Ep 218 The Lowdown on Statins

Last week, we set the stage by breaking down the science behind cholesterol: how it moves through our body, why it causes disease, and when we discovered the link between LDL and atherosclerosis. This week, armed with that knowledge, we’re asking the big question: what do we do about high cholesterol? Statins emerged as a highly effective intervention but one that is not without its share of controversy and misinformation. We delve into the story and science of statins and other cholesterol-lowering drugs, from their brilliant discovery to early promising trials, from barriers preventing their use to the heaps of misinformation abounding on the internet. How do statins actually work? What does penicillin have to do with their discovery? What’s the deal with side effects? Tune in for all this and more. Support this podcast by shopping our latest sponsor deals and promotions at this link: https://bit.ly/3WwtIAu See omnystudio.com/listener https://omnystudio.com/listener for privacy information.

• 0:01Speaker 00

  This is exactly right.

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• 1:45Speaker 07

  I was born into a rural farming family in northern Japan, where I lived for 17 years with my extended family, including grandparents, parents, three brothers, and two sisters. My grandfather, who had an interest in medicine and science, was a great home teacher to me. Thanks to his influence, at the age of eight, I dreamt of becoming a scientist. After finishing high school in Akita, I entered Tohoku University's College of Agriculture in Sendai in 1953. As a student, I was deeply impressed by the knowledge that antibiotics had saved the lives of many patients with infectious diseases. I received a PhD degree from Tohoku University in 1966.

• 2:26Speaker 07

  At this point, I became interested in cholesterol biosynthesis. I eventually studied from September 1966 to August 1968 at the Albert Einstein College of Medicine in New York. At that time, coronary heart disease was the main cause of death in the United States. The number of people with hypercholesterolemia, a precursor to coronary heart disease, was said to exceed 10 million. My experience of living in New York made me realize the importance of developing a cholesterol-lowering drug. After coming back to Tokyo in 1968, Sankyo Research Laboratories gave me an opportunity to work on a project of my own choosing.

• 3:07Speaker 07

  I speculated that fungi, like molds and mushrooms, would produce antibiotics that inhibited HMG-CoA reductase. Compactin seemed to be a wonderful gift from nature.

• 4:05Speaker 05

  I want to know everything more that you're about to tell me from that story.

• 4:11Speaker 07

  You will, you will. So that was excerpted from actually two different articles written by Akira Endo, who was the father of statins. He discovered the first statin. And he has written about this in multiple different places, but this was from two papers, one from 2008 and one from 2010. And we'll have them in our show notes. But yeah, I loved, I love just like, I'm still amazed at the logic link, leap that it took.

• 4:43Speaker 05

  That's what I, that's what I want. I want so much more of that, of like, what was he thinking? And how does he piece these things together? And like, I want to know it all because I'm really, I'm really excited for this episode. Erin, should we tell people?

• 4:55Speaker 07

  Yeah, me too, me too. It's going to be great. Hi, I'm Erin Welsh.

• 5:01Speaker 05

  And I'm Erin Allman Updike.

• 5:02Speaker 07

  And this is This Podcast Will Kill You.

• 5:04Speaker 05

  Welcome to Cholesterol, Part Two.

• 5:07Speaker 07

  Part Two.

• 5:08Speaker 05

  Where we lower it.

• 5:09Speaker 07

  Statin goo-goo-loo. Yes.

• 5:11Speaker 05

  Good ones, yeah.

• 5:14Speaker 07

  Yeah, to this, so if you didn't listen to last week's episode, you really should because it'll give you some great foundation for understanding why cholesterol does what it does in our bodies and why certain levels of different types of cholesterol mean diseases.

• 5:31Speaker 05

  I know that we're biased, but I think it's a great episode.

• 5:36Speaker 07

  I do too.

• 5:37Speaker 05

  So if you haven't listened to it, check it out. And then today, we're going to build on so much of that and talk about how we deal with high cholesterol and how we figured out how to deal with it. And it's going to be really great.

• 5:49Speaker 07

  Yes.

• 5:49Speaker 05

  But before we can start, it's quarantine time.

• 5:52Speaker 07

  It is. Once again, we are drinking Plaque Attack.

• 5:59Speaker 07

  Again, are we attacking Plaque as Plaque attacking us?

• 6:01Speaker 05

  A little bit of both.

• 6:03Speaker 07

  Yes.

• 6:04Speaker 05

  What's in Plaque Attack?

• 6:06Speaker 07

  It's a pretty, it's a pretty delicious, straightforward, nothing to do with cholesterol, just delicious. It's blueberries smashed with lemon juice and club soda and simple syrup.

• 6:19Speaker 05

  And mint.

• 6:23Speaker 07

  I have it written down and yet it's like not, I just didn't pull it up, so.

• 6:27Speaker 05

  We'll post the full recipe on our website, thispodcastwillkillyou.com, on our social medias, which include Instagram and Blue Sky and Facebook.

• 6:37Speaker 07

  Facebook.

• 6:38Speaker 05

  Facebook and TikTok. I don't know if it's there on TikTok, though. Listen, just follow us there. You'll see what we're up to.

• 6:45Speaker 07

  Absolutely, you will. Yeah.

• 6:49Speaker 07

  You can also see a little bit of what we're up to by going to our website, thispodcastwillkillyou.com. It's got, yeah, not, not quite, but like, it's got, it's got resources, right?

• 6:59Speaker 05

  Lots of resources.

• 6:59Speaker 07

  It's got lots, it's got all of the papers we use for all of our episodes. It's got links to our bookshop.org affiliate page, music by Blood Mobile, links to merch, links to Patreon. It's got a first-hand account form, a contact us form, things that you can explore.

• 7:19Speaker 05

  Everything we could think of is there.

• 7:21Speaker 07

  Yeah.

• 7:22Speaker 05

  Thank you to everyone who has rated and reviewed and subscribed on your podcatcher or YouTube of choice.

• 7:30Speaker 07

  Yes, yes.

• 7:31Speaker 05

  We appreciate it.

• 7:32Speaker 07

  We do. I know, we know, there are so much media out there that you could consume. And so it means, truly, it means so much to us. It feels surreal that you're choosing to spend any time with us at all.

• 7:43Speaker 05

  I know. Every time someone says they listen, I'm like, to me? To us?

• 7:47Speaker 07

  What?

• 7:48Speaker 05

  Really?

• 7:48Speaker 07

  Yeah. It's incredible.

• 7:50Speaker 05

  So thank you.

• 7:51Speaker 07

  Thank you.

• 7:52Speaker 05

  Okay, Erin, tell me about this guy and how he came up with statins and everything else, okay?

• 7:58Speaker 07

  Absolutely. Let's take a quick break and we'll do all of that.

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• 9:54Speaker 09

  Lisa, we should tell them about our new show.

• 9:58Speaker 03

  Oh, my God, Lexi. We have a new podcast. It's called Don't Lie To Me.

• 10:02Speaker 09

  I'm Lexi Iwanu. We're two best friends, 22 years apart, but so close at heart.

• 10:07Speaker 03

  And I'm Lisa DiGiulio, the old one, which means we have wildly different references, occasionally different opinions, and at this point in my 50s, I've lived it all.

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  Now in my 30s, being the founder of new shoes, good taste is my business, and I've always got something to say. If men were just honest about this, there would be so much more peace in the world.

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  We're going to talk about dating, relationships, beauty, getting older.

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  Listen on the iHeartRadio app, Apple Podcasts, or wherever you get your podcasts. I don't really care.

• 11:20Speaker 07

  Last week, I took us through the story of cholesterol and how it earned its reputation as a major cause of cardiovascular disease. Over the course of about seven decades, from the 1910s to the early 1980s, researchers put the pieces of the cholesterol puzzle together using a wide range of studies. We had experimental ones, like a Nitschka's atherosclerotic rabbits. There were analytical ones, epidemiological ones, like the Framingham Heart Study, genetic ones, and mechanistic ones, like Brown and Goldstein's Nobel Prize-winning work characterizing the LDL receptor. Lots of different studies, lots of different lines of evidence.

• 12:01Speaker 05

  Lots of different lines of evidence.

