Looking Beyond Statins For New Ways To Lower Cholesterol

IRA FLATOW: Hi, it’s Ira Flatow, and this is Science Friday. If you’ve scheduled your yearly physical, one of the blood tests your doctor will probably order is a cholesterol test, that lipids panel. The test is a way to peek inside your arteries. 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.

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. And in spite of eating your body weight in oatmeal, your numbers are still high, so what now? Should you try one of the new treatments for high cholesterol that is on the market now?

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? That’s what we’re going to be talking about this hour.

So let me introduce Neha Pagidipati, who is a preventive cardiologist and director of the Cardiometabolic Prevention Clinic at Duke University in Durham, North Carolina; and Kiran Musunuru, a cardiologist and professor of translational research at the University of Pennsylvania in Philadelphia. Thank you both for joining me. Welcome to Science Friday.

NEHA PAGIDIPATI: Thank you so much.

KIRAN MUSUNURU: Thanks for having us.

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

NEHA PAGIDIPATI: Yeah, it’s a great question and something we’re asked in clinic every day. 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.

So it’s not a mystery. It’s based on really good evidence, and I think that’s something that’s a really important for patients to know. So for patients who have had a heart attack or stroke or who have needed, 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 because we know the lower, the better for LDL cholesterol and LDL particle number in terms of reducing your risk.

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, 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.

IRA FLATOW: Neha, is there a model? I mean, how does it work that you fit into one of these models that we’re looking at?

NEHA PAGIDIPATI: It’s a great question. So traditionally what we have done is we have used risk scores. So risk scores that help to estimate your risk of having a heart attack or stroke over the coming 10 years. And they work pretty well. They don’t necessarily represent all people because they’re not based on populations that include diverse people, but they work pretty well.

However, there are some downsides to this. One is that individuals who are younger rarely achieve that high risk score over the next 10 years to then merit therapy. But we know that the disease process of atherosclerosis doesn’t just start right before a person has a heart attack or stroke, it doesn’t just start before the 60-year-old has their heart attack, it started decades before.

And if we had looked to see if they had atherosclerosis, we might have started to aggressively try to prevent that process much sooner. But just using risk scores, we will often miss individuals, especially younger individuals, whose risk might be high over 30 years or over a lifetime, but isn’t that high over the next 10 years. So I think this is something really important that we have to think about in the clinic when we see especially younger individuals.

IRA FLATOW: Kiran, how much is it a call by the doctor? I mean, it feels like one doctor might say, OK, you’re 55, time to start a statin, while another might say it’s OK to wait. You can try diet and exercise, right? Are there official guidelines? How are patients supposed to decide? I mean, do the guidelines take into account things like family history or ethnicity?

KIRAN MUSUNURU: Increasingly they do. And so a lot of factors can go into these risk prediction algorithms. So 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– so if you’re a smoker versus a non-smoker. I’m increasingly incorporating things like family history, your ancestral background. And even starting to incorporate genetic factors.

But because these aren’t the most precise things, they’re really geared towards populations and their estimates, and so you might have, say, a 10% risk of having a heart attack in the next 10 years, but it’s a little bit hard to decide, well, is that really high risk, is that low risk? Am I comfortable with that risk?

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

They might be a little bit more conservative and say, well, let’s hold off giving you a medication, let’s try some lifestyle interventions. Let’s try to have you lose some weight, get your blood pressure under better control, get better management of your diabetes. Others might be a little more aggressive and say, look, I really want to protect you as best as I can and I really think you should start a medication, that’s the best course of action.

So there is some fluidity there and there’s room for judgment. And so that’s why you can see differences of opinions between different doctors.

IRA FLATOW: Mm-hmm. Kiran, how statins work and why do they work?

KIRAN MUSUNURU: We have a very good sense of how statins work. What they do is they block the production of cholesterol in the liver. So we actually have multiple sources of cholesterol in the body. A lot of it comes in through the diet, the things that you eat.

But if you don’t bring in enough cholesterol in your diet, you have a backup mechanism. Your liver can actually synthesize cholesterol from scratch. 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.

And cholesterol is important, by the way. It’s not something that should automatically be feared, it’s not something that’s toxic. All the cells in our body need cholesterol to be intact. The integrity of our entire body relies very much on cholesterol. Cholesterol is used for other things. It’s used for various hormones that ensure that all the different organs in our body are working properly.

So cholesterol is essential, it’s just that you have to have the right amount of it. You don’t want too much, you don’t want too little either, and so that’s why the body has this backup mechanism of making it in the liver.

And what a statin does is it blocks one of the key enzymes that’s involved in the liver producing its own cholesterol. And so by doing that, you reduce the overall level of cholesterol.

IRA FLATOW: I’ve heard that there are different-sized cholesterol molecules and they could affect your risk. Is that correct?

