Hard Drugs

Jacob Trefethen: Statins are one of the coolest things invented by medical science. It’s just so rare you can have something that has a population-wide preventive effect.

Saloni Dattani: The first statin originated from penicillium citrinum, the same genus as the fungi that gave us penicillin.

Jacob Trefethen: Mortality rates for cardiovascular disease are down by around 75% since the 1950s.

Cholesterol treatment has actually gone through a revolution in the last few decades.

Saloni Dattani: siRNA drugs reduce the levels of lipoprotein A by… can you guess?

Jacob Trefethen: I’ll say 60%.

Saloni Dattani: 95%!

It’s a short sequence of RNA gets into your liver cells. It binds to the RNA and it says, what if I destroy you?

[jingle]

Jacob Trefethen: Heart disease is the most common cause of death globally, and it’s one of the most common health conditions. But what might surprise you is that we’ve made a huge amount of progress against it. Age-standardized mortality rates for cardiovascular disease are down by around 75% in the US since the 1950s, which means that for people of the same age, the annual risk of dying from cardiovascular disease is now just one quarter what it was in 1950.

Saloni Dattani: That’s the result of many, many efforts in biomedical research and public health. Smoking is much less common. People are much more aware of the signs of heart attacks and strokes. Emergency care actually exists. Remember a time before anyone knew CPR? It was only invented in 1960! And there are surgeries like bypass surgery and devices like pacemakers and medicines as well: statins, PCSK9 drugs, blood pressure medications, and clot-busting drugs - just to name a few.

And surprisingly, in some areas, we’ve also improved our dietary patterns.

Jacob Trefethen: In this episode, going to focus on cholesterol, how it causes disease, what lifestyle changes affect it, and the drugs that reduce it. Cholesterol treatment has actually gone through a revolution in the last few decades and has some nice recent results in the last few years.

There are now drugs that can reduce LDL cholesterol levels by more than 60%, and some newer drugs about to come out are effective for months with a single dose.

Saloni Dattani: But in the 20th century, very few people believed that blood cholesterol could be harmful. After all, cholesterol is a vital component of our cell membranes and it’s a precursor for sex hormones.

So what changed our understanding? How did we get here? What’s the science behind cholesterol and what are the treatments for it?

Jacob Trefethen: Welcome to Hard Drugs, hosted by me - Jacob Trefethen - and Saloni Dattani!

Saloni Dattani: Welcome!

Jacob Trefethen: You ready for this one?

Saloni Dattani: Yeah. I’m very excited for this one.

Jacob Trefethen: I like that we are just going for the jugular, picking the biggest cause of death and doing an episode on heart disease, that makes me feel good. And cholesterol for me, I mean, as a child, cholesterol was a very sort of chic adult-realm kind of concept.

You know I’d hear my grandmother or father talk about cholesterol, cholesterol. And it was sort of, this “Is this coming for me one day?” And all I remember as a child was the, of course you gotta stop eating so many eggs because that will give you too much cholesterol, which is as the one fact I got transmitted from culture, actually incorrect, I believe.

So maybe we’ll get to that later. But I realized coming into this episode, gosh, my background knowledge from society is not so strong, but it’s such an important concept.

Saloni Dattani: You’re right. I had the same thing. I guess I thought of cholesterol as just this boring, abstract- it’s just there, it’s like high blood pressure.

You hear it all the time from older people and it’s not very interesting. And it seems to affect almost everyone. I guess I just hadn’t thought about how it actually all works and how do the drugs work and anyway, so very excited for this.

Jacob Trefethen: Okay. Shall we get into it?

Saloni Dattani: Yes.

Jacob Trefethen: So maybe the right place to start before getting to cholesterol is with the diseases themselves. So what is cardiovascular disease?

Saloni Dattani: Cardiovascular disease? Well, we can split it into two, cardio and vascular. So it’s a range of diseases that include diseases of the hearts, “cardio”, and diseases of the blood vessels, which are the “vascular” part. And together they’re very related to each other and they’re the most common cause of deaths worldwide.

It’s estimated that in 2019, 18 million deaths occurred that were caused by cardiovascular disease. So it’s really a lot of deaths.

Jacob Trefethen: I think there’s 60 million deaths total around the world every year. So 18 million, we’re just almost a third of all deaths, oh my god.

Saloni Dattani: And so making progress on this has also meant, it’s sort of translated to an improvement in life expectancy overall. It’s so common and we have actually advanced a lot in our understanding and treatment and prevention of it.

Cardiovascular diseases, there are many of them. There’s ischemic heart disease; that’s when you have a blockage of blood flow to the heart. There’s stroke and there are different types of stroke.

There’s ischemic stroke, which is also a blockage. There’s hemorrhagic stroke, which is when there is a bleed in the blood supply and that causes pressure on, that puts pressure on the cells that it bleeds into, and it also means a loss of blood. And then there are hypertensive heart diseases, when you have high blood pressure, and there are various other circulatory diseases.

And one of the common risk factors for a lot of these, especially ischemic stroke, is atherosclerosis. And atherosclerosis is a disease of the blood vessels where a cholesterol plaque develops and it occludes, or blocks, part of the blood vessel because it’s so big, there’s less space for blood to get through, and that reduces blood flow to organs.

And also parts of that plaque can break off or get eroded and block a smaller part of your blood vessel later on, which can, if it gets blocked in the blood vessels in your brain, can cause a stroke and cause a heart attack. It can cause various other artery diseases where you lose blood flow in certain parts of your body.

And so that - atherosclerosis - is one of the things that is most driven by cholesterol, and that’s why we’re gonna talk about that in this episode.

Jacob Trefethen: Okie doke. And before we get into too much more about all the ways the heart is failing and our blood vessels are failing, and all of that, I just wanna say a note of appreciation to the heart.

You know, that organ has to beat every second for your entire life and every part of your body is getting oxygen delivered to it at all. I mean, that’s a very impressive job. I’m very grateful. Thank you to the heart. And it makes sense intuitively of - well, if that starts failing and, for many different reasons it could fail, your whole body’s gonna be in trouble.

Similar to when you just mentioned with a stroke actually, if your brain starts failing for some reason, you’re gonna be in trouble. The brain and the heart is, you gotta be on at all times, basically. So, thank you heart. All that said, I’m gonna be mad about some of the misfunctions for the rest of the episode.

Saloni Dattani: Well, I have a question for you on, because you brought up heartbeats. Do you know how many heartbeats a human has in their lifetime on average?

Jacob Trefethen: Oh gosh. Okay, so this feels like - so once a second. Oh, what’s the rent song? (he sings) 2,560 mana minutes is how many minutes there are in a year? Unfortunately, I can’t remember that number.

So we’re gonna do 60 per minute. We’re gonna do 60 minutes in an hour. So up to 3,600, we’re gonna do times up by 24. That’s a big number already. And then we’re gonna by - we’re gonna times by 80 I think the answer is like loads. I’ll go with a billion.

Saloni Dattani: It’s actually no, 10 times 10 to the power eight. Wait, that’s a trillion. That’s a trillion!

Jacob Trefethen: Trillion beats. Now imagine if you took all of those beats and put a baseline underneath them.

Saloni Dattani: Boom. Literally. Yeah. So you’re right. So the heart is really important for pumping blood around your body, making sure energy and nutrients get to lots of tissues. And because of that, the blood vessels that deliver that blood are by extension really important. And so if you get a buildup of fat or cholesterol and stuff in the walls of your blood vessels, that’s really bad. And this is something that accelerates with age. And for a long time people just assumed that cholesterol and cardiovascular disease was just this inevitable outcome of aging.

It wasn’t something that we could change. And now we know that that’s not true. It’s not inevitable; it does happen and it does accelerate, but we can actually reduce the rates in total across the lifespan with different behaviors, different environments, and then also drugs and treatments.

Jacob Trefethen: So I’d love to hear more about how that’s gone so far. So how has cardiovascular disease changed over time and what are the things that have led to reductions?

Saloni Dattani: Yeah, this was really surprising to me a few years ago when I was writing about cardiovascular mortality and how that’s changed. One of the problems is that we don’t really have long-term data on diagnoses of cardiovascular disease. We don’t really know how the rates of cardiovascular disease have changed over time. In part just because the data’s quite patchy. There are different definitions and we just don’t have this long-term view. But we do have that for cardiovascular deaths because deaths are recorded on death certificates.

And people will mention what, the doctor who’s signing off the death certificate will write down what they think the cause of death is. And we can collect that information every year and see what the overall mortality rate is. And if you look at that since 1950 in the US, there has been a decline of more than 75%.

So that’s an enormous decline. And it’s something that I hadn’t known about. And part of the reason that I didn’t know about it was that it’s affected by aging. So if we have a population that is older than in the past, the mortality rate will actually increase. So this 75% decline is when you standardize that age.

So you’re saying if we kept the population’s age constant, what is the reduction in death rates that you would see? And what that means is looking at people who are 50 or 60 now compared to in 1950, what are their chances of dying? And that is what has declined by 75%. So looking at people who are 50 years old now, or 70 years old now, they have a quarter of the chance of dying from cardiovascular disease as people who were 50 or 70 in the 1950s. So that is a huge drop.

Jacob Trefethen: The number of heart attacks hasn’t gone down 75%. But that’s actually in a strange way, a reflection of a happy fact, which is that people are living longer and as you age, your risk goes up. And so standardizing in the way you’re saying sort of gives a fairer look on our progress.

Saloni Dattani: Right.

So people are still dying. We haven’t solved death yet, but when they die, they die later and these diseases progress slower and that I think is worth celebrating. You have more years to live on this planet.

Jacob Trefethen: I’ll celebrate that.

Saloni Dattani: Yeah. So how did it happen? I think just so many different things.

One thing that I like to say, which is probably very annoying from a quantitative point of view, is that it’s really hard to separate out the different causes because they kind of interact with each other. If one of them reduces your risks by 20% and another one separately would reduce your risks by 20%, the total decline might be less than 40%, and it usually is, because there are interactions. They’re very difficult to cleanly distinguish from each other because they kind of interact with each other, but anyway, there are just a lot of different changes that we’ve made.

So there are new medicines. There are statins, which were only introduced in the 1980s, and they help keep our arteries cleaner by clearing LDL cholesterol and also by stabilizing the plaques that develop that can block our blood vessels.

There are also newer drugs called PCSK9 inhibitors and they help reduce cholesterol even more. Then there’s blood pressure medications, beta blockers, ACE inhibitors, all of these things that help keep your blood pressure under control and reduce your risk of stroke, heart attacks and heart failure.

And then there’s clot-busting medicines that break up these blockages and help restore your blood flow. And then there are dietary changes as well. This really surprised me. I feel like we hear a lot that people’s diets have worsened, and in many ways that is true. We eat a lot more than we did in the past and we eat a lot of unhealthy processed foods.

But there are certain ways that our diets have improved, such as reduced consumption of trans fats. So I think maybe you know more about this, but trans fats are banned in some countries.

Jacob Trefethen: Many, most, maybe.

Saloni Dattani: Right. And there are also recommendations that people get if they are diagnosed with different types of cardiovascular disease to reduce how much saturated fats they eat to change their dietary patterns. And I think that has actually, at least in some, in these higher risk populations and in certain food groups have actually made a difference.

And then there are surgeries and devices that have been introduced, there are pacemakers, for example, there are things like bypass surgery, there’s angioplasty where you try to unblock an artery by threading a balloon into the clogged artery and then inflating the balloon, opening up the artery and restoring blood flow.

And there are stents, which are tiny mesh tubes that keep arteries open. And then there are drug coated versions of those stents, which prevent the stents from breaking down and prevent re-narrowing. And then there are various other surgeries that we’ve introduced, like heart transplants, which didn’t exist before the 1960s.

And we have ways to completely replace heart valves with mechanical heart valves. Or you can have robot-assisted surgeries to make really precise changes that are very hard for someone to do as an individual.

And the most surprising thing to me was thinking about how emergency care has changed. So, before 1960 CPR didn’t exist, people didn’t - if you collapsed on the street, people generally wouldn’t really know what to do. They might have some thought that, I don’t know, let’s try to open up your chest or put you in a different position-

Jacob Trefethen: You would see someone collapse on the street and open up their chest? Come on.

Saloni Dattani: No one would know how, well not- I mean move their arm out of their, I don’t know.

Jacob Trefethen: Oh, open.

Saloni Dattani: Not, not literally open.

Jacob Trefethen: I was like, do you carry around a scalpel with you? It’s too late for this CPR. It’s time to go deeper.

Saloni Dattani: I meant put them in a different position like-

Jacob Trefethen: Now I understand why this 75% drop, you’ve gone from people performing unsterilized surgery on the street, which used to kill people and then when you stopped doing that…

Saloni Dattani: Well… no, but so I mean, just introducing basic things like that, like telling people what the signs of a heart attack are and what the signs of a stroke are. People didn’t know those before. I think until at the end of the 1930s, there was no 999 hotline here in the UK. There was no 911 hotline, I think until the 1970s in the US.

Then of course there were big anti-smoking efforts as well. Smoking increases the risks of heart disease and heart attacks, and all of the efforts, like the campaigns to reduce smoking, have also made a difference in reducing heart disease deaths.

Jacob Trefethen: It’s really interesting to hear that list of so many different contributors and you have this beautiful graph that’s probably a top five favorite Saloni graph for me.

Actually it might be a top three.

Saloni Dattani: Oh, really?

Jacob Trefethen: Putting a lot of those contributors dated on a declining line of, “Oh wow. We’re just making all of these improvements that stack on top of each other.” I mean, it’s interesting to think of that in comparison to our lenacapavir episode on HIV where with HIV there was, you know, there’s not just one thing that changes HIV rates, of course, that said one class of drugs, of antiretrovirals and combination therapy are so much of the driver of decline that it doesn’t feel like there’s 27 different contributors.

So it’s almost an easier story to tell than this story, which is, a lot of stacked improvements across medical research, societal infrastructure, knowledge, all of that. So that’s, yeah, the graph really stands with me for that reason, sticks with me. One question I have for you is, so you were just describing the adoption of these technologies, I think based on the US and UK. Do you have a sense of whether there’s a global drop that’s similar or have these technologies, practices been adopted in most other countries?

Saloni Dattani: So I think you do see decline in cardiovascular mortality in most countries, if you’re looking at the age standardized rate and doing this fair comparison by age. But you see an increase in the number of deaths more in poorer countries especially, that as populations grow in size and get older, we’ve had more deaths from cardiovascular disease.

Actually, what’s interesting is that in some richer countries, the number of cardiovascular disease deaths has also declined. The improvements that we’ve seen are so massive that even though we have an aging society, fewer people are dying from heart disease than in the past.

Jacob Trefethen: Okay. That’s great.

And then you mentioned anti-smoking efforts, which brings me to another question. Are there other risk factors for cardiovascular disease and how are those going?

Saloni Dattani: So I think there are a few really big ones. Smoking is a big one. Cigarettes carry a lot of carcinogens, chemicals that injure your blood vessels and cause inflammation. And that can eventually, that can accelerate atherosclerosis. It can increase blood pressure and that can worsen heart disease.

There’s also obesity, which is a big risk factor for heart disease that raises your blood pressure and cholesterol, but it also drives insulin resistance, inflammation and just puts more strain on your heart and other parts of your body. And so that worsens cardiovascular disease as well.

And then there’s high blood pressure, which has many different causes, but that’s when your blood vessels become stiffer or narrower, and that drives further damage because it puts extra pressure on your heart, it puts extra pressure on your artery walls and it means that they’re more likely to weaken or get clogged up or actually break and rupture. And that can lead to strokes, heart attacks and heart failure.

And then there’s the two that we’ll talk about mostly in this episode, which are cholesterol and triglycerides. And they will mostly put them together and they sort of fall under the category of lipids, but we’ll mostly focus on cholesterol and specifically LDL cholesterol and why that raises the risk of cardiovascular mortality.

So every increase of 40 milligrams per deciliter translates to an increase in cardiovascular disease by around 20%. And that’s an average. And the way that we know that is by looking at randomized control trials where we’ve reduced LDL cholesterol and how much does that reduce the risk of cardiovascular disease. So we know that if we reduce it by that much, we reduce the risk of heart attacks, strokes, and so on by around 20%.

So because cardiovascular disease is such a big proportion of deaths overall, that translates to a big change.

Jacob Trefethen: So the people who want to cure death, they can cure half of death if they just cure-

Saloni Dattani: Well, I guess maybe more like a third or somewhere between a third and half. One thing that was surprising to me about this, thinking about the risk factors is that some of these risk factors have actually improved over time. This also was surprising to me. So if we look, there are big surveys in the US for example, with people’s levels of cholesterol in their blood or their blood pressure, or you know, how many people smoke and things like that. And if we look at them over time, you’ll look in the last 20 years, let’s say, they’ve actually declined.