• 12:01Speaker 07

  Yes, yes. And this week, I'm going to pick up with the final piece of this puzzle, cholesterol lowering drugs, and some of the controversy that surrounds them. By the 1970s, much of the cardiology world, like researchers, physicians, and institutes, they saw the link between cholesterol and cardiovascular disease as a done deal. This is established. Okay, now let's proceed from here. But that knowledge didn't reach beyond that realm of experts, and many physicians remained either skeptical or oblivious to this new knowledge. So, for

• 12:39Speaker 07

  example, a 1983 study of internists in the US showed that 50% did not recommend any therapy, including diet, for cholesterol lowering unless levels were over 300.

• 12:54Speaker 05

  Fascinating. In like the mid 80s, basically.

• 12:57Speaker 07

  1983, yeah.

• 12:59Speaker 05

  Wow.

• 13:00Speaker 07

  Yeah. It just, it also shows how quickly things have shifted.

• 13:04Speaker 05

  Yeah. Which is so interesting also, because I just think about, like, we've talked about before how slow changes in medicine, and like, there are plenty of people practicing today, who were probably practicing in the 80s, like getting trained in the 80s. So that, oh, it's just so interesting.

• 13:21Speaker 07

  Yeah, yeah. It is, it is really interesting, and I think it also, like, okay, for you today, this, I wanted to share more of these numbers, because I think it'll come as a real, like, double take. Yeah, exactly. So, of that, of those 50% who wouldn't recommend any therapy unless over 300, nearly half said no therapy unless levels were over 340.

• 13:47Speaker 05

  340.

• 13:48Speaker 07

  And 27% of those said that they would never recommend drug treatment under any circumstances.

• 13:54Speaker 05

  For cholesterol.

• 13:55Speaker 07

  For cholesterol.

• 13:58Speaker 07

  Yeah. So, what would it take for high blood cholesterol to be seen as a pressing public health issue, at least among all medical professionals, if not the general public?

• 14:10Speaker 05

  Yeah.

• 14:12Speaker 07

  An available treatment, and evidence that intervention worked. Those two things would emerge at nearly the same time in the early 1980s.

• 14:22Speaker 05

  Erin, I don't want to interrupt you, because I'm loving this, but as a side note, you know what we should do an episode on?

• 14:28Speaker 07

  Tell me.

• 14:29Speaker 05

  Evidence-based medicine.

• 14:31Speaker 07

  Yeah, okay.

• 14:32Speaker 05

  Because that is a really new thing.

• 14:36Speaker 07

  Wait, wait, what do you mean by that is a really new thing?

• 14:38Speaker 05

  I mean, the idea that we should only make recommendations for things if we have evidence to support them is a relatively new concept in the history of medicine, and it would be really interesting.

• 14:50Speaker 07

  The humoral theory has tons of support, Erin.

• 14:55Speaker 05

  So anyways, sorry to sidetrack.

• 14:57Speaker 07

  No, we should definitely do, we should definitely do that. We've had ideas to do things like randomized control trials as well.

• 15:02Speaker 05

  Yes.

• 15:03Speaker 07

  And

• 15:04Speaker 05

  I know.

• 15:04Speaker 07

  Just like, yeah.

• 15:05Speaker 05

  There's too long of a list.

• 15:07Speaker 07

  We have such a long list. It's, it's great. It's a, it's a good problem to have. Okay.

• 15:10Speaker 05

  It is. We're in the 80s.

• 15:12Speaker 07

  We're in the 80s.

• 15:13Speaker 05

  A lot of people are like, "Nah, dude, give me some evidence."

• 15:16Speaker 07

  Right. And the cardiologists or the cardio, cardiology research people are like, "Oh, my God, we're, this, we're in trouble. We're in trouble." Okay. So, we needed treatment and proof that any sort of intervention worked, whether it was the treatment or just lowering cholesterol, that that led to actual results.

• 15:34Speaker 05

  Right.

• 15:35Speaker 07

  Those two things, a treatment and proof of intervention, would emerge at nearly the same time in the early 1980s.

• 15:42Speaker 05

  Okay.

• 15:43Speaker 07

  So, at the National Institutes of Health, plans had been underway since 1970 for a large-scale study that would measure the impact of cholesterol lowering drugs on cardiovascular disease. Previous studies had shown that high, high blood cholesterol levels overall correlated to higher rates of heart attacks, but the next step was showing that lowering those levels would then lead to fewer cardiac events.

• 16:07Speaker 05

  Exactly. We know that there's this positive correlation between high levels and bad outcomes. Can we change that?

• 16:14Speaker 07

  Can we change that? Can we do something? Because then that would also suggest it would be a very great evidence for causation.

• 16:21Speaker 05

  For causation, exactly.

• 16:22Speaker 07

  Yeah. So, the coronary primary prevention trial was designed to do exactly that, show this line of causation. The study enrolled 3,800 men aged 35 to 59 with high total blood cholesterol, so 265 or higher, and they were to be followed for at least five years. The treatment group was supposed to take a cholesterol lowering drug, cholestiramine. Statins weren't yet approved at this point, and all participants were instructed to follow a cholesterol lowering diet.

• 16:54Speaker 05

  Okay.

• 16:55Speaker 07

  Knowing what we know today about the link between cholesterol and cardiovascular disease, a trial like this would not be conducted in the same way, where you would withhold drugs from one group. But at the time, the evidence was not as firm, especially for medication, and so that's why it went forward. By the early 1980s, after an average of seven years follow-up for each participant, the results were in, and they were unambiguous. Lowering blood cholesterol in high-risk men reduced the risk of heart attack. Those who took, period. Those who took the full dose of treatment had a 35% reduction in total cholesterol and a 49% decline in the rate of cardiac events. But even those who didn't follow

• 17:40Speaker 07

  the treatment to a T, like the, the cholestiramine, had lowered cholesterol and fewer heart attacks. Now, the study was not perfect, but when the results were published in 1983, it led to a moment of reckoning for the field. Like, it was no longer enough to simply acknowledge that this relationship exists. Something had to be done about it.

• 18:03Speaker 05

  Right.

• 18:04Speaker 07

  And that something was to be decided at the 1984 NIH Consensus Development Conference. So, there was a panel of experts at this conference who came up with a set of guidelines for what would be considered high or low blood cholesterol, for certain ages and how that fell out, and also diet and exercise recommendations for how to reduce cholesterol. They also advocated for a nationwide educational program in which general practitioners, as well as the general public, were taught about the importance of cholesterol.

• 18:36Speaker 05

  I love that.

• 18:37Speaker 07

  Yep. This conference had a substantial impact over the next decade, with the percentage of physicians pointing out LDL as an important marker for the risk of heart disease that increased from 1986 to 1995, from 34% to 75%.

• 18:56Speaker 05

  So, like, in 1986, only like 30% of your physicians would be like...

• 19:01Speaker 07

  LDL is important.

• 19:02Speaker 05

  Yeah.

• 19:02Speaker 07

  Okay.

• 19:03Speaker 05

  Okay.

• 19:04Speaker 07

  95, and then it was 75% in 1995.

• 19:07Speaker 05

  Better than before.

• 19:08Speaker 07

  Better than before. At the time that the panel was making these recommendations, there still wasn't really a good cholesterol lowering medication available. So, the one that they had used in the study, cholestiramine, came in a sandy powder, which you had to mix into water and consume throughout the day. So, you had to consume 24 grams a day was like the goal in the study, which was like six packets of, of this or something like that.

• 19:32Speaker 05

  No one's shaking that.

• 19:33Speaker 07

  It was quite a heavy lift, and it was made even more daunting by the GI upset that it caused in many, you know, bloating, diarrhea, constipation, and stuff like that.

• 19:41Speaker 05

  Yeah.

• 19:42Speaker 07

  So, there was clearly a need for a safe, effective, and easy medication to lower cholesterol. Fortunately, researchers were well underway in their quest for such a wonder drug.

• 19:54Speaker 05

  Okay.

• 19:54Speaker 07

  In 1971, the firsthand account provider for this episode, Dr. Akira Endo, was working as a research biochemist at the Japanese pharmaceutical company, Sankeo, when he got an idea. Endo had long been fascinated with Alexander Fleming's serendipitous discovery of penicillin. And after a research stint in New York, he had become intrigued by this problem of hypercholesterolemia. And he figured that, okay, if, if fungi produce antibacterial compounds like penicillin to compete with other fungi, it's not like they produce it because they're like, "Oh, humans could use this."

