and improving life expectancy.

那么，我们对饮食如何影响胆固醇水平了解多少？

Well, what do we know about how much what we eat affects our cholesterol levels?

这是一个复杂的问题。

So that is a complicated question.

每当您询问饮食对身体的影响时，这都是一个复杂的问题。

Anytime you're asking about the influence of diet on on what's going on in the body, it's a complex question.

很难开展非常高质量的研究。

It's hard to do very high quality studies.

很难开展持续多年的这类研究，因为这种临床试验要求人们长期严格遵守某种饮食，而不是仅仅短期坚持。

It's hard to do those studies that extend over many years because clinical trials of that type would require people very strictly adhering to, you know, this diet versus another diet, not just in the short term, for the long term.

因此，很难获得关于这种饮食与那种饮食之间真正益处的可靠信息。

So it's hard to get really good information on, you know, what are the benefits of this diet versus that diet.

我们知道饮食确实会影响胆固醇水平。

We do know diet has an influence on cholesterol levels.

根据您改变饮食的程度，这会影响您胆固醇水平的变化幅度。

Depending on how much you change your diet, that can influence how much you change your cholesterol levels.

因此，我认为在现代社会，典型的美国饮食，即使您做出重大改变，也不太可能显著降低您的低密度脂蛋白胆固醇（即坏胆固醇）。

So I think in modern day society, a typical American diet, I think, you know, even if you make major changes, it's not gonna change your LDL cholesterol, your bad cholesterol so much.

但它确实有帮助。

It can help.

它不可能达到他汀类药物等医学治疗那样的效果。

It's not gonna be anywhere near to the extent that medical therapy that is statins will do.

但如果你真的不愿意服药，改变饮食是一个非常好的第一步。

But if you're really reluctant to take medications, making dietary changes is is a very good first step.

而且这些改变很可能效果有限，但可能已经足以充分降低你的风险。

And then the changes are they're gonna be modest most likely, but that might be enough to to, you know, sufficiently reduce your risk.

这将带来巨大益处，或许还能让你觉得没必要开始药物治疗。

That'll be of great benefit and may, you know, make it less compelling to start medical therapy.

嗯哼。

Mhmm.

内亚，那新推出的膳食金字塔又把肉类和乳制品放在顶端，说饱和脂肪没问题，你怎么看？

Neha, what about the new food pyramid that put meat and dairy at the top again and saturated fat is okay?

是的。

Yeah.

说实话，这完全与事实相反。

Well, that's like the opposite of what's true, frankly.

我的意思是，大量数据表明，饱和脂肪确实与胆固醇水平升高以及总体不良健康结果相关。

I mean, tremendous amount of data has shown us that saturated fat is associated, yes, with elevated cholesterol levels and just poor outcomes in general.

我不认为有可靠的数据支持彻底推翻过去几十年我们所积累的所有认知。

I don't think that there is good data to support the idea of flipping on its head all of the learnings that we've had over the last several decades.

因此，我强烈反对饱和脂肪对健康有益这种观点。

So I I strongly disagree with the idea that saturated fat is good for you.

事实上，我们知道，比如那些采用生酮饮食的人，他们摄入大量饱和脂肪，吃很多黄油和红肉，他们的低密度脂蛋白胆固醇水平可能高达400到500，这与遗传异常所导致的水平相当。

And in fact, we know, you know, that individuals who, for example, are on the ketogenic diet, they have really high intake of saturated fat, eat tons of butter and, you know, lots of red meat, they can develop LDL cholesterol levels in the four and five hundred range, the kind that we see with genetic abnormalities.

因此，虽然保持健康饮食很重要，但反过来说，不健康的饮食会显著恶化你的胆固醇水平。

So while it is important to have a healthy diet, the flip side of that is that if you have an an unhealthy diet, it can really, worsen your cholesterol levels.

所以，如果我面对的是患有心血管疾病或有心血管疾病风险的人，我认为目前关于健康心脏饮食的最有力证据来自地中海饮食，已有大量随机对照试验表明，地中海饮食有助于降低心脏病发作、中风和死亡的风险。

So if I have somebody with cardiovascular disease, or who is at risk for cardiovascular disease, I think that the greatest amount of data that exists for, a heart healthy diet is around the Mediterranean diet for which there are large randomized controlled trials that suggest that a Mediterranean diet can help to reduce the risk of heart attack, stroke, and death.