So having high levels of cholesterol, that used to be, that used to affect maybe around 20% of people at the turn of the century, so 1999. Now only around 10% have high cholesterol levels.

Jacob Trefethen: Hmm, wow.

Saloni Dattani: And then if you look at blood pressure, if you look at uncontrolled blood pressure that has declined slightly.

So from around 42- 43% to around 35%,

Jacob Trefethen: Blood pressure has gone down. I feel like in the last 10 years, everyone’s blood pressure’s been through the roof.

Saloni Dattani: So, this was really confusing to me, and I’ll tell you why. And it’s because the way that we measure it is very confusing- the definition is if you have high blood pressure or if you’re on blood pressure drugs, even if they’ve reduced your blood pressure, if you’re taking those drugs, you count as having high blood pressure [hypertension].

And that is very confusing, right? Because more and more people have been taking blood pressure drugs and they’ve reduced those people’s blood pressure. But that’s not reflected in the statistic that usually goes around. And so when I was looking at this, I was incredibly confused. And you can instead look at a different metric, which is called uncontrolled blood pressure. And that’s when you have blood pressure that’s higher than 130 over 80, you’re considered having uncontrolled blood pressure.

Jacob Trefethen: Not that high. God.

Saloni Dattani: Yeah. So that has reduced from 43% ish to 35%.

Jacob Trefethen: You’re saying that, so I thought the word uncontrolled meant that you’re not on drugs, so you’re not controlling it, but you’re saying uncontrolled means? Uncontrolled just means high.

Saloni Dattani: Yep. Yeah.

Jacob Trefethen: Okay, so then is the drop attributable to blood pressure reducing medications, do you think?

Saloni Dattani: I don’t know, I would guess that part of it is, and then I would guess that another part of it might be reductions in smoking and so on, and lifestyle changes. It’s probably a combination of both of those things. But yeah, that was very confusing to me and also surprising.

And then of course, this thing that a lot of people will find kind of obvious and noticeable is that smoking rates have dropped. So, you know, in 1999, about 25% or so of people smoke cigarettes. Now it’s just above 10%.

Jacob Trefethen: Let’s say it’s a very special night and it’s late, and you have had a few glasses of wine and you have one single cigarette. Do I appear in the 10% or the 90%? Obviously I’d never do that.

Saloni Dattani: Oh, you actually would count under a non-smoker. So the definition of cigarette smoking, according to this survey, which is the National Health and Nutrition Examination survey, or NHANES, the definition is: people who have smoked at least a hundred cigarettes in their lifetime and currently smoke every day or some days.

Jacob Trefethen: I think I’m under a hundred. I’m definitely under, I’m under a hunderd. Are you under a hundred?

Saloni Dattani: If you’re just, I’ve never smoked a cigarette.

Jacob Trefethen: Zero?!

Saloni Dattani: Yeah.

Jacob Trefethen: Zero. Zero? Wooooow!

Saloni Dattani: I have, I have no temptation. It smells bad. It’s weird. Feels so outdated.

Jacob Trefethen: Have you ever hit a vape?

Saloni Dattani: No.

Jacob Trefethen: Oh my God. Saloni.

Saloni Dattani: I’m really boring.

Jacob Trefethen: You’re quite the opposite. You’re living a dream that all of us can aspire to.

Saloni Dattani: This will surprise a lot of people. I don’t drink coffee either.

Jacob Trefethen: Oh my, that’s, okay. So people on the video-

Saloni Dattani: I also don’t really drink tea, except occasionally.

Jacob Trefethen: I have a jug, a mocha pot right next to me to keep topping myself up. So what is your favorite drug then?

Saloni Dattani: None.

Jacob Trefethen: Don’t tell, don’t tell me. Tell me offline.

Saloni Dattani: You know what I do instead of drinking coffee? I sleep more.

Jacob Trefethen: Noooo! Owned. Nooooooooo! Oh damn. We’re hosting a podcast called Hard Drugs with the reveal that she sleeps well and has smoked zero cigarettes.

Saloni Dattani: Well, I don’t really sleep that well. I guess I just sleep more, like I have naps and, you know.

Jacob Trefethen: Oh, that’s fun.

Saloni Dattani: My watch tells me that I’m a very poor sleeper.

Jacob Trefethen: Oh, that’s not fun. Do you sleep with the watch on? That might be the cause.

Saloni Dattani: I have always slept with a watch since I was like five.

Jacob Trefethen: Oh, cool.

Saloni Dattani: Learning a lot of facts about me.

Jacob Trefethen: Yeah. You’re learning lot of facts—

Saloni Dattani: I mean, you’re learning.

Jacob Trefethen: Okay. Well, I refuse to share anything, but back to risk factors. I mean it’s interesting that cigarettes have gone down a lot in the US over the last 25 years.

Obesity, sadly has gone up. Is that true? Am I lying?

Saloni Dattani: Yeah. Yeah. Obesity. So yes, some risk factors have worsened for sure, and specifically obesity has increased from around 30% to 40% in the last 20 years.

Jacob Trefethen: And it’s interesting, those two risk factors we’re mostly talking about cholesterol today, the risk factor of obesity and risk factor of cigarettes though, or smoking, both also increase your risk of cancer.

So it’s not just a heart disease story. Those are having chronic negative effects that, you know, hit the other main cause of death too.

Saloni Dattani: Mm-hmm. Yep. Lots of different problems. That’s why I don’t smoke.

Jacob Trefethen: Got it. Okay. Well now that you’ve told me that smoking can have bad effects, maybe I won’t smoke either! Why didn’t you tell me until this episode?

Saloni Dattani: Sorry!

Jacob Trefethen: In case my mom is listening, I don’t smoke. I actually don’t. I actually don’t.

Saloni Dattani: I think that just to make me sound more like a normal person, I think that I’m afraid that I could get addicted to stuff and so I’m just unwilling to start taking them ever.

Jacob Trefethen: Okay. That is very sensible. That is very sensible. Don’t hit a vape. That’s my advice.

Saloni Dattani: It’s not just because I’m a boring person.

Jacob Trefethen: Okay, good.

Saloni Dattani: So the other thing that is one of the reasons that cholesterol levels have declined is because the usage of statins has increased. So I think there’s probably multiple reasons for the reduction in cholesterol.

One of them is statins. And statins have increased from about, 30% of people who are eligible, taking them to around 40% now. So in the last 20 years, we’ve increased that by around 10%.

Jacob Trefethen: Statins, statins, statins, those again, when I was growing up, were a very sort of chic concept of ‘a statin?’. You know I grew up in England but with an American father.

And so anything to do with taking medication preventively was very American. It was very American. And the idea that Americans used to take aspirin, for example. Taking aspirin? Maybe if I grow up one day I can take aspirin.

Saloni Dattani: Life goals!

Jacob Trefethen: Life goals. And I asked my British mother one day about aspirin or statins, I can’t remember what, and she was like, “Oh yeah, no, that’s just an American thing. They do checkups every year as well.”

Saloni Dattani: That has actually been so shocking to me. So I grew up in Hong Kong. And my parents are quite health conscious and we’ve tried to, when we were at school we’d have a health checkup every year. And now my parents also try to get us to have a health checkup every year. And the fact that people don’t do that here is crazy to me.

Jacob Trefethen: You wanna take up a doctor’s time? They could be dealing with a sick person.

Saloni Dattani: But it’s also funny that you considered statins to be chic. I just thought they were boring adult things that I wasn’t interested in. I was like, “Oh God, they keep talking about that.”

Jacob Trefethen: Yeah. I dunno something about any daily pill when you’re a child, it’s like, “Ooh, ooh, ooh..”

Saloni Dattani: “Can I have that?”

This must be also the difference between our drug consumption. And I was just like, “My god, that sounds boring as hell.”

Jacob Trefethen: Fair enough, yeah.

Saloni Dattani: There’s so many things that I think were new to me when I was doing research for this episode that I think you will enjoy. I have a bunch of fun facts or questions, trivia, that I wanted to ask you.

Jacob Trefethen: Okay, I’m ready.

Saloni Dattani: So first question. Out of the top 10 most prescribed drugs in the US, how many are statins?

Jacob Trefethen: Ooh. Okay, let me check I understand. Top 10 most prescribed. Does that mean by volume? So if I get a daily pill that gets renewed every month, is that counting here or you mean it’s just per person?

Saloni Dattani: No, this is per person.

Jacob Trefethen: Okay, got it. Okay, cool. Okay. Well, statins are absolutely gonna be up there because they’re one of the few drugs that has very broad population effect.

So I’m gonna say it’s gonna be more than one at the top 10. And then of course, no one person is gonna be on, oh, maybe they are gonna be on more than one. You can correct me on that if you want… So I’m going to go with… three.

Saloni Dattani: Three. That’s very close. It’s two actually, and they are Rosuvastatin, whose brand name is Crestor. And then there’s Atorvastatin, which is commonly called Lipitor.

Jacob Trefethen: Yes, yes. Lipitor, a classic.

Saloni Dattani: And it made me think that, it sounds like Lickitung, the Pokemon.

Jacob Trefethen: It does, it’s true. And there’s actually a relation, that’s the organism it was discovered in.

Saloni Dattani: Oh?? Well, we were talking about this before with our amazing video editor, Graham, and he said, Lipitor sounds like a water or steel Pokemon. It’s moving slowly, smoothly through the bloodstream. It’s a defense against cholesterol, and maybe it involves into ‘Statin-ite’, and its final form is ‘Lipi-titan’.

What do you think?

Jacob Trefethen: I think that that is a evolution that I wanna watch, and I guess this is a very small Pokemon because it’s in my bloodstream.

Saloni Dattani: So I had a question for you.

Jacob Trefethen: Hit me.

Saloni Dattani: On Lipitor, which is, what is your favorite drug name?

Jacob Trefethen: My, I mean, actually Lipitor does roll off the tongue - Lickitung reference.

Saloni Dattani: Mm.

Jacob Trefethen: And so I do like Lipitor. What’s my favorite ever? Probably.. Oh, here, here, ready?

Saloni Dattani: Okay. Okay.

Jacob Trefethen: Acid. You have to admit that is the coolest!

Saloni Dattani: Yeah, I wasn’t expecting that.

Jacob Trefethen: You’re just naming something after acid? Wow, I can’t wait to take alkaline.

Ok but actual drug name, I’ve said Atorvastatin a lot in my life as well. The generic name.

Saloni Dattani: You have?

Jacob Trefethen: Because we funded a trial involving Atorvastatin.

Saloni Dattani: Mine is ‘axicabtagene ciloleucel’.

Jacob Trefethen: No, no, no, no, no, no, no, no. Nope.

Saloni Dattani: I was like, I remember reading this for the first time and I was reading about, so this is a type of CAR T-cell therapy.

Axicabtagene ciloleucel. And I was reading this and I was like, what? How do you read that? How do you pronounce that? And then there’s another one called ‘tisagenlecleucel’.

Jacob Trefethen: No.

Saloni Dattani: What is going on with these?

Jacob Trefethen: Why do they do that?

Saloni Dattani: So that is a very good question and the answer is the suffix, this thing at the end, ‘-leucel’ is what you call - that is the suffix for CAR T-cell therapies. All of them have that ending. And then the starting thing is just something unique to distinguish it from other CAR T-cell therapies.

Jacob Trefethen: I see. I think ‘leucel’ is too long of an ending. We need to contract it. Like an antibodies ending ‘ab’ that’s shorter.

Saloni Dattani: Yeah. ‘mAb’. Like Ipilimumab.

Jacob Trefethen: Ipilimumab. Aducanumab.

Saloni Dattani: We have a lot of statins that end in -statin, Atorvastatin.

Jacob Trefethen: Very true. That’s a long ending. I like, well you know, one brand name I really like - it’s just so iconic is Tylenol. I think it’s also very American. It’s very, Americans love it.

Saloni Dattani: I didn’t know what that meant ’cause it’s paracetamol here.

Jacob Trefethen: Exactly. Yeah. If you hear the word Tylenol in England, you’re like, oh, is that a far away land? Where they- is that Kansas? Where they get a headache?

Saloni Dattani: When I’ve gone to the US and I’ve asked for paracetamol, the people are just like, what? Who?

Jacob Trefethen: Who’s that? Oh, another classic - ethanol. Pretty good, ethanol’s pretty good.

Saloni Dattani: So there’s a difference between the chemical names like Atorvastatin, ipilumumab, axicabtagene ciloleucel, et cetera. And then those are kind of governed by this prefix suffix thing, right?

But there are brand names that are just something unique that should distinguish it from other drugs. And I think that’s quite hard ’cause there are quite a lot of drugs and you have to find a name that’s sufficiently unique that people won’t accidentally prescribe the wrong thing.

Jacob Trefethen: The thing I love about some of these cases is that the brand name is so forgettable that people just end up calling it the original thing, like malaria vaccines.

It’s like that’s RTS,S!, It’s like, no, no, no, that’s technically called Mosquirix. Yeah that’s RTS,S!

Saloni Dattani: I actually like Spikevax as a name. It’s pretty cool.

Jacob Trefethen: Nice and violent.

Saloni Dattani: True.

Jacob Trefethen: That’s steel type for sure.

Saloni Dattani: Yeah. Yeah. But it’s very memorable. There’s another one that I found called Xeljanz, and I wonder if you can guess how it’s spelled.

Jacob Trefethen: Xeljanz… C-E-L-L-G-A-N-S?

Saloni Dattani: No, it’s X-E-L-J-A-N-Z.

Jacob Trefethen: Okay. That’s it. That sounds like an insurance company.

Saloni Dattani: That is an enzyme. Well, that is a drug that inhibits an enzyme and it’s very important in autoimmune diseases and inhibits JAK enzymes.

Jacob Trefethen: I’ll take your word for it.

Saloni Dattani: Alright, next question. I’ve actually given you a bit of a hint on this one, that’ll help you figure it out, I think. So the question is: How many people in the US take statins?

Jacob Trefethen: 40% of eligible people. I’m just gonna squint and pretend eligible means like you’re over 40 and male and if you’re over 50 and female you can, I dunno. And then that’s gonna leave me with, let’s just call it half the American population, which is probably 170 million people. So what’s 40% of that? And so I get to, you know, something along the lines of 70 million, but that sounds too high, so I’m gonna take it down to 50 million.

Saloni Dattani: Wow. That was incredibly close, mostly because of your adjustment. It is roughly 50 million people in 2023.

Jacob Trefethen: Yes!!!

Saloni Dattani: And this is according to the medical expenditure panel survey, which is a large survey that asked people what drugs they are prescribed and what they’re taking. So, roughly 40% of American adults are recommended or eligible to take statins, but only 40% of them actually take them.

And so that recommendation, if you have high levels of LDL cholesterol and family history and various other things, you’re usually recommended to just start taking statins. And then there’s a broader population of people who could take it.

Jacob Trefethen: Cool. Okay. Yeah. I must have got something wrong in the age pyramid slightly, if only 40% or- I was probably yeah, I was claiming more, but whatever. Whatever. Let’s just take the win.

Saloni Dattani: Alright, another question. How much blood cholesterol comes from your diet?

Jacob Trefethen: Now, I think I know the answer to this.

Saloni Dattani: Okay.

Jacob Trefethen: Because I think that the egg thing is a lie, meaning that most of the cholesterol in my body and my blood is- oh wait, what do you mean by comes from your diet? I mean, everything in some sense comes from my diet.

Saloni Dattani: Oh, yeah, well, I guess more immediately.

Jacob Trefethen: Yeah, yeah, yeah. Yes. I think it’s probably, I think most of it’s produced in my body, so I think that’s coming from my diets less than 50% and I’m gonna go with 10%.

Saloni Dattani: Very good guess; it’s somewhere between 15 to 20%, is the general estimate. And this actually varies a lot because you can get cholesterol from mostly animal products, so meat, dairy, and eggs.

And obviously people’s diets vary lot. Like I’m vegetarian, I basically get very little cholesterol from my diet. And then vegans don’t get any cholesterol from their diet. And then depending on how much dairy or meat you eat, you might get more. So the estimates are roughly 15 to 20% of your blood cholesterol comes directly from your diet.

Jacob Trefethen: So just to be explicit about, when I keep saying the egg thing, what I mean is if you’re trying to reduce cholesterol, but your dietary intake is only, as you just said, 15 to 20% of your cholesterol, you probably shouldn’t be going by the direct contribution of diet.