• 20:32Speaker 05

  No. Right, right.

• 20:35Speaker 07

  It's part of the ecology of this, of penicillin. Then it's possible that they would produce other types of compounds that would interfere with or help them compete against fungi in other ways, such as maybe a compound that interferes with cholesterol production.

• 20:53Speaker 05

  Because cholesterol is so essential for life.

• 20:56Speaker 07

  Yeah.

• 20:57Speaker 05

  Fascinating.

• 20:58Speaker 07

  Yeah.

• 20:59Speaker 05

  So he just was like, bro, Fleming did this once.

• 21:03Speaker 07

  Fleming did this.

• 21:04Speaker 05

  Maybe I can find something here because cholesterol is so important.

• 21:09Speaker 07

  Yeah. And he was, I mean, part of the thing too, he was like, he was like fungi is all I knew. So that's where I looked. But it also like that, that logic is very clear, but it had no direct support from any studies. Like there was penicillin and the fact that we found other antibiotics through this sort of like, oh, this thing is producing this thing that kills this bacteria or this fungi in the environment. But like, yeah.

• 21:36Speaker 05

  But to think of it for, for use on cholesterol, like that's so, that's so interesting that his brain just did that.

• 21:41Speaker 07

  Right. Yeah. And he found it.

• 21:45Speaker 05

  And he was right.

• 21:45Speaker 07

  He found it. Yeah. I mean, so it, it took a while. It took two years. He and his colleagues over that time screened 6,000 strains of microbes searching for a compound with cholesterol lowering properties, like searching for a needle in a haystack, really.

• 22:00Speaker 05

  Wow.

• 22:01Speaker 07

  And the first hit on this was less of a needle and more of a crochet hook. But the second was exactly what they were looking for. The compound came from the mold Penicillium citrinum, which another penis, another penicillium. And they named it Compactin, also known as Mevasstatin later on.

• 22:21Speaker 05

  Okay.

• 22:21Speaker 07

  Yeah. And this was the first statin. Yeah. So over the next several years, Endo and other researchers at Sankyo tested Compactin's safety, efficacy and commercial viability. And other pharmaceutical companies got wind of this, like Merck, who was like, can we get a sample of that and see what's going on? And then they were like, how did you find this? Well, we're going to look for our own statin in the same way. They had to kiss way fewer frogs, only 18, before they found their prince in Lovastatin in 1978.

• 22:56Speaker 05

  Oh, competition.

• 22:58Speaker 07

  Competition. Yeah. And then there's some, there's like a lot, there is so much more to the story of like statin production, statin approval, statin testing and stuff like that, which I will have some papers there if you want to dig more into that.

• 23:13Speaker 05

  Okay.

• 23:14Speaker 07

  But essentially there were some early trials in animals that hit some hiccups, but then those were smoothed out. Trials in humans then went forward in the early 1980s and results were striking. People with high cholesterol saw their LDL levels drop dramatically after taking the medication with few side effects. But did this drop translate to protection from cardiovascular disease?

• 23:39Speaker 05

  Right.

• 23:40Speaker 07

  You betcha.

• 23:41Speaker 05

  Yeah.

• 23:42Speaker 07

  You betcha.

• 23:43Speaker 05

  Yeah.

• 23:43Speaker 07

  Yeah. So there was one study sponsored by Merck, who was testing out their statin, found a 42% decrease in death rate in those taking a statin. This is the second generation statin, Simvastatin.

• 23:57Speaker 05

  Simvastatin. Still use it today.

• 23:59Speaker 07

  Yeah.

• 23:59Speaker 05

  Wow.

• 24:00Speaker 07

  Yeah. Statins look to be the next blockbuster drug. And soon every pharmaceutical company wanted in on the action.

• 24:08Speaker 05

  Of course.

• 24:09Speaker 07

  And by the last year of the 1980s, three statins were approved and available on the market.

• 24:15Speaker 05

  Wow.

• 24:16Speaker 07

  The following decade saw new statins and an expansion in their use, which allowed for large scale clinical studies, not just ones headed by pharmaceutical companies who were trying to get their drug approved.

• 24:29Speaker 05

  Right.

• 24:30Speaker 07

  I also just can't believe how recent it all is.

• 24:33Speaker 05

  Me neither. I really did not realize that this was all in the last 40 years, like since the 1980s. That's really wild.

• 24:40Speaker 07

  It is wild. And I think it also is part of the reason why there's been such controversy.

• 24:46Speaker 05

  Hmm. It's so interesting though, Erin, because there's so, there's newer, newer, newer drugs that I feel like have way less controversy surrounding them.

• 24:55Speaker 07

  I know.

• 24:55Speaker 05

  And I'm just like, what?

• 24:57Speaker 07

  I, there's a lot, there's a lot and we're gonna, we're gonna get into it in a second. But, but yeah. But these studies, these large scale studies that were done, not just by pharmaceutical industry, they conclusively and consistently showed that statins were life-saving drugs and that they had earned their blockbuster status.

• 25:15Speaker 05

  Correct.

• 25:16Speaker 07

  Across the board, statins led to a 25 to 30% reduction in LDL, coronary artery disease and death from cardiovascular disease. In the 40 or so years since statins have been on the market, death from cardiovascular disease has dropped by over 75% in many industrialized countries. Statins are a major tool in that fight, along with big advancements in medicine, lifestyle modifications and diagnostics. But of course, the story doesn't end here. The potential benefits of statins are enormous, both at a population and individual level, especially with cardiovascular disease being the leading cause of death in many countries.

• 25:57Speaker 07

  But increasingly, the benefits of these drugs are not realized because people aren't taking statins when it's recommended that they do. Why is that?

• 26:08Speaker 05

  Why?

• 26:09Speaker 07

  Why? As it turns out, it's for many different reasons. A couple of recent papers looked into the issue and they presented some themes that they found in why people either refused or discontinued statins. There were, you know, practical and logistical considerations, so concern about taking multiple medications, polypharmacy burden, financial barriers, you know, having to drive to the clinic to get low cost statins, things like that.

• 26:35Speaker 05

  That's so annoying because they're all generic and like should not, especially in this country, be high cost, but they are.

• 26:42Speaker 07

  And there should be, you know, by mail, et cetera. Yeah.

• 26:44Speaker 05

  Yeah.

• 26:45Speaker 07

  Yeah. Pregnancy and breastfeeding is another sort of practical reason, or preferring lifestyle modifications over a daily pill. Like I'm not going to be able to take a pill every single day. I'm going to forget that.

• 26:56Speaker 05

  Right.

• 26:57Speaker 07

  There were also preconceptions about side effects or impact on someone's identity. So people reported negative side effects or a fear of negative side effects. And others felt that taking statins was like giving up, that it signified sickness and that they didn't want to be on a medication for the rest of their life. They didn't want to be dependent on this drug for health.

• 27:18Speaker 05

  Yeah.

• 27:19Speaker 07

  And then there was another big reason or another big theme was mistrust in medicine and kind of a lack of understanding or belief in the drugs and how they worked. So some questioned their utility, like I have high cholesterol. The doc says I have high cholesterol, but I don't feel bad.

• 27:38Speaker 05

  Right.

• 27:39Speaker 07

  Statins doesn't make me feel any different, or it makes me feel worse.

• 27:42Speaker 05

  Right. I have this side effect that came from it, I think. And, and I didn't feel bad to begin with.

• 27:48Speaker 07

  Right. Exactly.

• 27:49Speaker 05

  Why would I be on a medicine forever?

• 27:52Speaker 07

  People didn't also understand how statins lowered cholesterol. So it was just sort of like, well, I don't understand how they work, so I don't know that they do work. And many people also questioned the motives of doctors in prescribing the medication, like Big Pharma has a hand in this. And they felt that over prescribing was an issue, especially with levels being revisited every so often and being like, now we recommend that you're, you know, you didn't recommend this last year when my LDL was the same.

• 28:20Speaker 05

  Exactly. Now, now we need your LDL to be less than 70. Now we need it to be less than 55. Now, yeah, without, without a good explanation. They just updated the guidelines in March of this year. So they're changed yet again.

