Speaker 1: I was born into a rural farming family in northern Japan,
Speaker 1: where I lived for seventeen years with my extended family,
Speaker 1: including grandparents, parents, three brothers, and two sisters. My grandfather,
Speaker 1: who had an interest in medicine and science, was a
Speaker 1: great home teacher to me thanks to his influence. At
Speaker 1: the age of eight, I dreamt of becoming a scientist.
Speaker 1: After finishing high school in Akida, I entered to Hoku
Speaker 1: University's College of Agriculture in Sendai in nineteen fifty three.
Speaker 1: As a student, I was deeply impressed by the knowledge
Speaker 1: that antibiotics had saved the lives of many patients with
Speaker 1: infectious diseases. I received a PhD degree from Tohoku University
Speaker 1: in nineteen sixty six. At this point, I became interested
Speaker 1: in cholesterol biosynthesis. I eventually studied from September nineteen sixty
Speaker 1: six to August nineteen sixty eight at the Albert Einstein
Speaker 1: College of Medicine in New York. At that time, coronary
Speaker 1: heart disease was the main cause of death in the
Speaker 1: United States. The number of people with hypercholesterolemia, a precursor
Speaker 1: to coronary heart disease, was said to exceed ten million.
Speaker 1: My experience of living in New York made me realize
Speaker 1: the importance of developing a cholesterol lowering drug. After coming
Speaker 1: back to Tokyo in nineteen sixty eight, Sankyo Research Laboratories
Speaker 1: gave me an opportunity to work on a project of
Speaker 1: my own. Choosing I speculated that fungi like molds and
Speaker 1: mushrooms would produce antibiotics that inhibited hmg CoA reductase compactin
Speaker 1: seemed to be a wonderful gift from nature.
Speaker 2: I want to know everything more that you're about to
Speaker 2: tell me. You from that story, you will, you will.
Speaker 1: So that was excerpted from actually two different articles written
Speaker 1: by Akira Endo, who was the father of statins. He
Speaker 1: discovered the first statn and he has written about this
Speaker 1: in multiple different places. But this was from two papers,
Speaker 1: one from two thousand and eight and one from twenty ten,
Speaker 1: and we'll have them in our show notes. But yeah,
Speaker 1: I loved, I love, just like I'm still amazed at
Speaker 1: the logic link leap that it is.
Speaker 2: That's what I that's what I want. I want so
Speaker 2: much more of that. Like what was he thinking and
Speaker 2: how did he piece these things together? And like I
Speaker 2: want to know it all because I'm really, I'm really,
Speaker 2: I'm really excited for this episode. Erin, should we.
Speaker 3: Yeah, me too, Me too, It's going to be great. Hi.
Speaker 2: I'm Aaron Welsh and I'm Erin allman Updyke.
Speaker 3: And this is this podcast will kill you.
Speaker 2: Welcome to Cholesterol Part two, Part two where we love in.
Speaker 3: Blue Blue Yes, good ones. Yeah, yeah to this.
Speaker 1: So if you didn't listen to last week's episode, you
Speaker 1: really should because it'll give you some great foundation for
Speaker 1: understanding why cholesterol does what it does in our bodies
Speaker 1: and why certain levels of different types of cholesterol mean disease.
Speaker 2: I know that we're biased, but I think it's a
Speaker 2: great episode. You haven't listened to it, check it out.
Speaker 2: And then today we're going to build on so much
Speaker 2: of that and talk about how we deal with high
Speaker 2: cholesterol and how we figured out how to deal with it,
Speaker 2: and it's going to be really great. Yes, But before
Speaker 2: we can start, it's quarantine time.
Speaker 1: It is once again we are drinking plack attack.
Speaker 3: Again.
Speaker 1: Are we attacking plaque? Is plac attacking us?
Speaker 2: A little bit of both? Yes, with black clack attack.
Speaker 1: It's a pretty it's a pretty delicious, straightforward, nothing to
Speaker 1: do with cholesterol, just delicious. It's blueberries smashed with lemon
Speaker 1: juice and uh club soda and simple syrup.
Speaker 2: And it meant.
Speaker 1: I haven't putten down and yet it's like not, I
Speaker 1: just didn't pull it up.
Speaker 2: So we'll post the full recipe on our website, this
Speaker 2: podcast with Killy dot com on our social media's which
Speaker 2: include Instagram and blue Sky and Facebook, Facebook and TikTok.
Speaker 2: I don't know if it's there on TikTok though, listen,
Speaker 2: just follow us there.