You should be thinking about other things that are leading your body to produce cholesterol and not, you know, get rid of the LDL.

Saloni Dattani: And in fact, this was actually something that I updated on while sort of reading for this episode. One thing that I didn’t know was, okay, dietary cholesterol, there isn’t very good evidence that changing that will affect your blood cholesterol.

It’s a small effect, probably real, but modest. But saturated fats increase your LDL cholesterol, and if you eat more saturated fats, that actually increases the LDL cholesterol that’s circulating in your body. And so changing how you eat in terms of the fats you eat, that can actually make a difference. It’s still small compared to the effects from drugs, but it is pretty meaningful, I think it’s like you can get up to a 10 to 15% decline in cholesterol from strict dietary changes.

Jacob Trefethen: Okay. Well, if the bigger effect is drugs, then ask me a question about drugs, please.

Saloni Dattani: All right. So statins. Statins were one of the first effective cholesterol drugs. They were actually not the first, and we’ll maybe talk about that later, but statins were discovered from an organism and a lot of these organisms were screened before discovering them.

So can you guess what the organism was? Where, what organism did the first statin come from? And this is funny because if you think about a different drug, you might just land up on the same organism and it’ll be the same answer.

Jacob Trefethen: Oh?

Saloni Dattani: There’s another drug that has the same source.

Jacob Trefethen: Oh my gosh. Wow. Now I’m gonna be doubly embarrassed when I don’t come up. Gila monster?

Saloni Dattani: Gila monster? No.

Jacob Trefethen: Okay. How about…

Saloni Dattani: This is very hard. There’s so many organisms, obviously.

Jacob Trefethen: Yeah. Give me a size of the organism.

Saloni Dattani: Okay. I will say that it is a different kingdom from us and also that it was a big breakthrough in the 1920s and ’30s, getting a very important drug from the same genus.

Jacob Trefethen: 1920s and ’30s. Oh my God. It’s not because ’30s or ’40s, I would’ve said maybe it’s the microbes in the soil and we’re talking about some TB drugs, but now you’re telling me twenties or thirties, so maybe that means it’s, oh God, maybe it’s a fungus?

Saloni Dattani: It’s a fungus. Yes.

Jacob Trefethen: Okay, great.

Saloni Dattani: Very good.

Jacob Trefethen: Before, I have to guess, what is it?

Saloni Dattani: What is it? It is actually the same genus as the first natural antibiotic as - it’s the fungus Penicillium citrinum.

Jacob Trefethen: Wow. Penicillium gave us statins?

Saloni Dattani: Yeah.

Jacob Trefethen: How did I not know that? That’s wild. That is a real, I love that family.

Saloni Dattani: I did not know that. I was like, wow, that’s so cool.

Okay, so this first statin was discovered from the fungus Penicillium citrinum by a Japanese researcher called Akira Endo, and he screened many samples of this fungus before discovering the first statin.

So how many steps does it take for your liver to synthesize cholesterol?

Jacob Trefethen: Oh. Oh, well, these diagrams always have so many steps that you can’t remember them. So that means it must be over six. And so, but probably way over six. I’m gonna go with 12 though. I’ll go 12.

Saloni Dattani: Oh, it’s actually around 30. So it depends how you count. Like do you count the individual, I don’t know, something combining and then breaking apart as two steps or one? But it’s roughly 30 depending on how you count.

Jacob Trefethen: The liver is a magical place. It, there’s just so much going on down there; I personally think of it as none of my business.

Saloni Dattani: The liver’s doing so many amazing things. It’s cleaning up the toxins in your body. It’s producing important stuff like cholesterol. Did you know that the liver is the organ that can regenerate itself the most? It can regenerate, I think up to 80% of it.

Jacob Trefethen: That is, yeah, I did know that. And it is wild. Did you know that the liver is the organ along with the brain that uses the most energy?

Saloni Dattani: Oh, I didn’t know that.

Jacob Trefethen: It’s kind of amazing because if you ask an 8-year-old what organ of the body’s doing the most?

Saloni Dattani: Mm-hmm. I feel like as an 8-year-old, I wouldn’t even know what the organ, I would be like. I know five organs, maybe.

Jacob Trefethen: Fives a lot though. And I just don’t think the liver; the liver, what the heck is going on down there? Like it’s not a very charismatic organ, but it’s actually doing, it’s doing an awful lot.

And I once was talking to a friend who’s a software engineer who was like, yeah, it’s sort of like the body’s sort of like, you really put a lot of time into coding up the brain, and you know the heart maybe, and some of the other organs, and then you have a bunch of leftover resources and haven’t really got time to be very careful about how you do the liver and you’re like, just, just let it do all the other stuff. You can have - it’ll figure it out. It’s kind of a junkyard doing all this crap. And we’ve never sort of optimized it to use energy very well.

Saloni Dattani: I also think of the liver as just like a big purple blob. It’s obviously doing lots of stuff.

Jacob Trefethen: True. Yeah. Confirm. That was actually the question I was gonna ask you. What is the liver? And the answer was ‘a big purple blob’.

Saloni Dattani: You know what’s funny is that I have been listening through our episodes and in probably every episode we’ve done, we’ve talked about blobs in some ways, and this episode is all about blobs. It’s all about fatty blobs and how they circulate around your body and how they cause disease.

Jacob Trefethen: We’re obsessed with fatty bobs.

Saloni Dattani: Yeah.

Jacob Trefethen: Also, we’re slightly obsessed with the liver. Now I think about it, you know, hepatitis B, last episode.

Saloni Dattani: Oh, that’s true. That’s true. Okay, last trivia question. What common vitamin also reduces LDL cholesterol?

Jacob Trefethen: Oh, I think I know the answer to this. But I know it for reasons that are slightly circuitous. Do you have, do you have a couple minutes?

Saloni Dattani: Yes.

Jacob Trefethen: So I think it is B3, niacin.

Saloni Dattani: Mm-hmm. Correct.

Jacob Trefethen: Okay. And the reason I think that’s true is because there’s also a relation between vitamin B3 in the form of nicotinamide, which I’m sure we all know and love, to tuberculosis.

But I don’t think that the relation is mechanistically actually relevant to LDL cholesterol, but I will just explain it in a little bit more detail.

So tuberculosis, the bug, can create a latent infection that sticks around for a long time where it’s inside one of your cell types, macrophages, and when it’s inside there, it’s actually eating cholesterol.

Saloni Dattani: Oh!

Jacob Trefethen: You know that?

Saloni Dattani: Oh yeah. Well we will talk about that. Oh, macrophages sometimes try to eat up cholesterol and sometimes it goes wrong.

Jacob Trefethen: Right? Well, now imagine you’re a bug and you are taking up residence inside a macrophage and you’re like, wow, there’s a lot of food here. I don’t need glucose. I’m just gonna eat the cholesterol. And so that is one of the tricks they do.

Now, I think that is all intracellular, I think. So I don’t actually think that that is that related to what we’re discussing today, which is cholesterol in the blood mostly.

That said, there’s this strange connection with B3 as well where tuberculosis is particularly, can be a problem for people who are malnourished. So if you have more macronutrients, more micronutrients, you have a better chance of fighting off tuberculosis. And you might wonder well, what are the most important micronutrients?

It looks that nicotinamide is one of the most important. So there’s some evidence in mice and there’s some evidence in humans. So if you supplement people with nicotinamide plus maybe one other thing, take one other favorite micronutrient, you might have quite a protective effect against tuberculosis. Now..

Saloni Dattani: Wait, wait. So the nicotinamide or the vitamin B3 reduces cholesterol, LDL cholesterol, and that means there’s less of it for the tuberculosis bacteria to eat. Is that what you mean?

Jacob Trefethen: That is, what I would ask you to do is, forgive me for the digression, because I’ve told a story where that’s the natural conclusion. I think in fact it’s not true.

Saloni Dattani: What?! What??

Jacob Trefethen: Surprising, what I think, in fact what is happening mechanistically is more like you just needed B3 to get healthier, generally speaking.

Saloni Dattani: Okay.

Jacob Trefethen: And the healthiness than helps your immune system fight back more. I don’t think the B3s get inside the macrophage and- I don’t think-

Saloni Dattani: Right.

Jacob Trefethen: Now, that’s why-

Saloni Dattani: But if it’s reducing cholesterol in general, then there’s less cholesterol for the macrophages to eat.

Jacob Trefethen: That could be the right story. And I just don’t wanna go on record in case someone’s listening who’s a TB researcher like, oh my gosh. But there is a connection to land the plane here in a way that is more positive.

People do- there is some suggestive evidence that if you give people who are getting treated for TB, also give them a statin, you might be able to reduce the amount of time that they are on TB treatment. And we’re funding a trial actually, in my day job on that right now.

And that is, I don’t wanna over claim the mechanistic story, but it is possibly related. Yeah.

Saloni Dattani: Wow. I had no idea. I didn’t know that. I didn’t know that tuberculosis bacteria eat cholesterol and sit in your macrophages. That’s crazy.

Jacob Trefethen: Well, you knew they sit in your macrophages.

Saloni Dattani: I didn’t know that.

Jacob Trefethen: Oh, really? Oh, okay. They do. Yeah.

Saloni Dattani: I didn’t, no.

Jacob Trefethen: No, they do. It’s really sad. I mean, it’s very clever because if you wanna hide somewhere, just like HIV was doing with a different immune cell, they hide in one of your immune cells. So it’s like, oh my God, there’s sneaky bugs. It’s like, oh yeah, well I’ll be fine here.

Saloni Dattani: Right. It’s like you’re trying to eat me. Well guess what? I’m part of you now.

Jacob Trefethen: A hundred percent. It’s creepy.

Saloni Dattani: Can you eat yourself? Exactly.

[jingle]

Saloni Dattani: Have you heard of the lipid hypothesis?

Jacob Trefethen: I have heard of the lipid hypothesis.

Saloni Dattani: So just for our listeners, the lipid hypothesis is the idea that high blood cholesterol levels, especially LDL cholesterol causes atherosclerosis and heart disease, and reducing them reduces those risks. So that is the lipid hypothesis, and it took a really long time for people, for scientists, to actually come to the consensus that that hypothesis was true.

It took, I would say, almost a century. So the first evidence for it was in the early 20th century, and it was really only in the 1980s and 1990s that it became the scientific consensus. But there are still some people out there, often podcasters not like us, who don’t believe it.

Jacob Trefethen: Yeah, I’m not convinced yet. Wots your evidence?

Saloni Dattani: Okay, so I have seven lines of evidence, and maybe you can rate them on how convincing they are to you.

Jacob Trefethen: I will, but before you tell me, I just wanna say what I agree with going in. I agree that heart disease exists. I agree that lipids exist and I agree that atherosclerosis exists.

What I’m not yet convinced of is the causal relation. Is it what you are telling me it is or not? So that’s what you gotta convince me of.

Saloni Dattani: Fair enough, fair enough. Okay. So first point, number one. So there are rare cases of, there are severe cases where people have something that’s called familial hypercholesterolemia, which is when they have an inherited condition where they have really high levels of cholesterol.

And those people, if they have two copies of that gene, often also get heart attacks and strokes at very young ages. So often when they’re children or teenagers, they can still get heart attacks even then. And if you look at autopsies after they’ve died, you’ll often find cholesterol deposits in their arteries. And this is something that was noticed in the early 20th century. So what do you think, are you convinced?

Jacob Trefethen: It’s suggestive, but I am not convinced! And here’s why. Let’s just think of the parallel with Alzheimer’s. There’s also familial Alzheimer’s where you can have a gene mutation, PSEN2 I believe, whole families can get early onset Alzheimer’s - so you are very likely to get Alzheimer’s in your forties, for example. The reason is that, there’s similarities of course, between the Alzheimer’s that people in those families develop and the Alzheimer’s that people outside of those families develop, but I don’t believe that it’s the same causal pathway fully.

I mean, there’s probably that hundreds of genes are implicated in how most people get Alzheimer’s, and I don’t think that a drug that targeted that one gene would work for most people. Sure enough, they make some mice for Alzheimer’s research that the way that they give them Alzheimer’s or sort of the phenotype of Alzheimer’s will give them dementia is by editing one gene.

And I just don’t believe a lot of that’s gonna translate because it’s more complicated when it shows up outside of the rare genetic case.

Saloni Dattani: It’s like when I see those medical studies where they found something and it works in mice and it’s far away from working in human trials.

But it makes me think, what if we could benefit from all of those early treatments by turning ourselves into mice? If someone could correct that, we would have so many treatments available to us.

So basically you’re saying maybe in the general population the condition has other causes or that is just one contributor and it’s not the cause? That seems fair, but I feel like there are some drugs and there are some diseases where studying a family that was inheriting that condition was quite helpful in developing an effective drug, and that will come in later in this episode.

Jacob Trefethen: If I’m being less the skeptic. Do I think that studying those families in my comparison to Alzheimer’s is irrelevant to Alzheimer’s? No, I actually think it’s pretty useful because you can learn some very important things from that. For example, in that case, there’s a couple people in an extended Colombian family are actually resilient to Alzheimer’s.

So they’re in their forties, they’re in their fifties, they’re in their sixties, and they haven’t developed Alzheimer’s or haven’t developed dementia, but do actually have plaques in their brain. So, oh my gosh, what’s happening there? And you can really hone in on the gene variants that those people have and learn a lot from that.

So that’s true. But I stick by my original point that I don’t think the causation is exactly the same. So we can learn stuff, but it’s not the same.

Saloni Dattani: Okay. Okay. Fair. What if… Second line of evidence: animals. So you mentioned mice, but, in the early 20th century, there were some Russian scientists who decided to feed rabbits with pure cholesterol.

And they were like, let’s see what happens. And what happened was, sadly they got hypercholesterolemia, which is high levels of cholesterol in their blood. And they developed things that looked like atherosclerotic plaques. And so you could see that giving them cholesterol gave them atherosclerosis. How about that? What do you think?

Jacob Trefethen: I think that … here’s what I’m interpreting. I’m interpreting in a different animal it’s sufficient for atherosclerosis to jam ’em with a bunch of cholesterol. Now that’s useful. What is it missing? Well, it might not be the only cause of atherosclerosis.

Maybe atherosclerosis just happens when you jam full of anything. And guess what? Sticks to some of their blood vessels. Okay, number one. And number two, of course, animals are not humans. Okay, but whatever. And then number three…

Saloni Dattani: What if rabbits are just weird?

Jacob Trefethen: What if rabbits are weird? Number three, I would say it doesn’t give me the link to heart disease.

I mean, it gives me a link to atherosclerosis, so, okay. It ain’t nothing, I’ll take it, but I’m not convinced yet.

Saloni Dattani: There’s another thing, which is that when these Russian scientists did these experiments in the 1910s, other scientists were not convinced because they tried to do the same experiments in other species and they didn’t find the same effect.

So they did this in rats and dogs, and they didn’t find the same effect, and so they just didn’t believe it. And we know now that actually the reason for that is that rats and dogs actually process cholesterol differently. So they mostly don’t even have LDL cholesterol. They have very low levels.

They mostly carry them around in HDL. But yeah, I think you’re right that they’re not humans, and also maybe it’s just jamming them with stuff that’s bad. Okay. Third piece of evidence, I think this might update you a little bit.

Jacob Trefethen: We’ll see.

Saloni Dattani: If you correlate cholesterol levels with heart disease, you will find that certain particles, especially LDL, are predictive of coronary heart disease. And cholesterol levels in general are also predictive of coronary heart disease. What do you think?

Jacob Trefethen: Well, I remember learning in school that correlation equals causation, so I’m convinced!

Saloni Dattani: Well, at least this is in a human general population.

Jacob Trefethen: Fair enough. I do think it is useful evidence. I really want to see that present. I bet you I could find a ton of correlates though.

Saloni Dattani: Yeah.

Jacob Trefethen: So I’m not, yeah, I definitely don’t feel convinced by that, that there’s an important singular driver that is LDL, but I’m glad it’s there.

Saloni Dattani: Okay, that failed.

Jacob Trefethen: Useful. Useful info. Useful info.

Saloni Dattani: You know, when I was reading about this, it was very funny because I was reading this historical review that said Michel Macheboeuf is known for being the father of plasma lipoproteins. And I was like, what? The father of what?

Jacob Trefethen: It’s like mitochondrial Eve and lipoprotein Macheboeuf.

Saloni Dattani: No, you know when people are like, oh, you know the father modern epidemiology, John Snow, and the father of bacteriology, Robert Koch, and have you heard of the father of plasma lipoproteins? This is getting outta hand. This is so specific.

Jacob Trefethen: He’s still a father to me.