• 28:33Speaker 07

  Right. So there's this sort of fear of like diagnostic creep. Is that happening with cholesterol and statins? Or is there evidence to support this shifting of the levels and the recommendations? But often with all these different reasons, there was, it was a combination of things that led people to either refuse statins or stop taking them. Within two years, roughly 40% of people who were taking them for primary prevention and 25% of people on statins for secondary prevention end up stopping the medication. So to say that these negative attitudes towards statins are worrisome, I think is quite an understatement. It could have serious, even fatal consequences. So what do we do

• 29:16Speaker 07

  about it? The first step is understanding why, you know, where are these attitudes, these beliefs coming from? Many of the reasons that people give for not taking or discontinuing statins can be attributed in part to misinformation or, or negative beliefs promoted across social media. When statins first came on the market in the late 1980s, the cholesterol-heart disease link had not yet been fully embraced by the general public. And in fact, there were some highly publicized, front page stories written by vocal deniers. Controversy sells, consensus doesn't.

• 29:57Speaker 07

  Yes. And so all of a sudden you go to the doctor, your doctor is telling you, you should take this drug for your cholesterol, but just that morning you read how the cholesterol-heart disease link is overblown so that Big Pharma can rake in the dough and get people on meds for life. Why would you do this? Right?

• 30:13Speaker 05

  Yeah.

• 30:14Speaker 07

  And it would take years after statins were introduced to put together those big data sets that show the life-saving benefits of the drugs and the relatively low rate of side effects. And so doubt has really been sown into statins from the very beginning, along with a mistrust in how the pharmaceutical industry is involved. And I get it. Like there is some truth to this involvement, especially early drug trials being designed by pharmaceutical companies. Many researchers in this area hold board positions or receive funding from these companies or have a patent for these drugs and they're trying, you know, like there is, there are financial ties that are undeniable.

• 30:55Speaker 05

  A hundred percent, a hundred percent. And I will say, like in today's day and age, not just with pharmaceutical companies, also with radiology companies and imaging companies and genetic testing companies. And so as our guidelines shift to incorporate more of these, like it is very valid to question these conflicts of interest, whether they are real or perceived. Like they matter.

• 31:17Speaker 07

  They matter. They do matter. And I, I think that this is, like you said, as these, as these guidelines are shifting, there's these questions around like who, what's, what's behind these guidelines? Is there evidence for it, et cetera?

• 31:31Speaker 07

  At the same time, decades of statin research, these drugs have been around for almost 40 years.

• 31:36Speaker 05

  Forty years now. Yeah.

• 31:37Speaker 07

  Decades of research have proven the value of statins. And that research is not solely conducted by industry, but large scale work being done across the globe, not just within pharmaceutical sectors in the United States, but across the globe. And while yes, of course pharmaceutical companies love a drug that someone has to take for long periods of time, many statins today are available in a generic form. And so they're not as profitable as they once were. In any case, your primary care doc is not getting a kickback from prescribing these drugs. They simply don't want you to die from heart disease.

• 32:14Speaker 05

  It's so true, Erin.

• 32:15Speaker 07

  It's true. It's true. Okay, another big reason that people cited was side effects, including or specifically muscle symptoms. This is one of the top reasons that people stop taking or never start taking statins. Side effects are real and important to take seriously because they can truly impact quality of life. But the story of side effects when it comes to statins is complicated. Until 2001, there were very few reports of tolerability or safety concerns for people taking statins. But that year, a statin, serivastatin, was removed from the market due to safety concerns, specifically for rhabdomyolysis,

• 32:57Speaker 07

  which occurred at a rate of 0.01% in people taking it. Promptly after its removal from the market, all information sheets included warnings about, for all statins,

• 33:09Speaker 05

  All statins.

• 33:10Speaker 07

  Included warnings about muscle symptoms. And physicians counseled patients to report muscle aches as an early warning sign of rhabdomyolysis. This issue was highly publicized, as it should have been. You know, this is a potentially serious side effect. And so let's, you know, make sure you look out for this. And many patients who felt muscle aches often would interpret them as myopathy or go to their doctor with concerns about myopathy. They would stop taking statins and their symptoms improved, which reinforced the belief that these statins might be dangerous.

• 33:42Speaker 05

  Right, were the cause of that.

• 33:43Speaker 07

  The cause of that, right. And certainly, these muscle symptoms were and are real. But there is also something called the nocebo effect that seems to be at play here, at least to some degree. So the nocebo effect is the opposite of the placebo effect. It's anticipation of negative symptoms that leads you to experience them. Studies on statins have shown that when both researcher and patient don't know whether someone is getting medication, statin or placebo, both control and treatment groups experience similar rates of muscle aches, which suggests that it might not be the statins themselves directly responsible for those symptoms.

• 34:25Speaker 05

  Right.

• 34:26Speaker 07

  At least in all cases. The symptoms are absolutely real. The nocebo effect does not mean that it's all in your head. You're experiencing these symptoms. They just might not always be caused by the drug itself.

• 34:38Speaker 05

  Right. It's not like there's a direct mechanistic link between the drug that is directly causing that muscle symptom necessarily.

• 34:46Speaker 07

  Right. But it could be. It could be. And so this is where it's really, really tricky to tease apart, both for patient and provider. And so it might be just like feel like the easiest course to go, I'm just going to stop because I don't want to feel this way. I don't want to, I'm worried about this and this is hurting my quality of life. I'm going to stop. Other research has also shown that people who are exposed to more negative stories surrounding statins and side effects are more likely to discontinue use. And I think that what's also at play here is, and we kind of touched on this, is that we don't feel high cholesterol. Like, we don't feel any different when our cholesterol is low. But we do expect a lot of the time

• 35:28Speaker 07

  that the medications we take will make us feel different. We're supposed to feel better from these medications.

• 35:34Speaker 05

  We're supposed to feel something.

• 35:36Speaker 07

  Something, yeah. And so it makes sense that if you read horror stories about side effects of statins that abound on the internet, you're predisposed to expect that those bad outcomes will happen to you. And what doesn't help this is that there is a vast amount of misinformation and disinformation about statins circulating on social media and generative AI. There is a motive for people to be spreading some of this misinformation. So in fact, there was a recent study that showed that many generative AI models, when fed prompts asking about statins, especially if those prompts were leading, sort of like, what can I take?

• 36:15Speaker 05

  Isn't there some evidence of these side effects with statins? Like those kinds of questions?

• 36:20Speaker 07

  Yeah, yeah. Or like, what should I take that's safer than statins? Like, what natural product should I take that's safer than statins? But many of these models gave inappropriate and inaccurate answers.

• 36:33Speaker 05

  That doesn't surprise me at all.

• 36:34Speaker 07

  Right, right. The sheer amount of misinformation that's out there and just sort of the overall decline or disregard of expertise that's happening around the globe. Then there are the people who are very vocal in their opposition to statins that at the same time are telling you, don't go on statins, buy my red yeast rice supplement instead. Or buy this diet book. Or they're trying to make money off of you in some way. You know, subscribe to my Substack that says, you know, day one, diet with me.

• 37:05Speaker 05

  Right, I'll tell you.

• 37:06Speaker 07

  You'd throw away your statins. Yeah, yeah. And that, the thing is, like, I also understand why that's appealing when you've been dismissed by your physician or your physician is saying, it's not the statin causing this. Just like that, simply across the board. Or if you can't even afford to go see a doctor. This, this information is, is out there and that is filling a hole that you want.

• 37:30Speaker 05

  Right. And it feels like you're being taken seriously for the first time, when you're like, I went to my doctor with these concerns and you were totally dismissed. Or they were like, oh, you're fine? I'm not fine if I'm having symptoms, right?

• 37:42Speaker 07

  Yeah. And I mean, again, like, all of this, I think, what it, what it does is it speaks to a need to more closely examine the side effects that people report. Not just muscle symptoms, but the other side effects that people report and how best to address them. How best to measure them? How can we make it so that people can take drugs that will lower cholesterol and potentially save their lives? So again, what do we do about it? And I think that as a start, we can look at the reasons people take statins. So that same systematic review that I mentioned earlier also showed many people have positive sentiment towards these drugs. They trust their efficacy.