Speaker 3: You'll see what we're up to here, Absolutely you will.
Speaker 1: Yeah, you can also see a little bit of what
Speaker 1: we're up to by going to our website.
Speaker 3: This podcast will kill You dot com. It's got yeah,
Speaker 3: not not quite, but like it's got.
Speaker 1: It's got resources, right, got lots. We've got all of
Speaker 1: the papers we use for all of our episodes. It's
Speaker 1: got links to our bookshop dot org, affiliate page, music
Speaker 1: by Bloodmobile, links to merch links to Patreon, it's got
Speaker 1: a first hand account, form of contact us form things
Speaker 1: that everything explore.
Speaker 2: Everything we could think of is there.
Speaker 3: Yeah.
Speaker 2: Thank you to everyone who has rated and reviewed and
Speaker 2: subscribed on your podcatcher or YouTube of choice.
Speaker 3: Yes, yes, we appreciate it. We do. I know, we know.
Speaker 1: There are so much media out there that you can consume,
Speaker 1: and so it means truly, it means so much to us.
Speaker 1: It feels surreal that you're choosing to spend any time
Speaker 1: with us.
Speaker 2: I don't know. Every time and says they listen, I'm
Speaker 2: like to me to us, what really, Yeah, it's incredible,
Speaker 2: thank you, thank you. Okay, Aaron, tell me about this
Speaker 2: guy and how he came up with statins and everything else.
Speaker 1: Okay, absolutely, let's take a quick break and we'll do
Speaker 1: all of that.
Speaker 3: Last week I took us.
Speaker 1: Through the story of cholesterol and how it earned its
Speaker 1: reputation as a major cause of cardiovascular disease. Over the
Speaker 1: course of about seven decades, from the nineteen tens to
Speaker 1: the early nineteen eighties, researchers put the pieces of the
Speaker 1: cholesterol puzzle together using a wide range of studies. We
Speaker 1: had experimental ones like A. Nich Coow's athrosclerotic rabbits. There
Speaker 1: were analytical epidemiological ones like the Framingham Heart study, genetic ones,
Speaker 1: and mechanistic ones like Brown and Goldstein's Nobel Prize winning
Speaker 1: work characterizing the LDL receptor, lots of different studies.
Speaker 3: Different lines of evidence.
Speaker 1: Yes, yes, And this week I'm going to pick up
Speaker 1: with the final piece of this puzzle, cholesterol lowering drugs
Speaker 1: and some of the controversy that surrounds them.
Speaker 3: By the nineteen seventies, much of.
Speaker 1: The cardiology world, like researchers, physicians, and institutes, they saw
Speaker 1: the link between cholesterol and cardiovascular disease as a done deal.
Speaker 1: This is established, Okay, now let's proceed from here. But
Speaker 1: that knowledge didn't reach beyond that realm of experts, and
Speaker 1: many physicians remained either skeptical or oblivious to this new knowledge. So,
Speaker 1: for example, a nineteen eighty three study of internists in
Speaker 1: the US showed that fifty percent did not recommend any therapy,
Speaker 1: including diet, for cholesterol lowering unless levels were over three hundred.
Speaker 2: Fast total in like the mid eighties.
Speaker 3: Based nineteen eighty three.
Speaker 1: Yeah, wow, yeah, it just it also shows how quickly
Speaker 1: things have shifted.
Speaker 2: Yeah, which is so interesting also because I just think about,
Speaker 2: like we've talked about before, how slow changes in medicine,
Speaker 2: and like, there are plenty of people practicing today who
Speaker 2: were probably practicing in the eighties, like getting trained in
Speaker 2: the eighties, so that it's just so interesting.
Speaker 3: Yeah, yeah, it is.
Speaker 1: It is really interesting, and I think it also like,
Speaker 1: okay for you today this I wanted to share more
Speaker 1: of these numbers because I think it'll come as a
Speaker 1: real like double take.
Speaker 3: Yeah, exactly.
Speaker 2: So.
Speaker 1: Of that of those fifty percent who wouldn't recommend any
Speaker 1: therapy unless over three hundred hundred, nearly half said no
Speaker 1: therapy unless levels or over three point forty three, and
Speaker 1: twenty seven percent of those said that they would never
Speaker 1: recommend drug treatment under any circumstances for cholesterol.
Speaker 3: For cholesterol.
Speaker 1: Yeah, So what would it take for high blood cholesterol
Speaker 1: to be seen as a pressing public health issue, at
Speaker 1: least among all medical professionals, if not the general public. Yeah,
Speaker 1: an available treatment and evidence that intervention worked. Those two
Speaker 1: things would emerge at nearly the same time in the
Speaker 1: early nineteen eighties.