Saloni Dattani: So anyway, Macheboeuf discovered lipoproteins, which include LDL cholesterol, but he didn’t know what it was made of.

And then another scientist, John Gofman, he was studying the serum and he was ultra centrifuging it. He was spinning it around really fast in an ultra centrifuge, and he found that there was some component of it that floated to the top that was partially made of lipids and partially made of proteins.

Jacob Trefethen: Was he also the singer behind ‘you spin me right round baby, right round, like a record baby’? Because I think he was the father of that pop music as well.

Saloni Dattani: That should be the motto of ultra centrifuges.

Jacob Trefethen: Every time we press go, they play that song. Like, yeah, I gotta leave this one overnight, it’s gonna be a lot of repeats of the song.

Saloni Dattani: Well, it’s kind of a shame because often the process is quite fast and you don’t really do the spinning process for very long. You probably only hear the first few words of the song.

Jacob Trefethen: Noooo… ‘You spin-’ ‘Oh, we got a result!’

Saloni Dattani: Unfortunate. Okay, next piece of evidence. So not just a correlation, but this time: longitudinal study, the Framingham Heart study, of that town in Massachusetts, was it?

Jacob Trefethen: Framingham.

Saloni Dattani: Framingham. And that was launched in 1950 and it followed thousands of people who lived in that town, and they initially got measured for their cholesterol levels, blood pressure, smoking, obesity, diabetes, family history, blah, blah, blah.

After two decades of following those participants up, you could see that people who started off with higher levels of cholesterol had much higher rates of heart attacks, strokes, and other cardiovascular risks, even if you adjusted for their smoking or hypertension.

Jacob Trefethen: Oh, that last bit is quite interesting.

Okay. Yeah, basically I would put this as a notch better than the last correlation you told me. Longitudinal data is really cool. You get to follow an actual person’s whole trends, so that’s great. Now, that said, once again, there’s just a bunch of other stuff that might be co-correlated. Or, you know, maybe there was confounding there and you know, you can, that’s great that they tried some way of adjusting for smoking or adjusting for hypertension, but yeah, there might be a third thing you forgot to ask?

Saloni Dattani: Right. A secret third thing that caused both high cholesterol levels and cardiovascular risk. Okay. Fair enough. I think my fifth one might be more convincing.

So number five, if you change people’s diet…

So this is what I found really interesting because I feel like a lot of diet research today is observational, right?

It’s like, let’s see what people say they’re eating, and then let’s see how that correlates with their risks and stuff like that. Usually we’re looking at food diaries. So people are just writing down what they ate and then we’re correlating that. And I mean, who sits down and writes in a food diary.

Jacob Trefethen: I dunno if you’ve ever tried a food diary, but the classic thing I’ve experienced is you completely forget what you ate and it’s all made up.

Saloni Dattani: Right. And there are lots of- it’s very noisy as a measure that you can record. Instead, and this really shocked me. But it turns out that people actually did randomized controlled trials where they made people have the same diet for every day for years in the 1950s and ’60s.

Jacob Trefethen: You’re kidding.

Saloni Dattani: Isn’t that crazy?

Jacob Trefethen: How did they - wait? There were doctors in your home cooking for you?

Saloni Dattani: No, no, no. So it would be like a cafeteria. Where you get the standard meal every day.

Jacob Trefethen: Really?

Saloni Dattani: Yeah, yeah. There were several of these. There were some that were carried out in hospitals or mental asylums.

But then there were also others that were the general population, or they were like, the NIH ran a study called the National Diet Heart Study. There were a bunch of these, right, where they actually just randomized dietary interventions where some of the food that they were eating was, they were substituting the saturated fat parts of their food for polyunsaturated fats. So it was just that same thing that they were eating for every day.

Jacob Trefethen: ‘Please, sir, could I have some more?’ ‘No,’ said the NIH. ‘You’ll have your allocated fat.’ People wonder about scientific institutions declining and really it’s said they don’t get to control what we eat anymore.

Saloni Dattani: But I found this so interesting and I was like, wow, how come we don’t do that anymore?

And I guess maybe one of the reasons that it was possible to do the study at the time was that maybe food was expensive then. And if you were in the study, you would just get your food every day for free.

Jacob Trefethen: What the hell? This is crazy. This is one of those things you hit, this feels genuinely like Victorian England, but you’re telling me 1950s America, it’s like, wow, I’m running low on sloppy joes, so I’m gonna need state provided.

Saloni Dattani: So there was- This diet heart study was like around a thousand men who were in this trial and there were different cafeterias serving the different foods. So some of them were allocated to the normal saturated fat diet and some of them were allocated to the unsaturated fat diet and they found that blood cholesterol levels increased in the saturated fat group.

I think it was maybe the same trial, or maybe it was a different trial, they actually did a crossover trial. So the people who were randomized to one of those options were then later on randomized to the opposite one.

Jacob Trefethen: You know what? I like it. I like this, this makes me feel good.

I like it. I’m being too nitpicky. What I’m trying to say is show me someone who - I wanna see the contraindications. Someone got elevated heart disease risk but didn’t have cholesterol, or someone had lower heart disease risk but did have cholesterol. And I get, every time you give me more evidence that isn’t of that shape, I do get more confident.

Saloni Dattani: Well, this is the average. Yeah.

Jacob Trefethen: Yeah. But the anomalies would help me dis-confirm. So the fact I haven’t seen the anomalies fair enough. I’m more confident. I’m more confident. So I don’t know. What do you think about that one?

Saloni Dattani: I think, I feel like that is pretty good evidence, but it’s a bit indirect because it’s about saturated fat.

The thing that they change in their diet is how much saturated fat they eat, not how much cholesterol they eat. And we know that saturated fat reduces your cholesterol clearance, but people didn’t know that back then and they sort of just lumped saturated fats and cholesterol together. So it’s a bit indirect.

Jacob Trefethen: If they fed them cholesterol then, because we now know that most cholesterol is made in your body not consumed, that also might have not been- quite got it. So this stuff is tricky. Wow.

Saloni Dattani: Yeah, it’s tricky. So we know now, and I think since the ’80s, we’ve known that saturated fats work through this pathway in the liver and they reduce your clearance of LDL cholesterol. But people didn’t know that back then.

Jacob Trefethen: Okay. So that was, that was five. Were we already in a LDL world? Did they have, did they say LDL-?

Saloni Dattani: In LDL world? I love that. This made me think of the Barbie World song.

Jacob Trefethen: I’m an LDL. Yeah.

Saloni Dattani: I’m a fatty blob in a fatty world, life in fat.. cholesterol…

Okay, let’s try again. I’m a fatty blob in a fatty world. Life in lipids, it’s insipid!

Jacob Trefethen: Woo. Yay!

Saloni Dattani: Thank you.

Jacob Trefethen: That’s beautiful. That’s the career pivot we should be talking about.

Saloni Dattani: Okay. Number six is. Before statins were introduced, there were a few drugs that reduced cholesterol levels. One of them was called Cholestyramine, a bile acid sequestrant.

And there was this big trial that randomized about 4,000 men to either that cholesterol drug or placebo for about seven to 10 years. And they found a reduction in LDL cholesterol, so that was reduced by about 20%. And heart disease deaths or heart attacks were reduced by 20% as well.

And then the same thing was true also in another trial after that with a different drug that reduces cholesterol called niacin, which is vitamin B3, and also similar. So they had a reduction in cholesterol levels and also a reduction in heart attacks and strokes.

Jacob Trefethen: It’s nice, I can feel myself yearning for more on the mechanism or ruling out alternative, basically, and I guess you told me in the case of- the closest I remember of the six so far was the rabbits.

So there we’re like really getting at, okay, we squeezed this cholesterol in and it led to, you know, so we don’t yet have necessarily the molecular mechanism of why, I guess that maybe happened earlier, but at least there’s some sort of link I can visualise.

What I’m struggling with in the trials you just mentioned is I want to know what else other than LDL went down and why are we singling out LDL? Why are we singling it out?

Saloni Dattani: So you’re saying maybe these drugs do reduce heart attacks and strokes, but what if they’re doing it from a different mechanism? Like what if they just happen to reduce cholesterol and happen to reduce heart attacks and strokes for some other reason that we don’t know?

Jacob Trefethen: Yes.

And what is special about cholesterol now for people who- you know, ’cause it might reduce all sorts of things; maybe it reduces your blood pressure by 20%? You know, I don’t know. Anyway, I don’t want to come off too skeptical. Basically, in all of these cases, that type of question is looming for me.

But the more you layer on these different lines of evidence, my skepticism is reducing. So the thing that would be lovely is if I knew there was a, either you gimme some mechanism, stuff that I can hang my hat on, or you’re like, okay, actually this is not just a vitamin, this is a drug literally just going after cholesterol and that we got rid of that only, and then heart attack went down. That would be, I’d be excited about that.

Saloni Dattani: Well, you are in for a treat because that is the seventh line of evidence.

Jacob Trefethen: Oh my goodness.

Saloni Dattani: So statins, I dunno if you’ve heard of them.

Jacob Trefethen: Statins. I’m gonna cry.

Saloni Dattani: They directly block an enzyme that is essentially vital to produce cholesterol in your liver.

So the pathway that the liver synthesizes cholesterol is very long, and there’s one really important step called the rate limiting step. It’s the bottleneck, if you don’t have that, if that’s step is blocked, then you get no cholesterol the out the other end. And statins block that enzyme to an extent.

So they were initially tested in the lab to see if they could block the activity of this enzyme, and some of them did, and then they were tried in clinical trials given to human participants.

And there were various clinical trials, but one of the biggest ones was in the 1990s and it’s called the 4S study, and it took place in Scandinavia. And they found that statins reduced LDL cholesterol and they also reduced heart attacks and strokes, and they’re actually quite big reductions.

So they reduced total cholesterol by about 25%, LDL cholesterol about 35%, and heart disease deaths by 42%. And that was highly significant as well. And this was done with Simvastatin, which is the second statin produced by Merck.

Jacob Trefethen: WOO!

Okay. I love it. And before I reveal that I’m convinced, I will give the final skeptical take, which is the, I would wanna read the paper in depth and be like, what else is that enzyme involved in?

Are we sure it’s only-? You’ve always gotta go a few steps deeper just to make sure there’s nothing more. That said, given the description you just gave me, that seems like pretty solid evidence. If you have a trial, you’re randomizing people, you’re going after the one fricking thing that we’re interested in. That’s pretty cool.

Saloni Dattani: And you know the mechanism because you know that that drug inhibits cholesterol production.

Jacob Trefethen: Love it. Okay. So that was pretty good.

Saloni Dattani: Oh wow! You’re convinced, boom.

Jacob Trefethen: That took a while though. I mean, could we know about statins earlier, that would’ve helped me.

Saloni Dattani: So I found this really interesting because I was reading this book called The Cholesterol Wars, and it’s about how the evidence was put together and all of these different lines of evidence and when people were convinced, and most scientists were convinced at the sixth step.

So when you had the earlier cholesterol reducing drugs. So they said, let’s look at all of these lines of evidence. We’ve seen the correlations. We’ve seen the correlations are longitudinal. We’ve seen the animal evidence, we’ve seen the families with high cholesterol levels, and we’ve seen a few drugs that reduce cholesterol and also reduce heart attacks.

And they said, this is enough evidence. And the FDA decided that they were happy to accept or approve any drug that reduced LDL cholesterol before seeing that it reduced heart attacks and strokes, but they also asked for that evidence afterwards. So they treated it as causal and they said, this is okay as a surrogate endpoint, and if you can show that your drug reduces LDL cholesterol, that’s enough for us to approve it, as long as you also collect this other evidence afterwards to see how much it reduces those things.

But yeah, there were still a bunch of holdouts and people who were not convinced until the statin trials.

Jacob Trefethen: So are there still holdouts after the statin trials?

Saloni Dattani: Yeah, but I wouldn’t take them very seriously. I think it’s possible to just not know about the evidence, but I think there’s some people who have read about all this and are still skeptical.

Jacob Trefethen: Right, right. Yeah. I would love to read their takes. I mean, basically I think it’s always useful to have holdouts who are up to date on all the evidence and then they can give you- there always will be some story that is technically possible. And then. You know, well, not always. In some cases you get so decisive, but you know, the human body’s complicated.

And so there’s effects that are different for different people and all that. So I’d love to read that take. I would be surprised with statins in particular, it’s just they’ve been used by tens, hundreds of millions of people. We’ve got so much data that I’m like, okay, well that’s actually, that would be extremely hard to convince me. I wanna stay open-minded, obviously. But that one is so studied. Oh my goodness.

Saloni Dattani: So instead of going through the enormous and complicated description of how LDL and other cholesterol transport works, I thought I would do a three minute version of how everything works in cholesterol. Why it’s bad.

Jacob Trefethen: Should have brought my timer.

Saloni Dattani: You should have brought a little sand glass.

Jacob Trefethen: Yes. Red sand. Like in Wizard of Oz, at the end there’s booming.

Saloni Dattani: Ooh… that would be very stressful. But I’m gonna try to explain how lipids are transported in your body, what cholesterol is, why LDL cholesterol is bad… in three minutes.

Jacob Trefethen: 3, 2, 1. Start the clock.

Saloni Dattani: Alright. Alright. So fats and cholesterol have to be transported around your body, but they can’t dissolve in water. They’re hydrophobic, they’re literally like oil and water, right? So they have to be transported in a special route. And the way that they’re transported is that they’re carried around by lipoproteins.

And the lipoprotein is a blob that contains the fats and cholesterol, so it carries them around, and it has an outer shell that’s made of proteins and phospholipids. So this blob, the lipoprotein, travels around the bloodstream and it delivers fats and cholesterol to the organs that need them. So fats are really useful because they can be stored for energy use later on, or they can be used by our muscles for energy.

So they can be broken down and go through the Krebs cycle and generate ATP, and they can be used for energy and cholesterol is really important for lots of reasons. So one, it helps keep our cell membranes stable. It’s also a precursor to lots of hormones like aldosterone, testosterone, progesterone, and estrogen.

And so basically these fats in the cholesterol are being carried around the body in lipoproteins to many different organs for these types of functions: energy use, storage, making hormones, and keeping cells stable.

You can get cholesterol in two ways. One, you can consume it in your diet. And when you do that, it gets absorbed in your small intestine. Or your body can synthesize cholesterol itself through other food that you’ve eaten before. And most of the cholesterol in your bloodstream is actually synthesized by your body, specifically by your liver. And your liver can synthesize cholesterol from other stuff. And that’s a very long process that involves many enzymes.

So either way, you have fats on cholesterol and they’re transported around your body in lipoproteins. And there are many different types of lipoproteins. You’ve probably heard of LDL, which is bad. (boo) And HDL, which is good. (they cheer)

Saloni Dattani: So those are two types of lipoproteins and there are others as well. And the different types of lipoproteins are classified by how large they are, how dense they are, how bouncy they are, what they contain.

The basic system is the fats and cholesterol transported around your body, starting in bigger lipoproteins, and then they get dropped off at different organs and then the particles get smaller and denser.

So the lipoproteins start off big. It’s a bit like they’re carried around in a bus; imagine a blobby bus going around your body, and then as more people get off the bus, the bus shrinks. And technically that bus or the lipoprotein is being remodeled at each step, but we don’t need to get into that.

So at a certain point, the buses or the lipoproteins are small enough that they’re called LDL, the bad one. (they boo) And that’s bad. Higher levels of LDL cholesterol cause higher risks of atherosclerosis, which is when you have a cholesterol plaque in your blood vessel. So what’s going on there?

So what happens is these particles, which are circulating in the bloodstream, they can actually pass through your blood vessel wall, especially if the lining is damaged, and then they can just get stuck there.

Jacob Trefethen: ’cause they’re so small?

Saloni Dattani: Yeah, they’re very small. And that means more particles containing cholesterol and carrying certain proteins on their outer layer. And those proteins get them stuck. And when they get stuck, they send out signals that make immune cells try to come and clear them up. And those immune cells are macrophages. So macrophages-

Jacob Trefethen: I wanna say, yay. Not too many.

Saloni Dattani: No, it goes wrong. So the macrophages usually try to eat things up like pathogens and debris, and we talked about them in our hepatitis episode, I think, and they’re trying to clear up the mess of these LDL cholesterols that have gotten stuck. But instead of actually clearing them, the immune cells just get filled with fatty blobs.

So they eat up, they’re trying to eat up the LDL, and then they just get fat. They get foamy, they become foam cells, and that makes things even worse. So that attracts smooth muscle cells, which cover up that whole mess. They turn it into a plaque and they add a cap to it and that is an atherosclerotic plaque. So it’s like an outgrowth in your blood vessel wall.