• 38:25Speaker 07

  Like, look how much my bad cholesterol dropped and my good cholesterol rose. They report that their health anxiety has eased thanks to the drugs, reporting an enhanced peace of mind. And they view them also as a way of taking control and ensuring a better, healthier future. Rebrand these drugs for what they are. Heart attack prevention, stroke prevention, a way to extend your life, your quality of life, and spend more time with the people you love, accomplishing all the things you want to do. These drugs might not make you feel any better instantaneously, but they will make it more likely that you're around to feel and do things 10 years from now.

• 39:10Speaker 07

  Having high cholesterol, it doesn't mean that you have failed. It should not be seen as shameful, as something that you should hide or feel embarrassed by. And taking these medications should make you feel like you're taking agency over your own life. Prevention is always harder, especially when the threat, like a heart attack, doesn't seem imminent or is so scary that you're like, I have to think that this won't happen to me.

• 39:32Speaker 05

  Right, right. I can't, I can't put my mind in that place.

• 39:36Speaker 07

  Yes. But that denial, it really does not serve us well. And so with that, Erin, I'm going to turn it over to you to tell us about how statins actually work and where things stand with cardiovascular disease around the globe today.

• 39:49Speaker 05

  I would love to.

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• 42:59Speaker 05

  So knowing that statins have made such a huge impact, or have the potential at least to make such a huge impact on disease, I think we first need to understand a little bit more about how they work. So I want to go through not just statins, but the strategies overall that we use today to lower LDL cholesterol specifically, how these strategies work. And then I want to wrap up by giving us all like a reminder of why lowering cholesterol is so important by looking at atherosclerotic heart disease kind of across the globe, okay? And so the first thing to know is that while statins are,

• 43:42Speaker 05

  because of how long they've been around and because of how strong the evidence is, that they are extremely effective, not just at lowering that cholesterol, but actually at preventing heart attacks, stroke and death. They are a mainstay of therapy today for cholesterol management. But they are not the only thing that we have. And the first thing that is always recommended across the board is diet and lifestyle changes.

• 44:10Speaker 07

  Yeah.

• 44:11Speaker 05

  And the thing is that we do have really decent data as far as like nutrition data goes, which we all know is limited.

• 44:19Speaker 07

  Yep.

• 44:20Speaker 05

  We do have decent data that lifestyle changes can work for a lot of people. But the problem is that we also know that your total cholesterol and your LDL cholesterol, so the packages of LDL cholesterol, are not entirely driven by your diet. They're not entirely driven by how much exercise you're getting, right? There are a lot of different things that go into determining what your cholesterol levels are and whether they are high or whether they are low. And one of the big things is our genetics. You talked in last week's episode, Erin, about familial hypercholesterolemia.

• 45:03Speaker 05

  This is one, or really kind of like one group of disorders that can seriously contribute to elevated cholesterol, especially LDL cholesterol. But it's not the only one. There are a whole bunch of other genetic contributions, whether that's multiple genes or things that we don't even know yet, right? Genes that we haven't even discovered yet that are associated with the like ratios and amounts of cholesterol. Whether that's because these genes affect how we recycle cholesterol, whether they affect how much cholesterol we produce in our liver, or whether, like in familial hypercholesterolemia, they affect our LDL receptors and how good our cells are

• 45:46Speaker 05

  at taking that cholesterol out of our bloodstream.

• 45:49Speaker 07

  Right.

• 45:49Speaker 05

  Right? So all of these things are going to play a role as well as our dietary factors and our lifestyle factors. And so that is usually the first thing that any physician is going to recommend if someone's cholesterol is elevated, is can we bring this down by reducing or stopping smoking, if you smoke? Because that has a huge effect. Lowering the amount of alcohol that you drink, which is going to help to lower your cholesterol levels. Switching out saturated fats in your diet for unsaturated fats, right? Switching out animal products for plant products. These are the kinds of dietary changes that we have good data to say that not only do they reduce your cholesterol levels,

• 46:34Speaker 05

  but they also can actually prevent cardiovascular disease. We have that data. It exists. But for many people, that isn't sufficient. And so that is when it is recommended that medication is actually used, right? Whether it's because somebody can't or doesn't want to change their diet or exercise, or they can't increase physical activity, or they are literally already doing the most. And it's still not enough. And that happens so, so, so often.

• 47:03Speaker 07

  Right. And I think it's like, this is where I feel like it can feel like I have failed, or I thought I was trying my best to do all these things and still it's not working. And it's like, that, that's okay. Like, this is not your, you're not a failure of...

• 47:19Speaker 05

  No.

• 47:20Speaker 07

  Yeah.

• 47:20Speaker 05

  No, it's, that's so true, Erin. Like, I, I see people in clinic all the time that this happens to, and I just say blame your parents. Like, it's probably your genes. Okay, so let's then talk about what are some of the big medicines that we use? And how do they actually work? Why are they working, right?

• 47:39Speaker 07

  Yes.

• 47:40Speaker 05

  Statins. So statins block an enzyme in our liver that's called HMG-CoA reductase. The Cliff Notes version is that this particular enzyme, HMG-CoA reductase, this one, is the rate-limiting step in cholesterol synthesis in your liver. So that enzyme is necessary in our liver for our liver to make cholesterol. And remember, our liver is making over 50% of the cholesterol floating around in our body, right?

• 48:12Speaker 07

  So you have, if you have more HMG-CoA reductase, then you have more cholesterol photogram in your body. If you reduce that reductase, that enzyme, then you have less cholesterol.

• 48:21Speaker 05

  And Erin, it goes even further than that, okay? Because what happens is that by blocking this enzyme in particular, because it is the rate-limiting step, meaning it's like the slowest one in the daisy chain, right? When you're moving stuff into a house. We dramatically reduce, not just like a little bit, do we reduce how much cholesterol your liver's making, you're dramatically reducing, like putting a huge brake on how much cholesterol your liver can make. And because all of our cells still need cholesterol, our cells have to get better at taking cholesterol out of our bloodstream. So they actually up-regulate those LDL receptors, those Velcro sticky hands on the surface of their cells

• 49:04Speaker 05

  that capture our LDL cholesterol floating around in our bloodstream. So it's not just that, oh, we're not making as much cholesterol. It's that we're not making as much cholesterol and our body cells still need cholesterol, so they start vacuuming it out of our bloodstream at really high rates.

• 49:20Speaker 07

  Beautiful.

• 49:21Speaker 05

  Isn't that cool?

• 49:22Speaker 07

  Oh, yeah.

• 49:23Speaker 05

  I love that. There's also some interesting evidence that statins also might have a little bit of like an anti-inflammatory effect as well.

• 49:31Speaker 07

  Yeah.

• 49:31Speaker 05

  And we talked in last week's episode about how important inflammation is in the process of atherosclerosis or in the process of that cholesterol actually forming a plaque in your bloodstream. Inflammation is an integral part of that. And so there's some thought that there's also an anti-inflammatory effect of statins, though we don't fully understand that mechanism there. So that's how statins work. And they're incredibly effective, Erin. There was a meta-analysis from 2016 that was really interesting. So it's kind of old now, but it looked at over 50 different studies that looked at all the different possible interventions that we had at that time and all of the like randomized control trials of those different interventions

• 50:16Speaker 05

  and the effect of lowering LDL cholesterol on cardiovascular disease risk by these different interventions, okay? We had 25 trials on statins. 25 of them compared to only four diet trials, compared to only two at the time on PCSK9 inhibitors, which I'll get to in a second.

• 50:37Speaker 07

  Right.

• 50:38Speaker 05

  One on ezetimibe, which is another medicine that we use. And so what that means is not only do we have so much data on their effect, it also means that our confidence intervals on just exactly how effective they are are really narrow for statins. So we know, like, without a doubt, that statins are extremely effective at lowering our LDL cholesterol and at reducing the risk of adverse cardiovascular events, period.

• 51:05Speaker 07

  Is that what, what did that study show? The meta-analysis show in terms of like the by-the-numbers impact?

• 51:11Speaker 05

  So by the numbers, statins are the most consistent. Diet is a, is, has a slightly less effect, but still a significant effect.

• 51:19Speaker 07

  Okay.

• 51:19Speaker 05

  PCSK9s, which I'll get to in a second, have the greatest effect. They lower LDL cholesterol the most and they reduce your risk the most. But the confidence intervals are super wide, because at least at that time, we just didn't have as much data on them.

• 51:31Speaker 07

  Right, right.