KIRAN MUSUNURU: So to be clear, cholesterol is a single molecule, there’s only one cholesterol molecule, but it is carried around the body in the bloodstream by these larger particles, what we call lipids, or lipoproteins if you want to use the technical term. And so those particles can have different sizes, and that’s actually quite important because it has a big influence on the risk of disease.

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, and we do think that those smaller particles, because they’re able to get into 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.

Again, you need these particles. You need cholesterol everywhere in your body, but over time, if they go off-course and they end up in the arterial walls, they can cause undesirable things to happen, like the formation of atherosclerosis or plaques in the wrong places. And the smaller particles, all the evidence suggests that the smaller particles, because they’re smaller, they can divvy into places that the larger particles can’t, are more problematic over time, and on the whole, they increase the risk of cardiovascular disease.

IRA FLATOW: Neha, there are some people who find statins very painful. Their muscles ache, and that is listed as one of the side effects. Are there some people who just can’t take statins? Do they not work or are– and are there other treatments available to them?

NEHA PAGIDIPATI: Yeah, these are excellent questions, and yes, there are some people who truly cannot tolerate statin therapy because it causes significant muscle dysfunction and even muscle damage, but the number of people who truly can’t tolerate statins because they have developed 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.

And this has actually been shown in a number of trials. There is such a thing as something that’s called the “nocebo effect.” So the placebo effect is I take a sugar pill, I think it’s going to make me feel better, I feel better because the mind is really influential. The nocebo effect is the opposite. I have read everywhere that statins are going to cause muscle aches. Everything has told me that they’re going to cause muscle aches. So if I feel achy tomorrow and I started a statin yesterday, it must be the statin medication.

The reality is that yes, statins can cause muscle damage, they can cause muscle aches, but it’s far less common than people just aching. As we age, as we get on statins, it tends to be people in their– as we age and muscle aches are common.

So it is something to be aware of. If you start a statin medication and you suddenly cannot walk, that’s a problem. But if you start a statin medication and then your right finger– your right index finger starts to hurt the next day, that’s probably not the statin medication. The types of muscle aches that are really more likely to be caused by the medication are proximal. They’re your large muscle groups– your thighs, your buttocks, your shoulders. It’s not more distal like your fingertips, and it’s never asymmetric. If it happens on one side, that’s not the medication, the medication is systemic.

For the people who do have– the second part of your question is also really important. 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 going to take it. As much as we might think that they can take it, if they’re not going to take it and it doesn’t help them, then it doesn’t help for me to force it.

And so for those individuals, there can be alternatives. 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. That could be something called PCSK9 inhibitors. There are monoclonal antibodies that you can take every two weeks that you can self-inject. There’s what we call an siRNA medication called inclisiran that can be taken every six months. It’s a subcutaneous injection that you can take every six months that also targets that molecule, the PCSK9.

And then there are other oral therapies as well that could be utilized. But truly, the first-line therapy for everybody really is a statin medication unless there’s some clear contraindication.

IRA FLATOW: When we come back, what if you could be vaccinated against high cholesterol for life, would you do it? We’ll find out more. Stay with us.

With everybody taking these GLP-1 medications, do they affect cholesterol levels? Are they something we should be worried about?

NEHA PAGIDIPATI: So not much to worry about. These medications are incredibly effective in various populations where they’ve been studied. They have often prevented heart attacks and strokes and heart failure and kidney disease and other things. 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.

And so what we do see across the GLP-1 receptor agonist and GLP-1 receptor agonist-like therapies, 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. You do see a little bit of an increase in the good cholesterol, HDL. 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.

So if you look at the amount of LDL cholesterol lowering that you get, which is often 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, it can’t hurt, but it cannot explain the degree of benefit that we see for heart health with GLP-1 receptor agonists.

IRA FLATOW: Kiran, when my Doctor started me on statins many years ago, he said to me– and he’s 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.” Do you know anything about this? Does that make any sense?

KIRAN MUSUNURU: Yeah, there’s been a long-running discussion going back decades now over so-called what– the technical term’s pleiotropic effects, meaning it has more than one effect in the body. And so it’s indisputable that it reduces cholesterol and there’s benefit from reducing cholesterol. And so the real question is, does it have added benefits on top of that by reducing some of the inflammation in the body?

And the jury is still sort of out. We don’t know for sure how big a role the inflammation is playing and whether the statin’s effects on reducing inflammation are having a relatively larger or smaller effect, I mean. But what is incontrovertible is that statins will reduce the risk of heart disease.

And in a sense, it doesn’t really matter that much what the mechanism is. They’ve been proven in clinical trial after clinical trial, over and over and over again, many studies with collectively hundreds of thousands of patients in these trials over several decades now, they reduced the risk of heart disease.