Jacob Trefethen: So you got a blood vessel wall with these foamy cells trapped underneath.

Saloni Dattani: And cholesterol, lots of fat.

Jacob Trefethen: Right?

Saloni Dattani: And so this plaque can slow down your blood flow and if it’s loose, the whole thing can just break off and form a blood clot and then it can get stuck.

And if it gets to smaller blood vessels, as it travels through your bloodstream, it can just trap- it can just block the entire blood flow. And that’s very bad. But it depends on where it happens; if it happens near the heart, it can cause a heart attack. If it happens near the brain, it can cause a stroke or it can block the blood going through your legs or your arms, and that causes peripheral artery disease.

So there is a way to reverse this, and that’s the thing that does that is called HDL.

Jacob Trefethen: H! D! L! Woo!

Saloni Dattani: And that can help reverse this to some degree. So HDL is made in a totally separate process, also by the liver and the intestines. And what it tries to do is it tries to scavenge for cholesterol, tries to pick it back up from the tissues.

It gets into the blood vessels where the LDL gets stuck and it tries to take the cholesterol away from it. Or it can even go to the foamy immune cells and it can try to take up cholesterol from there. So it’s a good guy. And HDL is generally good, and LDL is generally bad. And that’s my summary.

Thank you.

Jacob Trefethen: Very efficient. We have a good witch. We have a bad witch. Although the good witch is kind of like a little scavenger. And the bad witch is older, in this case.

Saloni Dattani: Right? Well one of them, the bad witch is making a mess everywhere.

Jacob Trefethen: Yes. Everywhere.

Saloni Dattani: And the good witch is cleaning it up.

Jacob Trefethen: Ah. Marie Kondo the good witch.

My takeaway is: fat’s gotta get transported around so they start in a big package and drop stuff off along the way, different organs. And then they get so small that they turn into LDL, the bad word and can get stuck to your blood vessels in a way that you don’t actually want. And then your immune cells, macrophages come to try and deal with the problem, but they can end up making the problem worse.

Eating a bunch of cholesterol, getting really foamy and then getting trapped under a layer of more cells. And look, we do not want our blood vessels to be clogged up. We do not.

Saloni Dattani: Alright. Welcome back. I think we should talk about how statins were actually developed. What do you think?

Jacob Trefethen: I would love to.

Saloni Dattani: Alright. So drug development, how does it all work?

Jacob Trefethen: Well, you sort of stir something up in a test tube and drink it and then…

Saloni Dattani: Pour it in a big witch cauldron.

Jacob Trefethen: Right?

Saloni Dattani: That’s how they did it back in the day.

Jacob Trefethen: Those cauldrons are so regulated these days. They don’t even let you stir your cauldron anymore.

Saloni Dattani: The first statin called mevastatin originated from a fungus called Penicillium citrinum, and it is the same genus as the fungi that gave us penicillin, which is called Penicillium notatum. And I was like, this is whoa.

How? What? Well, I remember reading this and I was just like, wow, that’s shocking. And I think there are actually more coincidences than that. So the guy who discovered this, a scientist called Akira Endo, he’s a Japanese scientist. He was working in a company called Sankyo, which began as a fermentation company.

So he was working on fermentation, broth, and he was inspired by Alexander Fleming, he said, and he loved fungus. He loved studying fungi. So yeah, it was very interesting to hear. I had no idea about this. Did you know that?

Jacob Trefethen: The relation between them or..?

Saloni Dattani: Like that they were both from fungi and that they were both from penicillin, like penicillium fungi?

Jacob Trefethen: I did not know that. And of course it makes me wonder, number one, is there something special about that fungus? But it also makes me wonder, oh God, what else is out there that we just haven’t studied? There’s probably a ton of stuff that if we had taken into the lab, we would’ve learned by now. But this particular fungus just happened to be the one that we leaned in on.

Saloni Dattani: Right? The chosen one.

This is really also interesting because the way that he discovered it at least was quite different from Fleming. So it wasn’t just some sort of weird accident, but he did trial and error. He tested over 6,000 samples of fungi and different compounds before finding one that seemed effective in lab studies at inhibiting the specific enzyme, HMG-CoA reductase, which is crucial for synthesizing cholesterol.

And the source of this sample was that it came from a fungal mold that was growing on rice samples at a grain shop in Kyoto.

Jacob Trefethen: So if we’d just eaten more rice.

Saloni Dattani: Well, moldy rice.

Jacob Trefethen: I got it. Yeah.

Saloni Dattani: So this is really interesting because, okay, you found this compound that works in the lab. What are you gonna do next?

Jacob Trefethen: Eat it, sorry.

Saloni Dattani: Hopefully not.

Jacob Trefethen: Okay. I’ll try and test it out in a lab experiment or in animals. See if it does what I think it does.

Saloni Dattani: Fair enough. Fair enough. So probably purify the fungi, grow the fungi in the lab, try to produce more of this compound, and then let’s test it out in… dogs. And so they tested it out in a bunch of different dogs, and this was in the 1970s, late 1970s. So they were doing studies in animals, but they were also, immediately they started to treat patients with familial hypercholesterolemia because they had severe disease. And they were like, okay, well let’s try to see if it improves their condition, they have this very serious condition. And unfortunately the experiments in dogs seem to show what looks like intestinal tumors.

Jacob Trefethen: Oh God.

Saloni Dattani: And so they just shut down the clinical trials. They don’t report specifically what they found in the animals.

Jacob Trefethen: No!! Report! Report!! Oh my. You’re triggering me. You’re triggering me.

Saloni Dattani: They didn’t report it.

Jacob Trefethen: Anytime you generate negative data. Let. It. Out.

Saloni Dattani: Report!

Jacob Trefethen: Oh my.

Saloni Dattani: We need the negative data.

Jacob Trefethen: The negative data’s so useful.

Saloni Dattani: So they didn’t report it. And actually, I only found this out from a paper that was published by Akira Endo in 2017 or something.

Jacob Trefethen: When did his career start? I’m confused.

He was publishing in 2017?

Saloni Dattani: So he was working in the 1970s. And then after that in recent decades he was kind of writing retrospectives. So this was a bit scary, right? Like they just shut down their trials. They saw these intestinal tumors or what they thought were intestinal tumors.

And meanwhile, there was another big company that you might have heard of called Merck, and they were testing a very similar compound called Lovastatin. And Lovastatin, it’s almost the same as Mevastatin, it just has an extra methyl group. And they had, I think, heard of Akira Endo’s work.

They also started looking at fungal extracts and trying to test them in the lab, and they found this compound. And for them it was their 18th sample, not their 6000th or whatever. And they heard that these clinical trials had suddenly been shut down. And they’re like, what? Why did they shut it down?

Because they thought, we found a treatment for cholesterol. Cholesterol is such a big problem, right? So many people have high cholesterol levels and they expected it would be at least a multimillion dollar drug, if not a billion dollar drug. And so they were really surprised by this and they tried to find out what happened and they asked- they paused their own trials and they asked the people at Sankyo for further details, but they didn’t share them.

Jacob Trefethen: No. Well, the classic way that you do this now is that you hire someone who used to work there and in fact, what you’re doing is smuggling intellectual property from their brain.

Saloni Dattani: Isn’t that illegal?

Jacob Trefethen: Oh, for sure. Yeah. I mean, depends how it goes down. But yeah, this is why there’s so much litigation in biotech.

Saloni Dattani: So according to the book that I was reading, The Cholesterol Wars, and that book is by a guy called Daniel Steinberg, who was a scientific advisor to Merck at the time. So that is pretty good at a source of this information. So he says that executives at Merck offered Sankyo a business deal, if they shared this data.

And the head of Sankyo was interested and then he declined the offer and he said, I wanna cooperate, but other people are objecting. And that’s it.

I mean, imagine if you were in this situation, you’re a Merck, what would you do? You’ve heard these clinical trials shut down. They’re not sharing any data on exactly why, you’ve heard that it’s because of tumors and dogs, but you don’t really-

Jacob Trefethen: Oh, you have heard that on the grapevine?

Saloni Dattani: Yeah. You’ve heard rumors. Yeah.

Jacob Trefethen: Got it. Interesting. I mean, the honest answer is that these days there’s enough risk aversion in the system. It probably would just get shut down. I wouldn’t be surprised. Well, what I would want to do is, if I think that I have good enough signal that it’s gonna work out the other end, I just wanna figure out what the heck is going wrong with these tumors.

Saloni Dattani: I mean, you’re already in the middle of clinical trials at this point.

Jacob Trefethen: Oh, you’re in the middle of clinical trials?

Saloni Dattani: Yeah, you’ve paused your clinical trials, you’ve told the FDA something might be wrong.

Jacob Trefethen: I see.

Saloni Dattani: And yeah.

Jacob Trefethen: That’s really tough. Oof. I guess I would, in whatever way you can try and get more data from the people who’ve already gone through the clinical trials, see if there’s any side effects you didn’t expect, hone in on stomach cancer or whatever. Then other than that, I don’t know.

Saloni Dattani: So with your own, you would look for the people who’ve already been treated in your own clinical trial?

Jacob Trefethen: Yeah.

Saloni Dattani: Yeah. Okay. Got it.

Jacob Trefethen: Collect more data if you can that relates to the side effect in question.

Saloni Dattani: Okay. Next step. I feel like we’re playing a interactive video game, but what happens is they do that, they look at the trial data that they’ve already collected. They haven’t seen any increased risks, but there’s still this rumor, right? What are they gonna do next?

Jacob Trefethen: Also, they’re not collecting all the data that you could.

Saloni Dattani: So they’ve asked all the doctors-

Jacob Trefethen: Yeah. Okay. Got it, got it, got it.

Saloni Dattani: Have you seen anything going wrong?

Jacob Trefethen: Got it, got it. So then I’m thinking… you fly to Japan and you try and find these dogs.

Saloni Dattani: You try to find the exact dogs.

Jacob Trefethen: Have a reasonable conversation.

Saloni Dattani: Well, unfortunately the dogs were probably dead, ’cause that’s the only way, you know that they had tumors.

Jacob Trefethen: The tissues still preserved? I dunno, anyway. I don’t know, what do you do? I don’t know.

Saloni Dattani: Infiltrate the pharmaceutical company and try to find those dogs.

Jacob Trefethen: I guess, I mean it’s an interesting case of the benefits of and drawbacks of industry versus academia, where it’s industry is really good for iterating, changing a molecule, testing it out, trying it, and this, trying it and that, really pushing forward on the boring engineering stuff and, no offense industry for saying boring, and then taking things into trials and all of that.

Now, academia can take things into trials. It’s possible. It’s often a little bit less of a tweaking, boring, tweaking. Now the issue is if this had just been academics, there would definitely be egos involved, but in theory they would be publishing in public! So you would know!

Saloni Dattani: Well, they might have just not published their null or negative results.

Jacob Trefethen: That said, if you are an academic and you’re not publishing that kind of result, look yourself in the mirror. Look yourself in the mirror, don’t you believe in knowledge? Come on, what we doing? We’re advancing human understanding. Come on. Okay.

Saloni Dattani: What’s interesting is in this case it is the people in industry who have discovered the possibility that there are drugs that inhibit this enzyme. So they’ve actually done the basic research.

Jacob Trefethen: Right? Yeah. Which sometimes happens. Anyway, I’m really stalling for time because I don’t know, what should I do if I’m Merck?

Saloni Dattani: What are your options?

Jacob Trefethen: Shut down the trial and never return.

Saloni Dattani: And do what? Like move to a different field or?

Jacob Trefethen: Yeah, maybe move to the Caribbean, maybe move toMexico City’s gorgeous this time of year. Or I could do an early readout of the efficacy data if I’m allowed.

Saloni Dattani: Okay. Okay.

Jacob Trefethen: I guess I’m just still so hazy about what happened with the dogs. What happened with the dogs? What happened with the dogs? And I don’t know how to select a better candidate until I-

Saloni Dattani: Who let the dogs out?

Jacob Trefethen: Who let the dogs out? Would be my question, posed in flawless Japanese. Okay.

Saloni Dattani: So I will tell you what happened. I’ll finally reveal the mystery. So what they do is they continue the toxicology experiments. They try to see, do our dogs have the same side effects, do our animals have the same side effects?

And they do see those same tumor like appearances, but those changes are benign and they can be reversed by inhibiting the next step of cholesterol synthesis. So it’s not a huge deal.

Jacob Trefethen: So basically they’re like, okay, number one, do we generate the problem with the dogs? If not, let’s just pretend it never happened. And then they’re like - we are giving dogs tumors.

Saloni Dattani: That, yeah, yeah. Well, it’s something that looks like intestinal tumors but isn’t, and it’s reversible, and it’s benign.

Jacob Trefethen: Okay. So… it’s reversible. It’s reversible. You know, honestly, if I was a patient in those trials and they were like, look, it looks like intestinal tumors, but the great news is it’s reversible. I’m like, sorry, what?

Saloni Dattani: Well, it’s not that they’re actually tumors, they just look like tumors. And whatever has changed is reversible.

Jacob Trefethen: Do they look like… flesh? Like in what sense do they look like tumors?

Saloni Dattani: They’re just like blobby.

Jacob Trefethen: Okay. So if a patient comes up to me and says-

Saloni Dattani: So many blobs in this episode.

Jacob Trefethen: “Doctor, Doctor, I think there’s only a tumor.”

But then I’ll just say, “No, it’s actually just blobby. It’s just blobby. I know it looks-” Like, “Right, so why do I have a blob in my intestine?” “Don’t worry, it’s reversible.” It’s like, “Right, but did you give it to me?” “That’s correct. I did give it to you, and you should be grateful.”

Saloni Dattani: So what happens next is there are a lot of other doctors that are like, these patients really need these drugs.

They clearly are reducing cholesterol levels and they’re not causing tumors in humans, only the dogs.

Jacob Trefethen: Don’t-

Saloni Dattani: Which are not actually tumors.

Jacob Trefethen: I don’t think that Merck should hire you as their press person.

Headline: They’re not causing tumors in humans.

Saloni Dattani: Well, so what happened was they presented this evidence to the FDA and they said, let’s at least continue the clinical trials and see what happens. And the FDA said, okay. And it took three years until they resumed their clinical trials.

Jacob Trefethen: Really? Oh my gosh.

Saloni Dattani: Yeah.

Jacob Trefethen: So they had to re-enroll new people?

Saloni Dattani: I think so.

Jacob Trefethen: Oh no.

Saloni Dattani: And they did a bunch of the toxicology stuff, they also tried to get the data, didn’t get it. They asked a bunch of the doctors in the trial to see what their patients- what happened with their patients. Seemed like no side effects.

And so they resumed their clinical trials. And when the clinical trials were completed, they did show a large reduction in blood cholesterol reduction and very few side effects. And then the drug was approved in 1987. So they didn’t see the tumors in humans there either. And that was the first statin, lovastatin. Was approved in 1987 and we are now, almost 40 years since then. Millions, hundreds of millions of people have been treated with statins and monitored. And there is no increased risk of cancers from statins, which is good news. And they’ve probably saved millions of people’s lives by reducing the risks of heart attacks and strokes by roughly 20% and annual death rates by around 10%. And this is according to big meta-analyses of dozens of clinical trials.

Jacob Trefethen: That’s amazing. And I feel like there’s some, many drug development lessons encoded in that story. And one is just how messy the animal to human translation is, where people really wanna make sure they’re not harming patients, as they should. And that means that you have to do a ton of work to prove something’s safe enough before you even give it to a person.

And then you give it to people in a phase one trial to just collect more data to make sure it’s safe. If there’s any hint of something that could be a problem, you pause so that you don’t harm people and that’s great, but the animal- other animals are not humans.

And so you end up doing these trials that- you’re generating hints and if there’s a hint of efficacy, it might be worthless. If there’s a hint of safety issues, it might be worthless. And so it’s just not a good system, but it’s the best we got currently.

Saloni Dattani: Yeah. I don’t know. I feel like it’s strange that if something happens in dogs, we stop the whole process without- what if it didn’t happen in any other animals? What if it was just dogs? What if the dogs were just being weird?

Jacob Trefethen: So you do it, you do a trial on chocolate and you’re Cadburys, and you’re trying to sell new, a variant of dairy milk.

It’s like, okay, well we gotta do animal trials and then we give it to dogs first. And it’s like the chocolate’s harming the dogs!

Saloni Dattani: No, no!

Jacob Trefethen: Don’t let any humans near this!

Saloni Dattani: No! Don’t give them chocolate!

Jacob Trefethen: It’s like, yeah. Wow. That was a lot of people listening just threw their phone down and dogs should not have chocolate.