• 51:33Speaker 05

  Yeah. And then the other ones are in between. But statins are like, like pound for pound, I guess? I don't know if that's right. But like incredibly effective and like just so much good data to support them.

• 51:42Speaker 07

  Right. We're really dialed in on, on how statins work and how well they work. Are there, what are the differences between different types of statins?

• 51:50Speaker 05

  Great question. So different types of statins, a lot of the difference is in their potency. So some statins can lower your LDL cholesterol to a much greater degree than other statins. The exact of like, why? I don't know, okay? But that means that we have statins that vary in what we call their intensity. And by intensity, we mean how much? By what percentage are we lowering your LDL cholesterol? So if I can give you a medicine that's going to lower your LDL cholesterol by at least 50%, that's considered a high-intensity statin regimen. And if it's by less than 30%, then that's considered a low-intensity regimen. And then there's intermediate in between.

• 52:33Speaker 07

  Okay.

• 52:34Speaker 05

  Okay.

• 52:34Speaker 07

  Yeah.

• 52:35Speaker 05

  Moderate. There's also differences in like, some of them are more lipophilic, so they're more like fats. And some of them are more hydrophilic, so they're more like, they act more like proteins in that they're more like soluble in water. And so that might differ in how much they build up in different tissues in your body. But there's not great data that says that one is more or less likely to cause side effects than the other. And that's the next thing I want to briefly talk about. Because it's an important part of the statin story. And you mentioned it as well, Erin. It is not the case that side effects don't exist.

• 53:11Speaker 07

  Right.

• 53:12Speaker 05

  Any medication, any therapy really, has the potential to cause side effects. And like you mentioned, Erin, the most cited side effect that causes people to stop taking a statin medication is muscle symptoms. And that's a really general term. It's often muscle pain or muscle aches, or sometimes muscle weakness. Now, there's also other things like gastrointestinal side effects or liver enzymes can increase, which is usually transient and can be completely reversed either by going down on the dose or stopping the statin. But muscle effects are like the, the big one, right? And there was a recent meta-analysis that looked at data from randomized controlled

• 53:56Speaker 05

  trials from over 150,000 people and 23 different studies that were comparing either statins versus placebo or different intensities of statin, so that high intensity versus low intensity therapy. And what they found is not that muscle symptoms were never reported by any means, but that by comparing all these different regimens, what they estimated was that less than 10% of all of the reports of muscle symptoms could actually be directly attributed to statins themselves. Does that make sense?

• 54:33Speaker 07

  I think so. So the, it's not talking about the rate of side effects that happen, but how much of those side effects are statins directly responsible for?

• 54:44Speaker 05

  Exactly.

• 54:45Speaker 07

  And is this based on, like, do we understand the mechanism?

• 54:49Speaker 05

  Oh, such a good question. We don't. We don't. Because the vast majority of these, even the side effects that could be attributed to statins are considered mild. A lot of people actually will continue their statin and the amount of people who report symptoms after the first year actually goes down. So it's usually in that first year of therapy. Realistically, it's usually within the first few weeks or months of starting a statin medicine that people are more likely to have effects directly related to the statin. But no, we don't understand exactly the mechanism. But most of them are mild and they do not result in actual damage to the muscle tissue or myopathy. Now, that does not mean that they can't ever, right?

• 55:33Speaker 07

  Right.

• 55:34Speaker 05

  There are more serious events like rhabdomyolysis, and that is estimated to occur about four excess cases per 10,000 people if you're on a high intensity statin. Doesn't mean there's only four, but like, some people get rhabdo that has nothing to do with statins?

• 55:49Speaker 07

  Right, right, right.

• 55:50Speaker 05

  So statins, we'll call it four excess cases for every 10,000 people on a high intensity statin.

• 55:56Speaker 07

  Is it more common? Okay, you were about to say?

• 55:58Speaker 05

  Yes, yeah. And one per 10,000 on less intensive. So it does go up, like, the chances of side effects and the chances of more severe side effects go up with intensity. So sometimes just going down from a high intensity regimen to a lower intensity regimen takes away side effects entirely for people, and that's enough. And then you're still getting some benefit, just maybe not quite as much as you were on a high intensity regimen.

• 56:21Speaker 07

  Okay, question about that meta-analysis. You said that 10% of the side effects experienced are directly attributable to statins. What is the 90%? Where does that get attributed to?

• 56:33Speaker 05

  I don't know. I don't, we don't have an answer to that.

• 56:36Speaker 07

  The paper didn't suggest any, any answers?

• 56:39Speaker 05

  No. No, I mean, some of it, they're like, is it just aging? Is it just placebo effect? Is it like a bunch of different possible things, but not like a clear answer? No.

• 56:50Speaker 07

  And so this was like, by looking at people who are on placebo are still experiencing these side effects and we don't know what's causing that? Okay.

• 56:57Speaker 05

  Right. So then you're looking at like, how many excess cases? How many excess reports will you get? It was estimated like 11 reports of muscle pain or weakness per 1,000 people on statins in that first year were from statins.

• 57:12Speaker 07

  Okay.

• 57:13Speaker 05

  11 per 1,000.

• 57:14Speaker 07

  Right.

• 57:15Speaker 05

  So.

• 57:16Speaker 07

  It's tricky. It's really, really tricky.

• 57:18Speaker 05

  It's really, really tricky because it's not that these symptoms are not real, right? And, and if you are one of those people who has that severe side effect, right, one of four per 10,000, that's a very real effect for you. And so it is always a tricky thing to balance because when we are talking about treating and preventing, especially when we're talking about preventing cardiovascular disease, we are talking both about population level reductions in risk and we're also talking about an individual risk benefit calculation, right?

• 57:54Speaker 07

  Right.

• 57:55Speaker 05

  And so, and those are not the same calculations on a population scale versus on an individual scale.

• 57:59Speaker 07

  Yeah.

• 58:00Speaker 05

  And yeah, it doesn't help when people's symptoms are completely ignored, or when they're told, oh, it's absolutely not from this.

• 58:06Speaker 07

  Right.

• 58:07Speaker 05

  Or when they're told from wellness influencers online that this medication that they've been on safely for 10 years is now causing the symptoms that they're having, right?

• 58:17Speaker 07

  Yeah, yeah, yeah, yeah.

• 58:18Speaker 05

  Which I see all the time.

• 58:19Speaker 07

  I mean, I think that what is a real challenge too is like, how do you balance saying, okay, these are real symptoms. You are experiencing this. This is very real. And deciding, is this caused by the statin? Is this not caused by the statin? Are you going to be someone who is the 0.001%? And then it's like, even if these side effects are not directly caused by the statin, they're still impeding your ability to say, exercise or something like that. And so it's like, it's just-

• 58:48Speaker 05

  Which is gonna be helpful for your health.

• 58:49Speaker 07

  Right. It's a mess. I'm very curious to hear suggestions on how to approach this.

• 58:55Speaker 05

  I mean, I don't know, like, I really think that what it always has to come down to is a good relationship with a physician or provider that you trust, right? Who knows you, who you know, who can explain these things to you. And like, it's why I don't think AI can take over for all doctors, Erin, but maybe that's my bias.

• 59:14Speaker 07

  Well, it's not, but I think it is the way that medicine is going and like, and has been trending in the last 20 years, more expensive, shorter visits, more video visits that don't always necessarily feel like you're having a connection with someone.

• 59:32Speaker 05

  Right.

• 59:33Speaker 07

  It all is just standing in the way of forming these relationships.

• 59:36Speaker 05

  I know. Cause they're the most important thing in my highly biased opinion. Okay, but we have more options too. Some people are gonna have side effects from statins, or they're just like, no, I will not take a statin. Cool. Don't worry. We have other options now. And I'm not gonna go through every single one, but I'm gonna call out two that are probably like the two biggest groups that we use. One is called ezetimibe. And this is a drug that blocks a protein that's in the cell membranes of our guts and our bile ducts. So what this does is it blocks the amount of cholesterol that we are absorbing and reabsorbing. So this one, it doesn't have as huge of an effect

• 1:00:19Speaker 05

  by any means, but it can still lower cholesterol, often by like 10%. We're talking LDL cholesterol. It can lower you. So that's not nothing to shake a stick at. So now let me talk about the one that people are so excited about and that I said multiple times, that is a nonsense word called PCSK9 inhibitors.

• 1:00:38Speaker 07

  PCSK inhibitors, yes.