And so a big part of it is absolutely lowering of the bad cholesterol. There might be extra benefits like inflammation, but the consequence is the same, you’re getting protection against heart disease.

IRA FLATOW: If you do have a lower risk of heart disease, do the studies also show it reduces mortality? Deaths?

KIRAN MUSUNURU: Oh, absolutely. 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. That’s a very, very clear relationship.

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.

Believe it or not, it is the leading cause of death, and the trend is getting worse. And so the more we can do to address cardiovascular disease, the better it will be for the entire population worldwide.

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 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.

IRA FLATOW: Well, what do we about how much what we eat affects our cholesterol levels?

KIRAN MUSUNURU: So that is a complicated question. Anytime you’re asking about the influence of diet on what’s going on in the body, it’s a complex question. It’s hard to do very high-quality studies. 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 this diet versus another diet, not just in the short-term, for the long-term. So it’s hard to get really good information on what are the benefits of this diet versus that diet.

We do know diet has an influence on cholesterol levels. Depending on how much you change your diet, that can influence how much you change your cholesterol levels. So I think in modern-day society, a typical American diet, I think even if you make major changes, it’s not going to change your LDL cholesterol, your bad cholesterol so much. It can help. It’s not going to be anywhere near to the extent that medical therapy– that is, statins– will do.

But if you’re really reluctant to take medications, making dietary changes is a very good first step. And the changes are– they’re going to be modest, most likely, but that might be enough sufficiently reduce your risk. That’ll be of great benefit and may make it less compelling to start medical therapy.

IRA FLATOW: Mm-hmm. Neha, what about the new food pyramid that put meat and the dairy at the top again, and saturated fat is OK?

NEHA PAGIDIPATI: Yeah. Well, that’s, like, the opposite of what’s true, frankly. I mean, tremendous amount of data has shown us that saturated fat is associated, yes, with elevated cholesterol levels and just poorer outcomes in general. 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.

So I strongly disagree with the idea that saturated fat is good for you. And in fact, we know that individuals who, for example, are on the ketogenic diet, they have really high intake of saturated fat, tons of butter, and lots of red meat, they can develop LDL cholesterol levels in the 400 and 500 range, the kind that we see with genetic abnormalities.

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

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.

IRA FLATOW: Great. All right, let’s move on. So much to talk about. Kiran, let’s talk about CRISPR technology for lowering cholesterol. I know you know lot about that, how would it work?

KIRAN MUSUNURU: Yeah, so the idea is that there are genes that influence cholesterol levels in the body. 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, but it’s also partly our genetics, what we were born with, what we inherited from our parents.

And what we know is that cholesterol is important. You need it for your body to function well. You don’t want it to be too high. You don’t want it to be too low either, to be perfectly honest. You want that perfect balance. And our bodies have evolved to help us maintain that right balance.

And so, as it turns out, a lot of the management of cholesterol levels in the body, they occur in the liver. So the liver is the master regulator of lipid levels in the body. 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. And it turns out that there are genes that have the opposite effect, they push down the amount of cholesterol in the blood. And the idea is they work in tandem in almost a seesaw fashion depending on how much cholesterol you’re getting in your diet.

And so now in modern-day society, none of us are really at risk of not getting enough cholesterol in our diet, let’s face it. We’re all eating much more cholesterol than we need for the most part.

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, they don’t have that gene be active anymore, they don’t make the protein from that gene anymore. And this probably happened tens of millions years ago.

For whatever reason, primates, including human beings, still have it active, but it is interesting that about 2% to 3% of the population have naturally occurring variations in the DNA that actually turn off PCSK9, at least partly in the body.

IRA FLATOW: So there are people who turn off the production of cholesterol naturally?

KIRAN MUSUNURU: Yeah. They’re natural, they were born, they inherited a variant from either one of their parents. And even without knowing it, just walking around, 2% to 3% of the general population has this gene partly turned off. 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 80% to 90% reduced risk of heart disease.

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.

And so there’s an argument there, wow, if we could intervene earlier and reduce cholesterols earlier, that would probably be a benefit. That would improve your life expectancy the earlier you started.

And if you want to take it to the logical extreme, you could say, well, these 2% to 3% of people who, in a sense, won the genetic lottery, can we do a similar thing that nature has already done to some people, some fortunate individuals? Can we actually use something like gene-editing, like CRISPR, to turn off the cholesterol gene in the liver, a gene like PCSK9? There are a few other genes you could turn off as well.

IRA FLATOW: And is it possible?

KIRAN MUSUNURU: Oh, it’s being done.

IRA FLATOW: It’s being done?

KIRAN MUSUNURU: It’s being done in clinical trials. Yeah, so I’ve been working on this in my research laboratory at the University of Pennsylvania for more than a decade now, going back to when CRISPR first came on the scene as a so-called gene-editing tool– this was back in 2012, 2013, I immediately, as a cardiologist, got excited because I saw the potential. Hey, 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.