However, humans should, in fact, humans must, in fact, it’s part of a healthy diet.

Saloni Dattani: I love, yeah. You need chocolate or you’ll die.

Jacob Trefethen: You heard it here first. Yeah.

Saloni Dattani: So. Should everyone get statins? What do you think?

Jacob Trefethen: Well, it’s - putting my cards on the table, I think that statins are basically one of the coolest things invented by medical science.

Saloni Dattani: Thank you! Oh, I didn’t do it-

Jacob Trefethen: Actually, you didn’t invent those, Saloni. I can’t believe you-

Saloni Dattani: I just love saying thank you.

Jacob Trefethen: Saloni accepted the award on behalf of medical science. Now the reason-

Saloni Dattani: Well, thank Akira Endo.

Jacob Trefethen: Yeah, thank you Akira Endo, and thank you, everyone else involved.

Saloni Dattani: But they should shared the data though, goddammit.

Jacob Trefethen: Yeah, no, that is annoying me. Now the reason I think that’s so cool is that it’s just so rare you can have something that has a population wide preventive effect.

The other obvious cases of childhood vaccines where you have a population-wide preventive effect, but in this case it’s like, wow, this is the biggest killer, heart disease, and we found something that reduces your chance of getting it meaningfully. And that’s just unbelievable. There’s just a huge number of people alive who simply would not be. So I’m…

Saloni Dattani: That’s your top drug?

Jacob Trefethen: It’s definitely up there, I think with, is it my top drug?

Saloni Dattani: Should we do a top 10 drugs episode?

Jacob Trefethen: Yeah. Write in the comments if you want us do a top 10 drugs episode. Okay. Now getting back to your original question, should everyone take statins?

Okay, well there’s this population wide effect. We have a really good biomarker LDL that we think should go down. Does that mean everyone should take statins and drive it down? You know, my guess is that it actually doesn’t matter that much, for people who are low risk, whether they take a statin or not is less important than for people who are high risk, and probably it’s good on net, if you made me guess, but then some people might experience some side effects they don’t like and it’s not the biggest decision in their life if they’re low risk. So that’s kind of my take. But what’s the correct answer?

Saloni Dattani: I think that I could come up with arguments for both sides.

So I think the argument for is that if we look at the relationship between cholesterol levels and risks of heart attacks and strokes and heart disease and all of that, it is basically linear as far as we know. In general, scientists agree that the lower the better. I think there’s another thing which is that people who have lower risks- we’re often thinking about an annual risk in these trials, we’re not talking about a lifetime risk. And if you think about their lifetime risk, most people are going to develop heart disease if they live long enough. And so if you could slow that down, that would be helpful.

Jacob Trefethen: So should I think about that as a linear accumulation type of- if I could go on statins now, or I could go on statins in 15 years, what would you recommend? Just hypothetically. I’m actually not on statins right now.

Saloni Dattani: Well, me neither. But the recommendation from scientists is the lower the better, the earlier the better. The lower cholesterol, the better. The earlier you start taking statins, the better. But in practice, they actually look at like, what is your overall risk of getting heart attacks or whatever in the next 10, 15 years? And it’s sort of based on that. But if you read the academic literature, they basically say earlier is better.

Jacob Trefethen: Cool. Okay.

Saloni Dattani: I assume that it’s also this thing of you’re taking it every day, that’s kind of annoying. Is that worth it? It’s other considerations that you would have.

Okay, but I can make a case for the other side as well. And that is that it does, in rare cases, cause side effects. And this isn’t like vaccines where you create a herd immunity effect and that it’s good for more people to be taking it even if the total risk is low, because you’re preventing it from spreading. That’s not happening here. It’s not contagious.

And the side effects are quite rare. They’re sort of one in a thousand or less of serious side effects. And those mostly are things like muscle weakness or muscle loss. And then I think there’s also a slight increase in diabetes, but it’s quite small and it’s only something that you can tell with large trials.

And yeah, this was quite interesting because there was recently a really big study of some 19 or so clinical trials where they had individual data from each of the patients in those trials, and they looked at this pooled analysis and they were like, which side effects on the labels of statins are actually increased in people who are taking statins versus people on the placebo?

And it turned out that most of the things on the labels of statins are not actually increased in risk. Basically here you’re seeing no difference in the risks of these things between the drug and placebo, or they’re so small that they’re not significant even in a trial with hundreds of thousands of people.

Jacob Trefethen: Fair enough.

Saloni Dattani: What I found weird about this though was like, why do the drugs have so many side effects on their labels, if that’s the case…

Jacob Trefethen: This is America. You heard of the legal system?

Saloni Dattani: What I heard was that it’s a legal liability issue and that they sort of want to avoid people saying, your drug gave me the side effects. And if you put that on the label, you can just say well, we told you.

Jacob Trefethen: We warned ya.

Saloni Dattani: But that seems bad, that probably reduces- that deters people from taking a medicine that could save them.

Jacob Trefethen: Oh, well, a hundred percent. And not only that, but it also, it degrades the trust that people have in the labels because of course people aren’t stupid.

If you hear a drug ad that says side effects may include nausea, vomiting, death, killing your mother-in-law, you know. People know that they have friends who are on statins and their friends are fine, so therefore I can ignore this label. So yeah, the whole thing just degrades.

Saloni Dattani: I heard from someone taking statins that- taking statins to reduce cholesterol levels because he has a family history of heart disease, but he also thinks it carries a risk of blindness and things like that. And I’m just like, this is just sad. This is not true and it probably means that a bunch of people don’t take it.

Jacob Trefethen: Yeah. You know, as I introspect on, why am I not on statins already, just for fun? One of the reasons is-

Saloni Dattani: Yeah, why are we both not on statins?

Jacob Trefethen: I think so one is laziness. I’m like, there’s other things I wanna spend my mental attention on and I’ll get around to that in a decade. Then the other one though is, I think there might be even better options than statins coming, which is part of my- I kind of want some of these newbies that are even better, but I don’t know if we’re allowed to talk about that.

Saloni Dattani: Yeah. That is next.

Jacob Trefethen: Okay.

Saloni Dattani: I think I have the same-ish take. Well, so I think reading for this episode has made me think I need to get my cholesterol level checked and if it’s high then I should probably be taking one of these drugs and that is something that I’ve been persuaded of, but I also think it’s kind of annoying to take a pill every day. I do take multivitamins every day though, so maybe it’s not a big deal.

Jacob Trefethen: Buckle up. We’re getting older. We’ll be taking a lot of pills everyday.

Saloni Dattani: Oh no.

Jacob Trefethen: Gonna get that pill bottle lined up.

Saloni Dattani: Okay. Okay. Back to the drugs. What is the next drug that you have heard of related to cholesterol?

Jacob Trefethen: Well, I probably am skipping ahead.

I don’t know, but I hear a lot about PCSK9 inhibitors, but probably there’s something in between. Is there?

Saloni Dattani: There’s stuff in between, but it’s not really important. So let’s just talk about PCSK9.

Jacob Trefethen: PCSK9. Sexy. Sexy, sexy.

Saloni Dattani: What, the name?

Jacob Trefethen: The target.

Saloni Dattani: PCSK9.

Jacob Trefethen: Yeah, firstly the name, because every time I say it I’m like, PSC, PCS? You know?

And then there’s sort of these, when you hang out with- Let’s just say nerds. There are these-

Saloni Dattani: Okay. I’ve done that.

Jacob Trefethen: Like biotech nerds. There are these particular targets where, yeah, it’s like, oh my god, oh my gosh. And I feel like PCSK9. I’m like, oh my God. You know, a couple years ago someone made it really deliverable, I can’t even remember, and it won molecule of the year.

You know, that that’s what I was like, oh my God. That’s kind of how I feel about PCSK9.

Saloni Dattani: That’s amazing. I haven’t heard that kind of effusive praise for it yet.

Jacob Trefethen: Oh, I actually genuinely, it’s one of those ones where I’m excited about progress because I’m like, oh my God, this one’s actually gonna be something I use, and it’s very helpful to me, is my guess.

Saloni Dattani: This it has a really interesting story. It also has some really effective drugs against it and there are some newer drugs that are probably even better. And so I think it is a very exciting story to tell.

Jacob Trefethen: I’d love to learn about it.

Saloni Dattani: Do you know how it started?

Jacob Trefethen: I have no idea actually, no.

Saloni Dattani: Okay. So it did start with familial cases of people who had inherited high cholesterol levels and there were- so this is kind of before, if you’ve heard of GWAS and if you’ve heard of genome sequencing and stuff, it came before that. So this was the 1990s and early 2000s.

Back then, people used something called genetic linkage studies where they were trying to trace markers that were shared between- in families, that were seen in people with the condition and not in people without.

Jacob Trefethen: I dunno if we’ve said out loud, PCSK9 is a gene, so that is the name of the gene.

Saloni Dattani: It is also the name of a protein that the gene encodes for.

So they were, people were doing these genetic studies. They were like, let’s try to find out what is causing this high cholesterol levels that these people are inheriting, you know, in families. It’s running through families, must be a gene, seems like it’s a single gene.

And in a bunch of these families, they did find a signal on chromosome one and it was a gene that was then called NARC-1, but they had no idea what the function was.

And so there’s something, some gene on chromosome one that is somehow linked to high cholesterol levels. And then in the early 2000s, people actually identified a specific mutation in that gene that was connected to having high LDL levels and they renamed the protein PCSK9.

Jacob Trefethen: Just to make it more catchy.

Who could remember NARC? Make it so catchy like PCSK.

Saloni Dattani: I think that it’s named after the specific mechanism, but it’s shortened. Well, so what they found was people with this specific mutation had an increased protein activity of PCSK9, and somehow that was linked to increased cholesterol levels. And so they were like, let’s investigate this further: What is this protein doing? What do you think the protein is doing?

Jacob Trefethen: I actually, I actually… I’m embarrassed to say I actually don’t know.

Saloni Dattani: I didn’t know either.

Jacob Trefethen: I haven’t really read about which people are gonna listen. Like wow. He works in medical research and doesn’t even know, but yeah.

Saloni Dattani: I didn’t know this until a few weeks ago.

Jacob Trefethen: Okay.

Saloni Dattani: I guess I just, I only remember the stuff that I personally have read and written about, and this fell out of that. So let me explain how your liver tries to clear out cholesterol in the first place because that’s how this drug works.

So in your liver cells there is a receptor called the LDL receptor. You can guess what that attaches to.

Jacob Trefethen: HDL?

Saloni Dattani: No. So imagine there’s an LDL cholesterol, swimming, swimming, it’s in the liver. It gets caught by the LDL receptor and now, the LDL receptor gets taken in by the liver cell; the whole particle with the LDL gets internalized. And then LDL gets released into the rest of the cell, and meanwhile the LDL receptor comes back to the cell surface and tries to grab more LDL cholesterol.

So it’s basically trying to clear out LDL cholesterol with this receptor. It’s grabbing it, taking it into the cell, releasing it for further processing, and then it’s coming back up. It basically comes back up and does this, it gets recycled and it’s grabbing these LDLs probably about a hundred times per receptor, which is pretty cool.

Jacob Trefethen: Yes, that’s a Sisyphean task.

Saloni Dattani: But what PCSK9 does is, it attaches to the LDL receptor, and instead of allowing it to come back up, it just gets degraded.

Jacob Trefethen: I see. I see.

Saloni Dattani: So it can’t catch cholesterols because it’s getting degraded and so your liver isn’t able to clear enough cholesterol if this protein is overactivated.

Jacob Trefethen: Which now makes sense to me because I know we’re gonna be dealing with PCSK9 inhibitors, so now I get why we’re gonna try and inhibit them.

Saloni Dattani: Yeah, we don’t want that. We want the LDL receptors to keep grabbing the LDL and internalizing it and clearing it from our bloodstream. And so if you had seen that mechanism alone, would you think this is a good target and what would you do next?

Jacob Trefethen: Well, I mean, that is pretty good evidence that it might be a good target, but then, you know, PCSK9 might be doing a bunch of other stuff too, so I’d wanna know that, but what would I do? I’d try and generate something that basically inhibits it.

Saloni Dattani: Great point. So I think what is difficult about this, I think there’s so what the next step is just like you said, what if PCSK9 has some important function? So what people did was, they had these big genetic studies at this point, so this is like the early 2000s.

There have been some big cohorts where people have been genotyped and they’re like, let’s see if anyone does not have PCSK9, or they have a mutation where PCSK9 is not produced at all. And turns out, there are a bunch of people who actually have that in both copies of their gene. They don’t produce any PCSK9 functionally at all, and they’re still alive.

So, okay. It’s not gonna kill you basically. Right? If you don’t have it, it’s not gonna kill you. And so, okay, let’s now try to generate a drug against it. What’s difficult about this is that PCSK9, the way that we want to develop something that specifically blocks its interaction with the LDL receptor.

Jacob Trefethen: Well, so let me just get there. So there’s a particular part of the protein that’s probably gonna do the binding. So that’s maybe what you wanna be inhibiting, blocking.

Saloni Dattani: Indeed. Yeah, yeah. I think you could develop a drug against it. I think it’s hard because I think the shape of it means that there isn’t a clear binding spot. There isn’t a clear pocket to bind to. So what are you gonna do?

Jacob Trefethen: Ooh, good question. Okay, so I… but this is extracellular, is that right?

Saloni Dattani: Correct.

Jacob Trefethen: So that gives me more options because I can use different modalities. So, but what would I really do? I mean really what I want to do is if I’m allowed to use all the tools in my toolkit, I wouldn’t mind doing a little bit of a, maybe a little gene edit or something. Or maybe do a little-

Saloni Dattani: That’s expensive though.

Jacob Trefethen: Yeah, that’s true. I mean, that’s where we’re headed presumably. I mean, that’s why I was asking is it extracellular? Because then I can use proteins.

Saloni Dattani: Yeah.

Jacob Trefethen: And I can use an antibody, I can use a binder. So antibody makes sense.

Saloni Dattani: Indeed. Yeah.

Jacob Trefethen: So the antibody tags it and we destroy it. Or the antibody blocks it, or what does the antibody do?

Saloni Dattani: I think the antibody blocks it. There are different mAbs that do that; Monoclonal antibodies. And what do they do? They bind and they block and they prevent it from binding to the LDL receptors.

Jacob Trefethen: Great. Love it.

Saloni Dattani: So there are a bunch of drugs with funny names like ‘Alirocumab’ and ‘Evolocumab’.

Jacob Trefethen: Evolocumab.

Saloni Dattani: Evo- Very good.

Jacob Trefethen: That sounds like a Pokemon.

Saloni Dattani: That does sound like a Pokemon. And both of these were developed in the mid 2010s, so in 2015 or so, that’s when they were approved. And they both have this same kind of mechanism that they’re blocking the PCSK9 protein from binding to the LDL receptor, which means the LDL receptor doesn’t get destroyed, so it can clear more cholesterol from your blood.

Jacob Trefethen: It’s so clean. It’s so clean. I love it.

How, wait, how do I get administered the antibody? Because I don’t wanna have to do blood, like-

Saloni Dattani: Injection.

Jacob Trefethen: Like IV or like?

Saloni Dattani: They are given by subcutaneous injection.

Jacob Trefethen: Okay. That’s way better than blood- that’s just a little pin-prick vibes.

Saloni Dattani: Yeah. So that’s not too bad. What’s so interesting about PCSK9 inhibitors and I think probably why you were, and many biotech people are interested in them is that they’re really effective. They’re effective over and beyond, beyond statins. So if you’re taking statins and you also take PCSK9 inhibitors, they reduce cholesterol levels by an additional 60%.

Jacob Trefethen: Epic.

So cool. Oh, also, do they have fewer side effects than statins or?

Saloni Dattani: Uh, yeah.

Jacob Trefethen: Okay. That is so cool. Oh, I want it so bad. Okay.

Saloni Dattani: And that’s with a injection that’s once every month.

Jacob Trefethen: That is so cool. Do you know if you just go straight to them and don’t do statins? Is that something people have tried?

Saloni Dattani: I am not sure. I think that’s possible. I think in the UK, the recommendation is that you should take statins first, but I think that might not be the case in the US.

Jacob Trefethen: I assume that for cost reasons alone, you would make that recommendation. I don’t know if there’s additional medical reasons.

Saloni Dattani: There’s another way to attack PCSK9 too, with siRNA drugs.

I think maybe to help understand, a lot of people have heard of gene editing and they’re like, okay, well if you don’t like this protein, let’s just edit the gene. Well what if we don’t wanna edit the gene? What if that’s too difficult? What if that’s too expensive?