Speaker 2: Arin. I don't want to interrupt you because I'm loving this.
Speaker 2: But as a side note, you know what we should
Speaker 2: do an episode on tell Me evidence based medicine.
Speaker 3: Yeah, okay, because.
Speaker 2: That is a really new thing.
Speaker 3: Wait wait, wait, what do you mean by that is
Speaker 3: a really new thing?
Speaker 2: I mean The idea that we should only make recommendations
Speaker 2: for things if we have evidence to support them is
Speaker 2: a relatively new concept in the history of medicine, and
Speaker 2: I mean.
Speaker 1: Really humoral theory has tons of support.
Speaker 2: Erin, sorry to cite.
Speaker 1: No, we should definitely do We should definitely do that.
Speaker 1: We've had ideas to do things like randomized control trials
Speaker 1: as well.
Speaker 2: Yes, and I know, just like, yeah, there's too long
Speaker 2: of a list.
Speaker 3: We have such a long list. It's great. It's a
Speaker 3: good problem to have.
Speaker 2: Okay, we're in the eighties.
Speaker 3: We're in the eighties.
Speaker 4: A lot of people are like, no, dude, give me
Speaker 4: some evidence, right, And the cardiologists or the cardio cardiology
Speaker 4: research people are like, oh my god, this we're in trouble.
Speaker 2: We're in trouble.
Speaker 1: Okay, So we needed treatment and proof that any sort
Speaker 1: of intervention worked, whether it was the treatment or just
Speaker 1: lowering cholesterol that that led to actual results. Those two things,
Speaker 1: a treatment and proof of intervention, would emerge at nearly
Speaker 1: the same.
Speaker 3: Time in the early nineteen eighties.
Speaker 1: Okay, so at the National Institutes of Health PLIANS had
Speaker 1: been underway since nineteen seventy for a large scale study
Speaker 1: that would measure the impact of cholesterol lowering drugs on
Speaker 1: cardiovascular disease. Previous studies had shown that high blood cholesterol
Speaker 1: levels overall correlated to higher rates of heart attacks, but
Speaker 1: the next step was showing that lowering those levels would
Speaker 1: then lead to fewer cardiac events.
Speaker 2: Exactly, we know that there's this positive correlation between high
Speaker 2: levels and bad outcomes. Can we change that?
Speaker 3: Can we change that? Can we do something?
Speaker 1: Because then that would also suggest it would be a
Speaker 1: very great evidence for causation.
Speaker 2: For causation, exactly, Yeah.
Speaker 1: So the Coronary Primary Prevention trial was designed to do
Speaker 1: exactly that show this line of causation. The study enrolled
Speaker 1: three eight hundred men aged thirty five to fifty nine
Speaker 1: with high total blood cholesterol so two sixty five or higher,
Speaker 1: and they were to be followed for at least five years.
Speaker 1: The treatment group was supposed to take a cholesterol lowering drug,
Speaker 1: a cholestyramine. Statins weren't yet approved at this point, and
Speaker 1: all participants were instructed to follow a cholesterol lowering diet. Okay,
Speaker 1: knowing what we know today about the link between cholesterol
Speaker 1: and cardiovascular disease, a trial like this would not be
Speaker 1: conducted in the same way where you would withhold drugs
Speaker 1: from one group, but at the time the evidence was
Speaker 1: not as firm, especially for medication, and so that's why
Speaker 1: it went forward. By the early nineteen eighties, after an
Speaker 1: average of seven years follow up for each participant, the
Speaker 1: results were in and they were unambiguous. Lowering blood cholesterol
Speaker 1: in high risk men reduced the risk of heart attack.
Speaker 3: Those who took period.
Speaker 1: Those who took the full dose of treatment had a
Speaker 1: thirty five percent reduction in total cholesterol and a forty
Speaker 1: nine percent decline in the rate of cardiac events. But
Speaker 1: even those who didn't follow the treatment to a t
Speaker 1: like the cholestyramine, had lowered cholesterol in heart attacks. Now,
Speaker 1: the study was not perfect, but when the results were
Speaker 1: published in nineteen eighty three, it led to a moment
Speaker 1: of reckoning for the field, like it was no longer
Speaker 1: enough to simply acknowledge that this relationship exists. Something had
Speaker 1: to be done about it right, and that's something was
Speaker 1: to be decided at the nineteen eighty four NIH Consensus
Speaker 1: Development Conference. So there was a panel of experts at
Speaker 1: this conference who came up with a set of guidelines
Speaker 1: for what would be considered high or low blood cholesterol
Speaker 1: for certain ages and how that fell out, and also
Speaker 1: diet and exercise recommendations for how to reduce cholesterol. They
Speaker 1: also advocated for a nationwide educational program in which general
Speaker 1: practitioners as well as the general public were taught about
Speaker 1: the importance of cholesterol.