此外，对于患有高血压或高血压高风险人群，特别是低盐的DASH饮食也极为重要，并且有充分的数据支持。

And also, especially for people who have hypertension or who are at high risk for hypertension, the DASH diet, especially the low salt DASH diet, is also extremely important and has good data to support it.

很好。

Great.

好的。

Alright.

我们继续吧。

Let's move on.

有太多话题要谈了。

So much to talk about.

基兰，我们来聊聊利用CRISPR技术降低胆固醇的事。

Kieran, let's talk about CRISPR technology for lowering cholesterol.

我知道你对这个很了解。

I know you know a lot about that.

它是怎么起作用的？

How would it work?

是的。

Yeah.

原理是，有一些基因会影响人体内的胆固醇水平。

So the idea is that there are genes that influence cholesterol levels in the body.

就像生活中的许多事情一样，这既部分取决于环境，也部分取决于我们如何选择自己的行为、饮食和锻炼等。

So as with many things in life, it's partly the environment and partly what we choose to do with our behaviors and our diet and exercise and things like that.

但同时也部分取决于我们的基因，即我们与生俱来、从父母那里继承的东西。

But it's also partly our genetics, what we were born with, what we inherited from our parents.

我们知道，胆固醇是很重要的。

And what we know is that cholesterol is important.

你的身体需要它才能正常运作。

You need it for your body to function well.

你不希望它过高。

You don't want it to be too high.

但说实话，你也不希望它过低。

You don't want it to be too low either, to be perfectly honest.

你希望达到那种恰到好处的平衡。

You want that right, that perfect balance.

我们的身体已经进化出帮助我们维持这种完美平衡的能力。

And our bodies have evolved to help us maintain that right balance.

结果发现，人体内胆固醇水平的许多调节过程都发生在肝脏中。

And so as it turns out, a lot of the management of cholesterol levels in the body, they occur in the liver.

因此，肝脏可以说是身体脂质水平的主要调节器。

So the liver is sort of the master regulator of lipid levels in the body.

肝脏中有一些基因会促进血液中胆固醇的含量增加。

And there are genes that are active in the liver that have a role of pushing up the amount of cholesterol that's in the blood.

但也有基因具有相反的作用。

And it turns out that there are genes that have the opposite effect.

它们会降低血液中的胆固醇水平。

They push down the amount of cholesterol in the blood.

这些基因几乎像跷跷板一样协同工作，根据你饮食中摄入的胆固醇量进行调节。

And the idea is they sort of work in tandem in almost a seesaw fashion depending on how much cholesterol you're getting in your diet.

在现代社会，我们当中没有人真的会面临胆固醇摄入不足的风险。

And so now in modern day society, none of us are really at risk of, you know, not getting enough cholesterol in our diet.

说实话。

Let's face it.

在大多数情况下，我们摄入的胆固醇都远超身体所需。

We're all eating much more cholesterol than we need for the most part.

非常有趣的是，如果你观察一下进化树上与我们关系较近的近亲——猫、狗等所有食肉动物，或者牛和其他反刍动物，你会发现，它们体内那些促进胆固醇升高的基因，比如一个名为PCSK9的重要基因，已经不再存在了。

And what's very interesting is that if you look at some of our close cousins on the evolutionary tree, cats, dogs, all carnivorous animals, or cows and other ruminants, it turns out if you look at their cholesterol genes, the genes that push up cholesterol levels, a very important one called PCSK9, they don't make that gene anymore.

它们不再拥有这个活跃的基因。

They don't have that gene to be active anymore.

它们不再从这个基因中产生蛋白质。

They don't make the protein from that gene anymore.

这可能发生在数千万年前。

And this probably happened tens of millions of years ago.

不知为何，灵长类动物，包括人类，仍然保留着这个活跃的基因。

For whatever reason, primates, including human beings, still have it active.

但有趣的是，大约有2%到3%的人群体内天然存在DNA变异，能够部分关闭PCSK9基因的活性。

But it is interesting that about two to three percent of the population have naturally occurring variations in the DNA that actually turn off PCSK9, at least partly in the body.

所以，有些人天生就能自然关闭胆固醇的产生吗？

So there there are people who have people who turn off the production of cholesterol naturally?