You’d have to get the cells first, then you’d have to edit them and then you’d have to replace them, and that’s just time consuming. And there aren’t really great ways yet of gene editing in vivo. Like you can’t just put something in your body that just edits the cell.. yet, not very well, anyway.

And so instead there’s another idea, which is what if we don’t target the gene but we target the intermediate RNA that’s gonna produce the protein? And that is a lot easier because the RNA is kind of hanging out in your cells and you can just get something like siRNA to go into those cells and block the RNA. So we stop that intermediate step instead of editing the gene. And that’s what’s happening here.

There is an siRNA drug against PCSK9 that was approved in Europe in 2020 and in the US in 2021. And its name is Inclisiran. And what it does is it blocks the production of that protein entirely. So it’s not blocking it from attaching or anything, it’s just saying. What if you just didn’t get produced at all?

And it’s basically a tiny bit of, it’s a short sequence of RNA and it’s either encapsulated in a lipid or a liposome. And it goes specifically to your liver, it gets taken up by your liver, gets into your liver cells, and it binds to the RNA that is going to produce the PCSK9 protein and it says, shut up. What if I destroy you? And then you can’t produce your protein anymore. And that’s what happens.

Jacob Trefethen: Pretty cool.

Saloni Dattani: That is a scientific explanation of what is happening here.

Jacob Trefethen: Well, I mean, just spelling out why that can be easier in more detail. So presumably we’re interfering in the cytoplasm of the cell, are we?

Saloni Dattani: Yep.

Jacob Trefethen: And whereas if you’re trying to edit a gene, you gotta get into the nucleus, you gotta somehow find that gene, you don’t wanna hit the other. It’s like, oh my goodness, that’s kind of crazy. Whereas, you know, cytoplasm, that’s a mess in there. You know? Everything can get in there.

Saloni Dattani: That’s easier. Yeah. Well, it’s a little bit hard, and it was kind of tricky to figure out because when siRNA initially gets into a cell, it gets trapped in an endosome and then-

Jacob Trefethen: Ah, right, right.

Saloni Dattani: It’s like, how do I get out of here?

Jacob Trefethen: Yeah. The cell’s like, no!

Saloni Dattani: But what is really cool is that that is actually a feature in this case.

Because what happens is, it’s stored in those endosomes and then occasionally, once in a while, one of them trickles out.

Jacob Trefethen: So it’s like a long lasting drug.

Saloni Dattani: Yeah!

Jacob Trefethen: Wow. That’s-

Saloni Dattani: So, it’s like they trickle out slowly. Slowly. Like one by one.

Jacob Trefethen: The original lenacapavir.

Saloni Dattani: Slowly. We silence that RNA. It prevents the protein because it’s released quite slowly, these drugs can last really long times. So there are some siRNA drugs that last a few months, so you only have to be dosed every three months or six months. And there are new ones that are gonna be once a year, and I just think that’s so cool.

Jacob Trefethen: You know what I’m, I really don’t wanna jinx it, but you know what I’m so hopeful for with siRNA, due to the property you just mentioned? Hepatitis B.

Saloni Dattani: Ooh-

Jacob Trefethen: Hepatitis B.

Saloni Dattani: We’re back to the previous episode. Why Hepatitis B?

Jacob Trefethen: Well, I mean, imagine, imagine, imagine, imagine if you could have- you know, gene editing is how you might wanna conceptually deal with Hepatitis B because it’s integrated into it.. it creates its own little chromosome or integrates into your own in the nucleus. But if that’s too hard, siRNA. That might be…

Saloni Dattani: Oh, you could block the Hepatitis B virus from producing itself or producing its proteins.

Jacob Trefethen: Oh my goodness. Oh, wow. Imagine. And there’s actually a siRNA going into a phase one two trial right now that’s recruiting.

Saloni Dattani: Oh.

Jacob Trefethen: So I forget the name of the company, but my friend McKayla sent me a link and I went, oh my God.

She’s like, I know one’s gonna really freak you out. Look at this. And I was like, oh my God. I’m so excited!

Saloni Dattani: Well, I really wanna talk about this a little bit more, but before we move on, there is another drug against PCSK9 that is newer, and it’s also really effective. It’s actually even more effective than the other one probably. And it’s not an siRNA.

Jacob Trefethen: What is it?

Saloni Dattani: Have you heard of it? It’s called Enlicitide. It just finished its phase three trial.

Jacob Trefethen: What does it do?

Saloni Dattani: What does it do? It’s a peptide.

Jacob Trefethen: Oh, it’s a peptide?

Saloni Dattani: It’s a peptide, and it’s a pill!

Jacob Trefethen: Yay! (he cheers) Oh, I did actually hear about oral availability. I didn’t know that was a peptide though. Okay. Interesting.

Saloni Dattani: It’s a macrocyclic peptide.

Jacob Trefethen: That’s quite a peptide. I’m looking at it right now.

Saloni Dattani: It’s quite a big it’s not that it’s quite small for a peptide, I guess.

Jacob Trefethen: Yeah, it exactly looks-

Saloni Dattani: -but it has a lot of rings.

Jacob Trefethen: I’m used to seeing small molecule diagrams. They’re like, oh my goodness, what a big small molecule. But it’s actually a peptide.

Saloni Dattani: So what is this? So this is an oral drug, so it’s a pill and it blocks the interaction of PCSK9 with LDL receptors. And like I said, that’s quite hard to do, to design a drug that can fit into a little gap.

But what they did was they use this RNA assay, and they said which of the peptides made by these mRNA bind to the PCSK9. And when they found some that bound, they then try to see what do they look like? And they found the crystal structures and they’re like, let’s tweak this to make it even better at binding.

And so what they did was, added a bunch of chemical rings to it, and that’s what we got. So we have this chemical ring thing, and there’s an additional small fatty acid which helps it be better absorbed in the small intestine. And so what I think is really cool about this is that it is really effective. So it reduces LDL cholesterol levels by an additional 60%.

Jacob Trefethen: The oral version? That is so cool.

Saloni Dattani: This was in people with the familial condition, so they have hypercholesterolemia, they’re already taking statins and other drugs, and this cuts cholesterol levels by an additional 60%.

Jacob Trefethen: Any side effects?

Saloni Dattani: Any side effects? I think there were maybe a few that were just like diarrhea and stuff, but I think they were very limited.

Jacob Trefethen: Yeah. If you go oral, usually get nausea or diarrhea or something. Yeah.

Saloni Dattani: But yeah. Very cool. It’s called a macrocyclic peptide.

Jacob Trefethen: Okay. That I have to admit, that’s really exciting. It’s funny. It’s very exciting. I’m like, that’s, you know, whoever invented that probably in my life, I will take that. How cool is that?

Saloni Dattani: Yeah. Yeah.

Jacob Trefethen: It’s so cool. Wow.

Saloni Dattani: Well, unless… there’s something even better.

Jacob Trefethen: Oh my goodness.

Saloni Dattani: Wait, I need, I should say this drug hasn’t been approved yet, so it probably is gonna be submitted for approval this year and it’s probably gonna become available next year.

Jacob Trefethen: Got it. And just to depress people because I was too excited, it probably will cost some number of tens of thousand dollars, so you won’t want to pay out of pocket and then your insurance probably won’t cover it…

Saloni Dattani: You might as well just take statins.

Jacob Trefethen: Now, that said, in the grand sweep of time it’ll go off patent and become cheap.

Saloni Dattani: And well, I guess there are other- because PCSK9 is such a good target, there are lots of other things in the pipeline.

There are other small molecule drugs, there are other monoclonal antibodies, there are peptides, and there are even some vaccines to help you make antibodies against PCSK9 yourself.

Jacob Trefethen: Yeah, why not? And the benefit there is everyone will remember is you only gonna need that once or twice and then it’s there forever.

Saloni Dattani: Boom. Long lasting. Have you heard of any other cholesterol drugs in recent times?

Jacob Trefethen: I probably have, but none are coming to mind. If you mention them, I might recognize them.

Saloni Dattani: They target something called lipoprotein A. Have you heard of that?

Jacob Trefethen: Yes. Yes. I have.

Saloni Dattani: LPA. What is lipoprotein A?

Jacob Trefethen: You know, I generously will let you explain.

Saloni Dattani: I didn’t know this until recently. So what it is, is a lipoprotein with a weird long peptide that is stuck to the outside. So the lipoproteins, the fatty blobs that are carrying around the cholesterol and fatty acids through your body, this is just a big long peptide that’s attached to that- It’s part of the shell of that fatty blob.

The reason that we think that it’s bad is that there’s evidence from epidemiological studies. So people who have higher levels of lipoprotein A tend to have worse outcomes, so they have higher risks of cardiovascular diseases.

They also have higher risks of aortic valve calcification, which is when your aortic valve - your artery valve from your heart - gets calcified. And so that has been seen in a bunch of epidemiological studies. And so people were like, what if we just blocked that? And that has actually happened with siRNA drugs.

So there are a bunch of drugs in the pipeline that are extremely effective. So there’s a phase two trial of one of them recently called Lepodisiran. Actually, there are a bunch of these which are really effective. And these siRNA drugs reduce the levels of lipoprotein A by… can you guess?

Jacob Trefethen: Um, I’m gonna guess a lot. So I’ll say, 60%.

Saloni Dattani: 95%.

Jacob Trefethen: WHAT? Okay, then I’m nervous. Are we sure I don’t need that?

Saloni Dattani: Well, I guess we’ll see.

Jacob Trefethen: 95%. Oh my goodness.

Saloni Dattani: That is crazy. So it’s like a single injection at the highest dose of this siRNA drug. There are two of them, Olpasiran and Lepodisiran. The first one, Olpasiran is taken every three months. The second one, Lepodisiran, is taken every six months. And it just reduces (she gestures), and then you just stay really low for a really long time, for at least six months, you don’t need another dose. And then there’s another one that’s an oral small molecule, which also does something similar and they. There’s one called Muvalaplin, which is by Eli Lilly.

Jacob Trefethen: That’s not a real one.

Saloni Dattani: That’s what it’s called, Muvalaplin.

Jacob Trefethen: The way that I would recommend reducing your risk of heart disease is if you move a lot. Oh, did you say Muvalaplin?

Saloni Dattani: This is in phase two trials, this just finished that phase two trials as well and the oral drug reduced lipoprotein A by 85% on the highest dose. I feel like these numbers are crazy to me.

Jacob Trefethen: They’re crazy. But at the same time, we went through how it took a hundred years to establish the LDL cholesterol as epic a biomarker as we thought.

So I’m gonna hold my applause until we get a little bit more knowledge about whether dropping something by 85% actually affects disease that much. But let’s hope.

Saloni Dattani: Let’s see what happens. I mean, I think the last thing to say about siRNA is that people have been developing drugs that target various liver diseases with these, and the reason is that people have sort of figured out how to target or how to deliver the siRNA to liver cells.

And so it can treat a bunch of different liver-related conditions like hemophilia, high cholesterol, and various other genetic conditions that are quite specific and have long names that I won’t pronounce. And this is just the start, I think, because the specific way that you address those siRNA drugs to the liver; if you use a different addressing system, you could in theory target them to the brain or the lungs or the muscles, and the principle of it is essentially the same.

We have to get the siRNA into the cells so that it can target the RNA, degrade it, and then whatever protein you choose doesn’t get produced, or at least it massively gets reduced in production. And the amazing thing is that these are really effective, they have very high potency and they’re also long-acting like Lenacapavir. One dose, it gets stuck in this endosome and then it trickles out one by one. And you could just have a long lasting drug that lasts for months. Instead of taking a pill every day instead of taking an injection every few weeks or whatever, once.

Saloni Dattani: Okay. Let me give you a quick summary of the different types of drugs. So there’s statins, which were one of the first cholesterol reducing drugs invented. They block cholesterol synthesis directly and they’re given as tablets, that are taken daily. They reduce cholesterol levels by 20 to 40% and reduce annual mortality rates by about 10%.

Then there’s PCSK9 drugs, which increase LDL clearance. They actually cause a 50 to 60% reduction, on top of statins. So if you’re taking statins, they cause an additional 50 to 60% reduction. They’re taken by subcutaneous injection every month or every two weeks.

And there’s some newer versions of PCSK9 drugs like siRNA therapies, like Inclisiran; those last much longer. They last about three to six months per dose, and they’re also very effective, reducing cholesterol by about 50%. And what they do is they silence the mRNA, so they silence the production of that protein itself.

And there are some new tablets that are kind of on their way, like Enlicitide, which is a pill. It’s a pill that inhibits PCSK9 as well. And that is, taken daily as an oral medication, again around a 60% reduction. So that’s really large. It hasn’t arrived yet. Probably, it’ll be available in the US next year if the review goes well.

And finally there are lipoprotein A drugs, and what these do is they block a particular harmful type of LDL particle and they are mostly in development right now. And there are various siRNA drugs and various other RNA drugs that essentially block the production of lipoprotein A levels. These seem to last for a very long time, so some of the drugs last three to six months per injection, but newer ones are taken every six months or maybe even longer than that.

And they cause around 90% reduction in lipoprotein A levels per dose, so that’s a very long lasting drug. And finally, there are some oral drugs that also block this. Their efficacy is around 50 to 85%, in reducing lipoprotein A, so these are really large effect sizes focusing on this one protein.

So if you’re listening to this and you probably have, or are thinking about, you know, is this something that I’m gonna be using, or is this something that I should check? I would say consider getting your cholesterol levels checked. If it’s high, it’s probably a good idea to start taking cholesterol drugs.

The earlier, the better; the lower that you can reduce them, the better – that is the general recommendation. But the decision is also made based on your overall risks of cardiovascular disease, like age, your smoking habits, blood pressure, diabetes, family history, et cetera.

There might be some people listening who have a family history of not just cholesterol but hypercholesterolemia - so inheriting particular genes that increase your risk to a very large extent. The recommendation for that is that people start taking cholesterol reducing drugs if they are diagnosed. If you test positive for that, generally you’re recommended to take drugs early and aggressively to reduce LDL as much as you can. And so, yeah, that’s my little summary.

Jacob Trefethen: So that is so much progress on all these different fronts quite recently. So what is going on? Why has the last decade been such a flourishing decade for these drug development programs?

Saloni Dattani: I don’t know for sure. I have a lot of hypotheses. So I think that one, we’re sort of starting to see the fruits of genetic data coming through.

So we’re starting to see the things that we’ve discovered from genome-wide association studies, genome sequencing, and even the linkage studies of the 1990s, it takes an average of 10 years or so to get a drug through clinical trials. And that’s when you have the drug.

So I think if we start off with the genetic studies, we find these targets like PCSK9, we test a bunch of candidate drugs, we developed them, and then there’s, it’s still another 10 years after that.

And so I think that that has only really started to come out in the last 10 years that final trickle of innovation that we’re finally seeing now. I think the other is that this sort of drug design and chemistry has really improved in the last two decades, so there are new things that we can do that we couldn’t do before.

And we’ve talked about some of them. Protein design, we talked about in our fourth episode, hallucinating proteins and tweaking proteins with the use of AI tools. But also before that, the use of other statistical models and data collection with things like Protein Data Bank.

And so I think it’s- partly it’s that, so it’s having more knowledge about which places to target with these drugs, having better ways to actually design drugs to get to those targets.

And then I think it’s various other related things as well. Like we know how to make siRNA drugs now, right? And we have much more research on drugs that are long acting in many different ways, like Lenacapavir, like siRNA, like oligonucleotides.

And I think those are some of the reasons, but I also wonder what you think, like are there other reasons that I haven’t thought of, and are there other types of drugs that might be developed soon?

Jacob Trefethen: Well, what stands out to me, because this is an area of drug development- heart disease is an area of drug development I know less well than some other areas. And so what stands out to me hearing about all these drugs is just how good the targets are, compared to some other areas. And so I wonder how come they’re so good. But you know, PCSK9 is just a really good target.

Saloni Dattani: I wonder if maybe it’s because a lot of them are liver related.

Jacob Trefethen: Yeah. Yeah. You can, the liver easy to get to, easy to mess with.

Saloni Dattani: A lot of things get to the liver, and the liver usually filters things and clears out the toxins. But that is also very useful for drugs that you want to target to the liver.

Jacob Trefethen: Yeah. And then it’s just so useful to have this clear biomarker in LDL cholesterol. And you know, I wish that other diseasesthat it’s this combination of an unbelievably clear biomarker plus the biggest killer.

I’m like wow, what an amazing situation. Whereas in a lot of other drug development you have kind of dodgy markers, or you have an okay thing you don’t really understand, and it isn’t one of the biggest killers. So yeah. Anyway, it’s a nice combination.