Speaker 2: I love that. YEP.
Speaker 1: This conference had a substantial impact over the next decade,
Speaker 1: with the percentage of physicians pointing out LDL as an
Speaker 1: important marker for the risk of heart disease that increased
Speaker 1: from nineteen eighty six to nineteen ninety five, from thirty
Speaker 1: four percent to seventy five percent.
Speaker 2: So like in nineteen eighty six, only like.
Speaker 1: Thirty percent said your physicials would be like.
Speaker 2: Yeah, okay, and then ninety okay, ninety.
Speaker 1: Five, and then it was seventy five percent in nineteen
Speaker 1: ninety five, better than before, better than before. At the
Speaker 1: time that the panel was making these recommendations, there still
Speaker 1: wasn't really a good cholesterol lowering medication available, So the
Speaker 1: one that they had used in the study, colostyramine, came
Speaker 1: in a sandy powder which you had to mix into
Speaker 1: water and consume throughout the day, so you had to
Speaker 1: consume twenty four grams a day, was like the goal
Speaker 1: in the study, which was like six.
Speaker 3: Packets of this or something like that. No one's chasing that.
Speaker 3: It was quite a heavy.
Speaker 1: Lift, and it was made even more daunting by the
Speaker 1: gi upset that it caused in many you know, bloating, diarrhea.
Speaker 3: Constipation and stuff like that.
Speaker 1: Yeah, so there was clearly a need for a safe, effective,
Speaker 1: an easy medication to lower cholesterol. Fortunately, researchers were well
Speaker 1: underway in their quest for such a wonder drug in
Speaker 1: nineteen seventy one. The first hand account provider for this episode,
Speaker 1: doctor Akira Endo, was working as a research biochemist at
Speaker 1: the Japanese pharmaceutical company Sanchio when he got an idea.
Speaker 1: Endo had long been fascinated with Alexander fleming serendipitous discovery
Speaker 1: of penicillin, and after a research in New York, he
Speaker 1: had become intrigued by this problem of hypercholesterolemia, and he
Speaker 1: figured that, okay, if fungi produced antibacterial compounds like penicillin
Speaker 1: to compete with other fungi, it's not like they produce
Speaker 1: it because they're like, oh, humans could use this, No,
Speaker 1: they right, it's part of the ecology.
Speaker 3: Of their penicillium.
Speaker 1: Then it's possible that they would produce other types of
Speaker 1: compounds that would interfere with or help them compete against
Speaker 1: fungi in other ways, such as maybe a compound that
Speaker 1: interferes with cholesterol.
Speaker 2: Collection because cholesterol is so essential for life. Yeah, fascinating. Yeah,
Speaker 2: So he just was like, bro Fleming did this. Once
Speaker 2: Fleming did this, Maybe there's I can find something here
Speaker 2: because cholesterol is so important.
Speaker 1: Yes, And he was, I mean part of the thing too.
Speaker 1: He was like, he was like, fungi is all I knew.
Speaker 1: So that's where I looked.
Speaker 3: Hah.
Speaker 1: But it also like that that logic is very clear,
Speaker 1: but it had no direct support from any studies, Like
Speaker 1: there was penicillin and the fact that we found other
Speaker 1: antibiotics through this sort of like oh, this thing is
Speaker 1: producing this thing that kills this bacteria or this fungi
Speaker 1: in the environment, but like, yeah, but.
Speaker 2: To think of it for use on cholesterol, like that's
Speaker 2: so that's so interesting that his brain just did that right, Yeah.
Speaker 3: And found he was right about it. Yeah. I mean,
Speaker 3: so it took a while. It took two years.
Speaker 1: He and his colleagues over that time screened six thousand
Speaker 1: strains of microbes searching for a compound with cholesterol lowering
Speaker 1: properties like searching for a needle in a haystack. Really wow,
Speaker 1: And the first hit on this was less of a
Speaker 1: needle and more of.
Speaker 3: A crochet hook, but the second.