是的

Yeah.

他们是天生的。

They were they were they're natural.

他们生来就是这样。

They were born.

他们从父母一方遗传了一种变异。

They inherited, you know, a variant from either one of their parents.

即使人们并不知情，仍有约百分之二到三的普通人群体内这个基因部分处于关闭状态。

And even without knowing, just walking around, two to three percent of the general population has this gene partly turned off.

如果我们仔细研究他们——我们现在已经这样做了——会发现这些人患心脏病的风险显著降低，大约降低了百分之八十到九十。

And if you study them carefully, which we have done now, what you find is those people have dramatically reduced risk of heart disease, something like eighty to ninety percent reduced risk of heart disease.

原因在于，从出生到生命终结，他们的坏胆固醇水平始终显著更低。

And the reason for that is because they are exposed to substantially lower bad cholesterol levels through the entirety of their lives from the time they're born through the very end of life.

因此，这里有一个论点。

And so there's an argument there.

哇。

Wow.

如果我们能更早地干预并降低胆固醇，这可能会带来益处。

If we could intervene earlier and reduce cholesterols earlier, that would probably be a benefit.

你开始得越早，就越能提高你的预期寿命。

That would, you know, improve your life expectancy the earlier you started.

如果把这一点推到极致，你可以说，那两到三%的人，某种程度上赢了基因彩票，我们能否模仿大自然已经为某些幸运个体所做的事情？

And if you wanna take it to the logical extreme, you could say, well, these two to three percent of people who, in a sense, won the genetic lottery, can we can we do a similar thing that nature has already done to some people, some fortunate individuals?

我们能否实际使用类似基因编辑技术，比如CRISPR，来关闭肝脏中的胆固醇基因？

Can we actually use something like gene editing, like CRISPR, to turn off the cholesterol gene in the liver?

像PCSK9这样的基因。

A gene like PCSK9.

还有没有其他一些基因也可以关闭？

Are there a few other genes you could turn off as well?

这有可能吗？

And is it possible?

哦，已经在做了。

Oh, it's being done.

已经在做了。

It's being done.

正在临床试验中进行。

It's being done in clinical trials.

是的。

Yeah.

自从CRISPR刚作为基因编辑工具出现时，我就一直在宾夕法尼亚大学的实验室里研究这个课题，至今已经超过十年了。

So I I've been working on this in my research laboratory at the University of Pennsylvania for the you know, more than a decade now going back to when CRISPR first came on the scene as a so called gene editing tool.

那是2012年、2013年的事，作为一名心脏病专家，我立刻感到兴奋，因为我看到了它的潜力。

This was back in 2012, 2013, I immediately, as a cardiologist, got excited because I saw the potential.

嘿。

Hey.

如果你能把这种工具实际应用于肝脏，靶向像PCSK9这样的胆固醇基因并将其关闭，理论上胆固醇水平就会下降。

If you could actually put this into the liver, this tool, and aim it at a cholesterol gene like PCSK9 and actually turn it off, flip it off, in theory, cholesterol levels should fall.

这将是一次性解决的方案，因为它不像每天都要服用的药片。

And it would be a one and done proposition because it's not like a pill you take every day.

你吃下去，但效果在24小时内就会消退。

You take it, but then the effects wear off within twenty four hours.

所以你得第二天接着吃，再第二天接着吃。

So you then you gotta take it the next day, the next day.

如果你想获得全程的保护和这种疗法的全部益处，你就得一辈子持续服用。

And you got to take it for the rest of your life if you want that full lifelong protection, the full benefit of that therapy.

但如果你在DNA层面进行操作，永久关闭肝脏中的胆固醇基因，那么在接受治疗后，你的胆固醇水平将永久降低。

But if you're doing things at the DNA level, if you're permanently turning off that cholesterol gene in the liver, that means your cholesterol levels after you get that treatment will be permanently reduced.

但成本怎么办？

But what about the cost?

你谈的是基因编辑，对吧？

You're talking gene editing here.

对吧？

Right?

这难道不是一件非常昂贵的事情吗？

Isn't that a very costly thing to do?

而且我们也不知道这样做的长期安全性如何？

And we don't know what the long term safety of doing that would be?

这些都是非常非常好的考虑因素。

Those are very, very good considerations.