• 1:00:39Speaker 05

  PCSK9 is the shorthand name for a protein that I'm not gonna tell you the name of because I don't know it, it's too long. But this is a protein that our liver makes. It's really interesting. Its job, this protein, is to degrade, break down LDL receptor proteins. Okay? So this protein is kind of like an anti-recycler of this protein, of this receptor, who usually collects the LDL in our bloodstream. Okay?

• 1:01:11Speaker 07

  Yeah.

• 1:01:12Speaker 05

  Why does this protein do this?

• 1:01:14Speaker 07

  Yeah.

• 1:01:15Speaker 05

  I don't know right now, but that is what it does. So if you can block this enzyme, this protein, then you will have more LDL receptors available to be reused and recycled to be collecting our LDL cholesterol in our bloodstream.

• 1:01:33Speaker 07

  So this is like a Velcro glove thief, this, this protein?

• 1:01:40Speaker 05

  Yeah, the protein, yeah, PCSK9, exactly. It's a Velcro glove thief.

• 1:01:44Speaker 07

  Then the Velcro gloves are numerous and available to catch all those tennis balls of LDL.

• 1:01:51Speaker 05

  I really like this analogy, by the way.

• 1:01:53Speaker 07

  It's a really good analogy. I'm, yeah.

• 1:01:55Speaker 05

  Thanks. You know, I don't always come up with good ones, so.

• 1:01:57Speaker 07

  I mean, the best I could do was Bill Buckner, so.

• 1:01:59Speaker 05

  I really enjoyed that. So much more than I can say. Yeah. So that is how PCSK9 inhibitors work. The, the main group, like, there's a couple of different medicines that we use that are mostly monoclonal antibodies. They're really interesting because a lot of times, like, they're not a pill that you have to take every day. It's like an injectable medicine that you take every week or two weeks, depending on the medicine. There's also something called inclisiran, which is a small interfering RNA molecule, okay, that binds to this protein's, PCSK9's mRNA and degrades it. So it's also affecting that same system. It's just not blocking the receptor itself.

• 1:02:44Speaker 05

  Isn't that so cool?

• 1:02:45Speaker 07

  Wow.

• 1:02:46Speaker 05

  And the data on all of these medicines that affect PCSK9, it is incredibly strong. So we talked about that meta-analysis from 10 years ago or so. PCSK9 inhibitors reduce your LDL drastically and can drastically also reduce cardiovascular events, especially in people who are very high risk, meaning people that we are doing secondary prevention.

• 1:03:10Speaker 07

  Right.

• 1:03:10Speaker 05

  Who already have, you know, cardiovascular disease, who have maybe already had a heart attack or a stroke, and we really need to lower that cholesterol, or people who are just very high risk, right? So in those populations is mostly where it's been studied. And so cardiologists love this medicine. The biggest issues are, as with all new drugs, especially ones that are fancy things like siRNA and monoclonal antibodies, they are expensive as heck. Especially in this country. We also just don't have nearly as much data on them as we do for statins. So the error bars on their benefit is still messier, even though they still have a really good effect.

• 1:03:54Speaker 07

  Do we have information about side effects?

• 1:03:57Speaker 05

  That's a great question. I should have looked into it more. There definitely can be side effects, but I honestly just did not do a good job of looking into them as much. So I will get back to you on that.

• 1:04:08Speaker 07

  Okay. And then I have a question sort of like about lowering. So we've talked about lowering and the importance of having lower levels, but there is such a thing as too low. What are consequences of that?

• 1:04:23Speaker 05

  That's a great question. I don't have a number for you.

• 1:04:26Speaker 07

  Okay.

• 1:04:28Speaker 05

  What the data shows is that the higher your individual risk of cardiovascular disease, right? Because cardiovascular disease is not only cholesterol.

• 1:04:40Speaker 07

  No, no, no.

• 1:04:40Speaker 05

  I hope that I have made that clear. It is not by any means only cholesterol. But lowering cholesterol is one of the big ways that we have to reduce the chances that you're going to develop or have really bad outcomes like a heart attack or a stroke or death from cardiovascular disease. And so what we know is that the higher your individual risk, based on all of your other risk factors, age, whether or not you smoke, how much alcohol you drink, your BMI, your blood pressure, whether you're on a blood pressure medicine, your kidney function, based on all of those things, the higher your risk, the lower we need to push your cholesterol to really lower your risk of bad outcomes.

• 1:05:20Speaker 07

  Okay, okay.

• 1:05:21Speaker 05

  So people who are very high risk, in the newest guidelines, people who are very high risk, the recommendation is to reduce their LDL to less than 55. And that's very low, and we haven't seen any bad outcomes from that, meaning we haven't found a number that is too low for those people who are very high risk.

• 1:05:39Speaker 07

  Okay.

• 1:05:40Speaker 05

  But for other people, we haven't necessarily shown that there is a benefit to pushing them that low.

• 1:05:47Speaker 07

  Okay.

• 1:05:48Speaker 05

  And so for most other people, the recommendation is going to be either less than 70 or less than 100, depending again on what your risk is of cardiovascular disease development.

• 1:05:58Speaker 07

  Huh.

• 1:05:59Speaker 05

  Yeah.

• 1:06:00Speaker 07

  So prolonged use of statins or like long time use of statins, basically if your blood cholesterol is high enough that you need to be on a statin or you are prescribed a statin.

• 1:06:09Speaker 05

  Or another lipid lowering medicine.

• 1:06:11Speaker 07

  Or something like that. You are on that regimen for the rest of your life?

• 1:06:16Speaker 05

  Often, yeah. Often, yeah. That, because again, that's the data that we have, right?

• 1:06:23Speaker 07

  Right.

• 1:06:23Speaker 05

  And we'll talk in a second about how much atherosclerosis is, it is a disease of, of long-term, right?

• 1:06:32Speaker 07

  Yeah.

• 1:06:32Speaker 05

  It's not a, it's not a short term, it's not the rabbits that just get it in a week or two.

• 1:06:37Speaker 07

  Yeah.

• 1:06:37Speaker 05

  It is a long-term disease kind of thing. And so that is why it requires long-term management.

• 1:06:43Speaker 07

  Plax weren't built in a week, just like Rome wasn't built in a week or whatever.

• 1:06:48Speaker 05

  Exactly. Isn't it a day?

• 1:06:51Speaker 07

  Probably. I'm terrible with like sayings like that. I cannot remember them. I mix my metaphors constantly.

• 1:06:57Speaker 05

  I love it. I want to just briefly, like, shout out is not the right word. Poo-poo upon rage about.

• 1:07:06Speaker 07

  Rage, okay, sure.

• 1:07:08Speaker 05

  Because there, there is a lot out there right now on like, oh, alternative types of medicines to lower cholesterol. And I'm not talking about lifestyle interventions like diet and exercise changes. We already talked about those. They have decent evidence. They're an important part of this. But one of the things that some people use or claim to have a benefit in lowering cholesterol are phytosterols, right? Those are plant-based cholesterols. And it is possible, based on some like observational data, that consuming high levels of these plant-based cholesterols or plant-based sterols might decrease LDL cholesterol, especially when you look at people on like vegan diets who have quite a lot of phytosterol consumption

• 1:07:52Speaker 05

  or who are taking other, you know, additives of phytosterols. But we have no randomized control trial data on these. And the data that do exist, what's really interesting is that they seem to be most effective when they're consumed with meals, meaning when you're getting it from foods rather than just a supplement or an addition.

• 1:08:15Speaker 05

  And of course, as we talk about so often on this podcast, Erin, there are no regulations on supplements, whether we're talking about phytosterols or other nutraceuticals. And one of the big ones out there for cholesterol is red yeast rice. You mentioned it, Erin. The mechanism of the compound produced by this yeast that's grown on rice is that it blocks HMG-CoA reductase.

• 1:08:46Speaker 07

  It's a statin.

• 1:08:47Speaker 05

  It's a statin.

• 1:08:48Speaker 07

  But because it's coming from a, it's extracted from a plant, plants produce different levels of these things, and so you have no idea how much you're getting. And so it can be dangerous. You could be on very low dose, non-existent dose versus intense, high intensity or whatever.

• 1:09:04Speaker 05

  And most brands in studies that have looked at this have no detectable levels of that actual compound, right?