Saloni Dattani: I do wonder if it just happens to also be one of the most studied areas. It’s probably an area where there is a lot of pharmaceutical investment into it because there’s so many people who are affected by these conditions. So there is a lot of incentive to develop drugs in the field.

Jacob Trefethen: That makes sense. So what is not yet known, do you think, and what does the future hold?

Saloni Dattani: There are a bunch of things that are not yet known. So some like the lipoprotein A, we don’t really have a great idea of how exactly that in seems to increase the risk of cardiovascular disease.

But I think there are also other questions that are unsolved. Are there ways to develop oral long-acting drugs?

Can we develop siRNA drugs that you can take by pill? I don’t know. I don’t think so yet, but maybe there will be.

And then I think there’s the other question about can we develop drugs or therapies that actually reverse the cholesterol buildup that people have? So most of the drugs that we have, they sort of have multiple effects.

The first is to reduce cholesterol circulating in your bloodstream. They also have smaller effects on plaques that are already in your blood vessels. So if you’ve already developed plaques, it’s not too late, these drugs do still have an effect. And the way that they seem to have an effect is by stabilizing those plaques so they don’t fall off, and that’s important, but I think that we don’t really have cures yet, right? We don’t have things that can reverse the damage that much.

And then there’s the question of HDL. Like, we don’t have drugs that can improve HDL and that are actually beneficial yet, so I think that’s another target that people could be working on in the future.

And then I think the next question is, can we develop drugs that are oral? So they’re easy to take, they’re cheap, they last a long time, and they’re really effective. Can we do something that is all of those things? And that hasn’t happened yet. But maybe it will.

Jacob Trefethen: I’m optimistic about this one.

Saloni Dattani: I’m pretty optimistic as well, and I think there’s a lot in the pipeline right now, and I think there’s a lot that’s just around the corner.

But I also think that in the future we will have a lot of even better drugs. So I think there’s a bunch of cool things, one is the programmable medicine, like the siRNA, the oligos, the gene editing techniques - basically we found a target, let’s go and hit that target directly with either a gene edit or an siRNA to stop the protein from being produced.

That I think is really cool. One because of how precise it is. You’re honing in on that one thing. And then I think the second thing is that if you develop a way to do that in general, then you can easily kind of swap out the gene that you wanna target for a different gene. You can develop dozens or hundreds of different drugs to target different, you know, rare conditions, let’s say, by just swapping that out, as long as you have a platform, you have a specific way to get it into a particular organ, let’s say. So I think that is really cool.

And then I’m excited for the vaccines that are in the pipeline against PCSK9 and like the other, these other targets like, wow, what if you just make your own body produce antibodies against these proteins that are doing harmful things?

One of the things that I was thinking about when reading about this was like, why doesn’t our liver just solve this itself? And also why are these proteins even there, if they’re bad for- if blocking them is so good, why do they even exist in the first place?

Jacob Trefethen: Yes. Always a question one must ask. I mean, I assume that a lot of the answer is that our diet and environment has changed so much versus the ancestral environment. Is that true?

Saloni Dattani: I think that’s, I think there are a bunch of reasons. I think that’s one reason. So we probably eat very differently to how people ate before - we eat more. We also eat more saturated fats and saturated fats reduce LDL cholesterol clearance and your diet can also increase the amount of cholesterol you produce, like these lipoproteins you produce.

And then there’s some people who just have genetic conditions where these normal proteins are dysfunctional and they’re not clearing up LDL cholesterol properly or they’re producing too much cholesterol or something like that.

And then I think that the other reason is that it’s a problem of aging and that after the point at which you have produced children, then evolution isn’t really acting that strongly.

Jacob Trefethen: It’s not picking up on that signal.

Saloni Dattani: Yeah.

Jacob Trefethen: It is a little.

Saloni Dattani: It’s not really selecting against that very much. And if you have high cholesterol and that causes heart attacks, if you’re 50 or 60 or 70, evolution is kind of like, yeah, I don’t care.

Jacob Trefethen: Evolution is very happy for us to die, which is very harsh.

Saloni Dattani: Yeah, that’s true. The way that I see it is also we’re pretty smart. We have developed lots of technologies to solve these problems. What if that’s… what if that’s the evolutionary goal? What if that’s the extended phenotype?

Jacob Trefethen: Oh my. That is quite an extension. Wow. So you are saying that evolution acted through our brains to build artificial intelligence so that-

Saloni Dattani: Yes.

Jacob Trefethen: Thank you, evolution.

Saloni Dattani: I mean a lot of these things are a result of age. When you get older, this balance between producing cholesterol and clearing it out from your bloodstream gets worse. There’s too many particles made and too few are removed, and this gets worse with age.

And so it’s sort of this thing where you’re like, okay, well maybe it’s fine if you’re young, but after a certain age, this is harmful, and we should reduce it. So that’s my answer, which I hope is correct, but I don’t know.

Jacob Trefethen: I can’t wait for the evolutionary biologist to come into the comments and say, “That’s not true because-!!”

But I think that you are right, we’re in a wonderful situation where we don’t die young as much as we used to. And so a lot of evolutionary pressure got spent on stuff that, you know, we would maybe not select ourselves.

Saloni Dattani: You know, I don’t trust evolution as well, ’cause I’m like, what about, you know, child mortality and infant mortality? That is surely bad, but it’s still common.

Jacob Trefethen: We have a few questions for you, evolution.

Okay Saloni! That was a lot of material and I think we reached the end for now. I learned a lot from you this episode, and we discussed a lot of different topics about cholesterol, about heart disease. What sticks out to you most? Let’s do a little summary.

Saloni Dattani: Yeah. I guess.. I learned quite a lot from learning about this.

One of the things that really stood out was just how common statins are. How common it is for people to be on these drugs. But even then it’s, so it’s the estimate is 50 million Americans were prescribed statins in the last year, and I also didn’t realize that even that is only about 40% of the people who are eligible to take them.

So a lot more people should be taking statins than are. And then I think, I didn’t realize how common it was to have high cholesterol, how common it was to have cardiovascular disease. And the other thing that I found really interesting, but was not new to me, was that cardiovascular disease mortality has reduced massively over history.

And if you look at the trend since 1950, the death rate from heart disease has dropped by three quarters. That’s enormous. And I didn’t know that. And that has many causes, not just statins, but you know, emergency medicine and public health efforts and surgeries and medicines, different diet and people changing their lifestyle sometimes if they’ve been diagnosed.

And it’s just a lot of different things coming together and making a massive reduction in cardiovascular disease. So I thought that was really interesting to me.

Jacob Trefethen: That was amazing to see. One thing that stuck out to me about cholesterol is just how long it takes for scientific consensus to build.

And you know, in this case with cholesterol now there is consensus that LDL cholesterol is bad and drives heart disease and these bad outcomes, including mortality. The different lines of evidence it took to get there were animal studies with cholesterol, were observational studies and correlations, were longitudinal observational studies like the Framingham heart study, and then experiments that were randomized or had controls with different drugs: first the vitamins and then drugs that specifically targeted cholesterol. And once you layer that all on top of each other, you can get to consensus. And that consensus is often what is needed to really have impact on a lot of people’s lives, because we are all sort of at the mercy of the recommendations of doctors.

Now that that theory has been proven out, we can all benefit from these wonderful drugs and of the different layers of evidence that I really want to give a shout out to the longitudinal evidence because a lot of people are just coming back and back over years and decades in these incredibly useful studies and you know, giving up biological samples, blood tests, whatever that doing it out of the goodness of their heart for the sake of learning these difficult truths to pin down, and it’s just so cool to think about the people of Framingham, Massachusetts! What an amazing town and what amazing people!

Saloni Dattani: You know, I’ll have to check that this is right, but I think what I read was that it was over 70% or so of the people in that town were part of the study.

Jacob Trefethen: So cool.

Saloni Dattani: Which is massive, I think that’s so cool. The other thing that I thought was really interesting was that in some cases, like with cholesterol, but also in other diseases, it’s often quite helpful to study rare conditions in order to understand a more common condition.

So in this case, the way that we found out that cholesterol was linked to heart disease was from people who had an inherited condition called familial hypercholesterolemia, which had really high levels of cholesterol and had really high risks of heart attacks at a young age. That I thought was really interesting.

But also the same population, that same condition, helped us to get PCSK9 drugs. That was the same condition that helped people find, specifically, what genetic mutation was linked t high cholesterol levels and find a protein that they could target with a drug. So that was really interesting and I think it’s, it just happens to be the case that that same mechanism is also the case in the general population.

So that is something that maybe isn’t as common, but you know, when you find people with rare conditions and they have really high levels of some traits, it makes it much easier to study biologically, what is the mechanism. It’s easier to study than predictors and, you know, what are the risks? And it’s easier to see the effects of reducing those risks with certain drugs, and I think that’s a great starting point for a lot of drug development.

Jacob Trefethen: I also found it interesting in this episode to hear more about the path of lipids through the body, and what LDL cholesterol really is, and how it can lead to atherosclerotic plaques and what those plaques are, how macrophages can get foamy in the middle.

Atherosclerosis is something that I sort of know of, but don’t know the details that in detail, so that was really interesting to hear. And the ways that can lead to downstream strokes or downstream blood clots in different areas makes sense to me and helps chain the mechanism all the way through.

Saloni Dattani: Yeah that was- I really didn’t know that macrophages could get foamy. I didn’t know that if you’re a macrophage and you eat fat particles, the fat kind of just remains in you and you’re foamy now? That was so strange to me and you can actually see this in microscope slides as well, so that was fun.

The other thing that was new to me, which I didn’t know, was that you actually don’t need to eat any cholesterol in your diet; your liver can synthesize all the cholesterol that you need, and if you’re vegan or vegetarian, you probably consume very little cholesterol and it doesn’t matter and it might even be good for you. That was wild. I didn’t know that.

Jacob Trefethen: Another one like that for me is you think saturated fats sound bad because it’s gonna be just fat floating around and then, but actually one of the main reasons saturated fats are bad is because they stop the removal of LDL cholesterol. Like, oh, that’s the reason.

Saloni Dattani: Yeah, it’s a bit sneaky. The whole pathway of cholesterol synthesis, transport, metabolism was really complicated and I sort of boiled it down to a much simpler version here. But I thought that it was so interesting because there’s so much stuff going on, and maybe that means that there are actually lots of different things that you can target, and the different drugs target many different parts of this pathway.

And I don’t know if you have come across this, but occasionally I used to come across these memes on Twitter that were like, they would just show you the entire biochemical pathway of loads of things. ‘Oh, if you just change one thing, you think you can solve this disease? No, you can’t!’ But sometimes you can!

And I thought that was so interesting, the whole pathway doesn’t necessarily correct itself. Right? Sometimes there is a rate limiting step or there is a bottleneck and if you stop that particular protein, you can actually make a really big difference.

Jacob Trefethen: I love how most people are seeing political memes, you’re seeing metabolic memes. Yeah. Very relatable. Me too. Another thing that stuck with me is funguses! Funguses rock. And the fact that it was the same genus of that got us the penicillin, and the first statin? That’s wild.

Saloni Dattani: That’s crazy. Maybe mold is actually good?

Jacob Trefethen: I’ve always had a suspicion, and that’s why my bedroom’s full of it.

Saloni Dattani: I don’t know if I told you this, but I had this very funny experience, I think one or two years ago. I was thinking about tick-borne diseases and diseases spread by ticks. And I was like, should we just get rid of all the ticks?

Would that be good? And I asked chatGPT, and this was 3.5 or something, and I asked chat

GPT: are there any benefits of ticks? And it said: ticks are very important for researchers to study tick-borne diseases.

Jacob Trefethen: Hahahaha! It’s not wrong.

Saloni Dattani: But then I thought the relation to this was, the mold is good because you can study the moldy diseases.

Jacob Trefethen: Hey, and that’s why you don’t want to get rid of mold or ticks.

Saloni Dattani: Yeah, well I do wanna get rid of ticks.

Jacob Trefethen: Okay, fine. If I’m allowed the mold, you can get rid of the ticks.

Saloni Dattani: The other thing I found that was interesting and was surprising to me, I wasn’t convinced before doing research for this episode that diet was important.

I was like, yeah, people just say that junk food is bad, but is it really? And what convinced me was that there were actually randomized trials where people randomized people’s diet and they actually had the same meal every day for months or years. And it was like, that surprised me.

Because I think a lot of nutrition research today is observational and it’s people recording stuff in their diaries and there are all kinds of things that correlate with eating healthier. And so I just thought this is kind of messy, and a lot of those studies, they had sort of messy conclusions, there wasn’t something clear. And I just thought we should do more of this randomizing people’s diet to see what is good for you or bad for you.

Jacob Trefethen: I’ll volunteer so long as I get the bagel arm.

Saloni Dattani: Fair enough.

Jacob Trefethen: I think finally the thing that I really enjoyed talking about this episode and stuck with me is the different ways that drug development has succeeded here.

And honestly, it sounds like it’s gonna succeed further in the next decade or two. The original drugs being.. I mean, there were drugs even before the statins that were not as targeted. And then the development of statins, the trial and error, the testing of different fungal samples, you know, really trying to figure out what was going on with those dogs and eventually benefiting humans.

Saloni Dattani: Sometimes more than 6,000 samples just to find a drug that inhibited cholesterol synthesis.

Jacob Trefethen: And of course my favorite, the PCSK9. I mean, really cool to have discovered that target from genetic evidence, from people who are at higher risk of cholesterol problems. And then to develop a drug, in this case, starting with monoclonal antibodies that targeted this one thing. And that one thing is really important because it binds to LDR receptors.

Saloni Dattani: I also thought it was cool to see, people were wondering, well do we need this protein? What if we block this, will it go bad? And actually using the genetic evidence to find people who just lacked the functional gene and they were healthy.

I think there’s a survivorship bias thing there that makes it complicated, but it does tell you that it’s not vital and I think that’s helpful. And then the siRNA, I think it’s just so cool that you can just decide to just silence the specific gene and you can just, you know, you pick a gene, you found that it’s bad for whatever reason, and you’re like, let’s just switch that off.

And there, you have a medicine, and I feel like we’ve sort of figured this out for a lot of liver diseases and a lot of things that act somehow through the liver, like cholesterol. But eventually we’re gonna find ways to do that for other organs as well. We’re gonna be able to just switch off genes that do things that we don’t like.

Jacob Trefethen: One of my main lessons from this episode is we’re going to have to do a future episode on siRNAs, because that’s just a whole new way of thinking about what you can do in medical intervention and oh my goodness. Oh my goodness. There’s gonna be a lot more that we’ll need to discuss.

Saloni Dattani: Do you have any final thoughts?

Jacob Trefethen: My final thoughts are… Despite what evolution is trying to get us to do, namely die, I don’t think it’s inevitable, and I think it’s great to see how you can really, as a medical research community, tackle the biggest problems and make progress on ’em. And it takes a lot of people’s work over many decades, its a really collaborative effort, and that’s a lot of doctors, a lot of scientists, a lot of patients, and even some podcasters too. No, I’m kidding.

And then we get to benefit, you know, you and I love to hear how all of this stuff is invented and why there’s this scientific consensus, but if you’re just going about your day, you can take a statin and you never have to know all of these arguments that happen between tens of thousands of people.

Saloni Dattani: But they’re so interesting!

Jacob Trefethen: That’s true. I know it’s horrible to consider that people might not get into the scientific weeds.

Saloni Dattani: Yeah. I think this is maybe one of those episodes that for a lot of people it’s personally relevant to them. It’s either them themselves or a family member or someone they know very closely that’s affected by one of these conditions.

And they are curious about a lot of the things that we talk about. And so hopefully it was interesting to a lot of you and fun, and you learnt a lot, I hope.

Jacob Trefethen: I hope so too. And I think one of the joys of medical progress is when it disappears into the background and you don’t think about it. So if you are someone who takes a statin every day without thinking about it much, I hope you had fun thinking about it a bit more for a few hours with us, and now you can go back to normal life.

Saloni Dattani: So if you enjoyed this episode, please share it with all your friends and subscribe and tell everyone you know about it.

Jacob Trefethen: And if you have a future episode request you’d like to make, we’re everywhere online. So just find us somewhere and make a suggestion.

Saloni Dattani: Oh yeah, I’m everywhere. I’m behind you right now.

Jacob Trefethen: No! She’s practically cholesterol, she’s everywhere. I had a lot of fun doing this one.

Saloni Dattani: I thought this was a great episode for the Fatty Blob fans.

Jacob Trefethen: True.

Saloni Dattani: This was an episode all about fatty blobs.

Jacob Trefethen: The fatty blob community has been served well today.

Saloni Dattani: Alright, bye!

Jacob Trefethen: Bye!