因此，这就是为什么我们需要进行临床试验来更好地了解这些情况。

And so this is why we have clinical trials to get a better sense of that.

对吧？

Right?

所以理论上，你知道，听起来很棒。

So in theory, you know, it sounds great.

然后，原则上，这应该是一个非常干净的解决方案。

Then, you know, in principle, it should be a very clean solution.

对吧？

Right?

我们再次受到那些天生携带变异基因、即让该基因失活的遗传改变的人的启发。

Again, we're inspired by people who are naturally born with the variants, the genetic changes that turn the gene off.

据我们所知，这些人群占总人口的百分之二到三，他们完全健康。

And as far as we can tell, all those people, two to three percent of the population, they are totally fine.

他们没有任何因该基因失活而带来的负面影响。

They have no negative consequences to speak of of having this gene turned off.

这似乎只有好处：降低胆固醇、降低心脏病风险、降低中风风险。

It all seems to be upside, reduced cholesterol, reduced risk of heart disease, reduced risk

是的。

Right.

降低中风风险。

Of stroke.

这简直是三赢。

It's a win win win.

因此，这让我们对这种疗法的安全性充满信心，这也是为什么我们开发了针对PCSK9的抗体、siRNA以及其他各种注射药物。

And so that gives us a lot of confidence that the approach is safe, and that's why we have antibodies and and siRNAs and all these other injectables that target PCSK9.

目前正在开发针对PCSK9的口服药物。

And there are pills that are being developed to target PCSK9.

但这些疗法需要反复服用。

But again, those are therapies you have to take over and over again.

但为什么不让那些没有天生赢得遗传彩票的人也能获得这种优势呢？

But why not make it like you who weren't born having won the genetic lottery, but we can give that to you.

你说得完全对。

But you're absolutely right.

你知道，安全性是首要关注的问题，这就是为什么我们要进行临床试验。

You know, safety is a foremost concern, and that's why we do clinical trials.

我们招募患者，首先从高风险人群开始，比如已经经历过心脏病发作的人，将他们纳入临床试验，给予治疗并长期观察。

We enroll patients, and we start with the patients who are at high risk, who've already had heart attacks or whatnot, enroll them in the clinical trials, give them the treatment and then observe them over time.

我们发现，虽然还处于早期阶段，但这类基因编辑疗法的首次临床试验于2022年启动。

And what we have found, it's very early days, but these clinical trials with this kind of gene editing therapy, first launched, in the 2022.

几年后的今天，我们知道这种疗法是有效的。

And what we now know a few years later is that the therapy works.

毫无疑问。

There's no question.

患者可以接受这种治疗，是的。

Patient can get this kind of treatment Mhmm.

它能将他们的坏胆固醇水平降低50%、60%甚至70%。

And it will reduce their bad cholesterol levels 50%, 60%, 70%.

这还处于早期阶段，但到目前为止，效果似乎非常持久。

And it's still early days, but so far, it appears to be very durable.

很可能会终身有效。

It looks very likely that the effect will last for the lifetime.

这是不是一种可以申请专利的东西，制药公司会这么做吗？

Is this is this a patentable thing that people drug companies?

是的。

Yeah.

所以制药公司正在研发这些疗法。

So so drug companies are are working on these.

根据我最新的统计，有十多家公司已经公开宣布了相关项目，它们正在使用各种类型的基因编辑技术来关闭多种不同的胆固醇基因。

By my latest counts, there are more than a dozen companies that have publicly announced programs where they're using various types of gene editing to turn off any of several different cholesterol genes.

你可以采用不同的策略。

There are different strategies you can use.

当它们开发出自己版本的疗法时，可以提交专利申请以获得保护。

And when they develop their own flavor of a therapy, they can put in a patent application and get some protection.

但基因编辑的类型足够多样。

But there are enough different types of gene editing.

值得靶向的基因也足够多。

There are enough different genes to go after that.

并不是所有疗法都能走完全程，但其中一些会成功。

Not all of them will make it all the way, but some of them will.

届时会有很多选择，我完全相信，这不会一夜之间发生。

And there will be options, and I fully expect, you know, it won't be overnight.

但在二三十年代，将会出现多种获批的基因编辑疗法，患者将拥有选择权。

But in the twenty thirties, there will be several approved gene editing therapies, and patients will have choice.