And it would be a one-and-done proposition because it’s not like a pill you take every day. You take it, but then the effects wear off within 24 hours, then you’ve got to take it the next day and the next day. And you’ve got to take it for the rest of your life if you want that full lifelong protection, the full benefit of that therapy.

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.

IRA FLATOW: But what about the cost? You’re talking gene-editing here. Isn’t that a very costly thing to do, and we don’t what the long-term safety of doing that would be?

KIRAN MUSUNURU: Those are very, very good considerations. And so this is why we have clinical trials, to get a better sense of that. So in theory, it sounds great. And then in principle, it should be a very clean solution.

Again, we’re inspired by people who are naturally born with the variants, the genetic changes that turn the gene off. And as far as we can tell, all those people, 2% to 3% of the population, they are totally fine. They have no negative consequences to speak of of having this gene turned off. It all seems to be upside– reduced cholesterol, reduced risk of heart disease, reduced risk of stroke. It’s a win-win-win.

And so that gives us a lot of confidence that the approach is safe, and that’s why we have antibodies and siRNAs and all these other injectables that target PCSK9. And there are pills that are being developed to target PCSK9, but again, those are therapies you have to take over and over again. But why not make it like you, who weren’t born having won the genetic lottery, but we can give that to you?

But you’re absolutely right. Safety is a foremost concern, and that’s why we do clinical trials, we enroll patients, and we start with the patients who are at high risk, who have already had heart attacks or whatnot, and enroll them in the clinical trials, give them the treatment, and then observe them over time.

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 summer of 2022. And what we now know a few years later is that the therapy works, there’s no question. A patient can get this kind of treatment, and it will reduce their bad cholesterol levels 50%, 60%, 70%. And it’s still early days, but so far, it appears to be very durable. It looks very likely that the effect will last for the lifetime.

IRA FLATOW: Is this a patentable thing that people– drug companies?

KIRAN MUSUNURU: Yeah. So drug companies are working on these. By my latest count, 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. There are different strategies you can use. And when they develop their own flavor of a therapy, they can put in a patent application and get some protection.

But there are enough different types of gene editing, there are enough different genes to go after that. Not all of them will make it all the way, but some of them will. And there will be options, and I fully expect– it won’t be overnight, but in the 2030s, there will be several approved gene-editing therapies, and patients will have choice, and that, in my opinion, that’s always a good thing.

IRA FLATOW: Neha, what’s your take? Do we know enough about these long-term side effects of knocking out a gene? Are you worried a bit about this?

NEHA PAGIDIPATI: I mean, this is a complete paradigm shift, and is so exciting for all the reasons that Dr. Musunuru just described. We know that patients don’t like to take therapies every day, and they don’t like to inject themselves all the time, and it would be lovely if you could take one therapy once and be kind of protected, have your heart protected for the entire lifetime.

So I think that this has the potential to be completely paradigm-shifting. And with the technology, it’s not just for cholesterol, it’ll be for other things as well that will also further protect your cardiometabolic health.

But I agree with Dr. Musunuru, it’s early days. And from– I’m not a genetics expert, I’m a regular doc in clinic, from my perspective, we need a lot of data to show that there’s safety over the long-term. I think– and that’s what’s being done right now. I mean, that data is being collected right now and will continue to be collected. Everybody’s well aware– the FDA especially is well aware that people are going to want to see that there are not any significant off-target effects, that this is safe in the long-run.

But I think where– in my opinion, where the real potential benefit for these agents is is in younger patients. Again, I’m getting back to this idea that disease starts at a young age. And if you were to give somebody one shot and be one-and-done, the time to do it is when they’re young.

If they already have high cholesterol levels, that’s where you’re going to get the true cumulative benefit over a lifetime. If you’re 70, 80 years old, sure, could take a therapy like this, but the relative benefit that you’ll get over your life is much less than somebody who starts decades earlier. But for the same reason, then, we need to make sure that the long-term side effects are not too significant. So I think that there is tremendous promise here, and I’m very excited to see how the field evolves.

IRA FLATOW: Well, we may be in the early days of trials, but we’re in the late days of our interview. We have run out of time. I’d like to thank both of you for taking time to be with us today. Neha Pagidipati, a preventive cardiologist at Duke, and Kiran Musunuru, a cardiologist at Penn. Thank you both for joining us today.

NEHA PAGIDIPATI: Thank you so much.

IRA FLATOW: Real pleasure, thanks for having us on.

IRA FLATOW: This episode was produced by Annette Heist. Thanks for listening. And please rate and review us on your favorite podcast platform– if you like the show, of course. We’ll see you soon.

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