• 1:09:13Speaker 05

  There's no regulation on the composition of those particular supplements. There's no regulation on how much of that compound, like you said, the yeast is actually going to produce when it's fermented. So there's batch to batch variation, there's brand to brand variation. And at the end of the day, it's an unregulated statin.

• 1:09:29Speaker 07

  It's unregulated.

• 1:09:31Speaker 05

  Yeah. And, and I don't want to make that sound like, oh, well pharmaceutical companies are just the best thing ever.

• 1:09:38Speaker 07

  Right, no, no.

• 1:09:39Speaker 05

  They're not. And it's also not the case that our guidelines might not be subject to some degree of bias because, like you mentioned, of the conflicts of interest that exist within cardiology and within, like, I mean, all fields of medicine realistically. A good number of the authors and the people who were involved in the peer review process for the newest dyslipidemia guidelines in the US have financial conflicts of interest, not just with pharmaceutical companies, but with imaging companies, with genetic testing companies. And that doesn't mean that all of our data that we have that is so strong isn't real or isn't strong, but it just muddies these waters even more. And it, it creates this gap where people can really exploit that uncertainty.

• 1:10:24Speaker 07

  Totally.

• 1:10:25Speaker 05

  And it's really, really a bummer because atherosclerotic heart disease, including heart attack and stroke, kills an estimated 19 million people worldwide every year as of the 2023 Global Burden of Diseases Study.

• 1:10:41Speaker 07

  Wow, yeah.

• 1:10:42Speaker 05

  An estimated 600 million people are living with cardiovascular disease right now. Every, across the globe. Cardiovascular disease is the leading cause of disability-adjusted life years. In some countries, it is a third to 40 to 45% of all deaths. And of course, especially in this country, the estimated costs to healthcare are in the hundreds of billions of dollars. And an estimated 80% of this disease is due to modifiable risk factors. And cholesterol, this relationship between LDL cholesterol and cardiovascular disease

• 1:11:26Speaker 05

  is so incredibly clear, and it is something that we really have the potential to treat, right?

• 1:11:34Speaker 07

  Yeah.

• 1:11:34Speaker 05

  So it's, uh, it's such a huge bummer that there are so many people who do not have access to this, right? And it's not just older adults. I think that we think of cardiovascular disease as something that only happens to older people. But the more that we look at and study the like pathogenesis of cardiovascular disease, the more we understand that especially cholesterol is a long-term exposure that increases your risk.

• 1:12:09Speaker 07

  Yeah.

• 1:12:09Speaker 05

  So having exposure to higher levels, greater than 100 of LDL cholesterol, especially greater than 160, younger in life and for longer periods, increases your risk more than if it just goes up over time, if that makes sense.

• 1:12:25Speaker 07

  Yes, it does make sense.

• 1:12:26Speaker 05

  And it's estimated that 12 to 13% of young adults have dyslipidemia in this country.

• 1:12:32Speaker 07

  Wow.

• 1:12:32Speaker 05

  So that's not a small number, right? It's estimated that in the US, if everyone, based on guidelines, who was recommended to be on medicine to lower their cholesterol, was actually on a medicine for this, like a statin, we could prevent 1 million cardiovascular disease events like heart attack, stroke, and death in 10 years. A million.

• 1:12:55Speaker 07

  Whoa.

• 1:12:56Speaker 05

  Okay. And, and that's just in the US where we have much better access. In low and middle income countries, it's estimated that only 1 in 10 people who would be recommended to be on some kind of medicine to lower their cholesterol are actually on a medicine because they don't have access, right? So that's a lot, Erin.

• 1:13:16Speaker 07

  It's a lot, Erin.

• 1:13:17Speaker 05

  It's a lot.

• 1:13:20Speaker 05

  But there is, I just think it's one of those situations where medicine has come so far, right? And the data that we have is so strong, but it's also not all just one thing. And I think that that is where some of the kind of confusion and uncertainty and doubt can come from, right? Because we look at cardiovascular disease events over time, they're still going up, right? But we have these great medicines, but they're still going up.

• 1:13:52Speaker 07

  Yeah.

• 1:13:53Speaker 05

  And that's because it is so many other things that play into it. So this was not an episode just only about cardiovascular disease, but cholesterol overall. And that is what I have to say, Erin.

• 1:14:04Speaker 07

  It is really complicated and it's so recent. And I think that's what contributes a lot to this. And it does go to show that you can have the data, you can have the treatments, you can have the, like, all of these different facets of, in support of this. And that's not enough. And so figuring out that gap, what will make, what will be enough? How do we actually either get the treatment to people who need it? How do we actually develop better treatments? Whatever it is.

• 1:14:37Speaker 05

  Right.

• 1:14:38Speaker 07

  How do we address those gaps where we're clearly failing?

• 1:14:41Speaker 05

  Yeah.

• 1:14:42Speaker 07

  Yeah.

• 1:14:43Speaker 05

  It's a great question, Erin.

• 1:14:44Speaker 07

  Hopefully someone figures it out.

• 1:14:46Speaker 05

  Yeah. If you want to read so many papers about how we got all of this information, we can tell you.

• 1:14:54Speaker 07

  We can tell you. I also want to shout out real quick, too, that they're speaking, like, on the subject of misinformation and social media wellness influencers, health influencers, stuff like that. There is, next week's book club episode is an interview with Deborah Cohen. It's a book called Bad Influence. And it's really a fascinating conversation. Definitely tune in. There's a whole, we have a little bit about statins in there, so check it out.

• 1:15:23Speaker 05

  Yeah.

• 1:15:24Speaker 07

  But papers for this episode. Okay, I have a bunch more. Again, I'll shout out again, that Steinberg series from 2004, An Interpretive History of the Cholesterol Controversy. Then by Ju et al. from 2018, Patient Beliefs and Attitudes to Taking Statins. And then by Endo, A Gift from Nature: The Birth of Statins. So that's the person who.

• 1:15:46Speaker 05

  Oh, I love it. Let me tell you where you can learn more. I really liked a paper by Silverman et al. from JAMA 2016. That was The Association Between Lowering LDL-C, which is LDL cholesterol, and cardiovascular risk reduction among different therapeutic interventions: A Systematic Review and Metaanalysis. That's the one that has really great graphs, honestly, on like, with the error bars and the risk reduction, loved it. I have links to the newest guidelines as well, too. The study looking at the, like, overall risk of cardiovascular disease and heart attack was from the Journal of American College of Cardiology from 2023. And that was one of the global burden of disease studies. So we have that one. There's also that 2022 paper by Reif et al. in The Lancet.

• 1:16:30Speaker 05

  That was The Effect of Statin Therapy on Muscle Symptoms and Individual Participant Data Metaanalysis of Large-Scale Randomized Double Blind Trials. But honestly, there's so much more there, Erin. So you, everyone can check it out on our website, thispodcastmckinney.com, under the Episodes tab.

• 1:16:46Speaker 07

  Thank you to Blood Mobile for providing the music for this episode and all of our episodes.

• 1:16:51Speaker 05

  Thank you to Leanna and Tom and Mark and Jessica and everyone at Exactly Right for everything that you do to make this podcast possible.

• 1:16:58Speaker 07

  Thank you, thank you. And thank you to you, listeners, subscribers, watchers, et cetera. We appreciate you engaging with this podcast so much. I know it sounds so clinical when I say that, but what I mean is like, anyone who is like, follows us on social media.

• 1:17:14Speaker 05

  Yeah.

• 1:17:15Speaker 07

  Whatever, anyone, it is, it truly means everything.

• 1:17:18Speaker 05

  It does.

• 1:17:18Speaker 07

  Thank you.

• 1:17:18Speaker 05

  Thank you. And thank you, as always, to our patrons for your support over on Patreon. It means, like, I can't believe that you're supporting us there. Thank you.

• 1:17:28Speaker 07

  Yeah.

• 1:17:28Speaker 05

  It really means a lot.

• 1:17:30Speaker 07

  Until next time, wash your hands.

• 1:17:32Speaker 05

  You filthy animals.

• 1:18:00Speaker 01

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  We have a new podcast. It's called Don't Lie to Me.

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  And I'm Lisi DiGiulio, the old one, which means we have wildly different references, occasionally different opinions, and at this point in my 50s, I've lived it all.

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