Speaker 1: Was exactly what they were looking for. A compound came
Speaker 1: from the mold penicillium citrinum with another penicillium, and they
Speaker 1: named it Compactin, also known as mevastatin later.
Speaker 2: Ok.
Speaker 3: Yeah, and this was the first statin h Yeah.
Speaker 1: So over the next several years, Endo and other researchers
Speaker 1: at Sanchio tested compact in safety, efficacy, and commercial viability,
Speaker 1: and other pharmaceutical companies got wind of this, like Merk,
Speaker 1: who was like, can we get a sample of that
Speaker 1: and see what's going on? And then they were like,
Speaker 1: how did you find this? Well, we're going to look
Speaker 1: for our own statin in the same way. They had
Speaker 1: to kiss way fewer frogs, only eighteen before they found
Speaker 1: their prints.
Speaker 3: In LoVa statin in nineteen seventy eight.
Speaker 1: Oh, competition, competition, Yeah, and then there's some there's like
Speaker 1: a lot. There is so much more to the story
Speaker 1: of like statin production, statin approval, statin testing, and stuff
Speaker 1: like that, which I will have some papers there if
Speaker 1: you want to dig more into that, Okay, But essentially,
Speaker 1: there were some early trials and animals that hit some hiccups,
Speaker 1: but then those were smoothed out. Trials and humans then
Speaker 1: went forward in the early nineteen eighties and results were striking.
Speaker 1: People with high cholesterol saw their LDL levels drop dramatically
Speaker 1: after taking the medication with few side effects. But did
Speaker 1: this drop translate to protection from cardiovascular disease?
Speaker 2: Right?
Speaker 3: You betcha yeah, you betcha yeah.
Speaker 2: Yeah.
Speaker 1: So there was one study sponsored by merk who was
Speaker 1: testing out there statin found a forty two percent decrease
Speaker 1: in death rate in those taking a statin. This is
Speaker 1: the second generation statin, simvastatin.
Speaker 2: Simvastatan still use it today, Yeah, wow Yeah.
Speaker 1: Statins look to be the next blockbuster drug, and soon
Speaker 1: every pharmaceutical company wanted in on the action, of course,
Speaker 1: and by the last year of the nineteen eighties, three
Speaker 1: statins were approved and available on the market.
Speaker 2: Wow.
Speaker 1: The following decade saw new statins and an expansion in
Speaker 1: their use, which allowed for large scale clinical studies, not
Speaker 1: just ones headed by pharmaceutical companies who were trying to
Speaker 1: get their drug approved. Also just can't believe how recent
Speaker 1: it all was.
Speaker 2: Me neither. I really did not realize that this was
Speaker 2: all in the last forty years since the nineteen eighties.
Speaker 2: That's really wild.
Speaker 1: It is wild, and I think it also is part
Speaker 1: of the reason why there's been such controversy.
Speaker 2: Hmmm. It's so interesting though, arin because there's so there's newer, newer,
Speaker 2: newer drugs that I feel like have way less controversy
Speaker 2: surrounding them.
Speaker 1: I know, And I'm just like, what, I there's a lot,
Speaker 1: there's a lot, and we're gonna we're gonna get into
Speaker 1: it in a second.
Speaker 2: Yeah.
Speaker 1: But yeah, But these studies, these large scale studies that
Speaker 1: were done not just by pharmaceutical industry, they conclusively and
Speaker 1: consistently showed that statins were life saving drugs and that
Speaker 1: they had earned their blockbuster status. Correct Across the board,
Speaker 1: statins led to a twenty five to thirty percent reduction
Speaker 1: in LDL coronary artery disease and death from cardiovascular disease.
Speaker 1: In the forty or so years since statins have been
Speaker 1: on the market, death from cardiovascular disease has dropped by
Speaker 1: over seventy five percent in many industrialized countries. Statins are
Speaker 1: a major tool in that fight, along with big advancements
Speaker 1: in medicine, lifestyle modifications, and diagnostics. But of course the
Speaker 1: story doesn't end here. The potential benefits of statins are enormous,
Speaker 1: both at a population and individual level, especially with cardiovascular
Speaker 1: disease being the leading cause of death in many countries.
Speaker 1: But increasingly the benefits of these drugs are not realized
Speaker 1: because people aren't taking statins when it's recommended that they do.
Speaker 3: Why is that? Why?
Speaker 2: Why?
Speaker 1: As it turns out, it's for many different reasons. A
Speaker 1: couple of recent papers looked into the issue and they
Speaker 1: presented some themes that they found in why people either
Speaker 1: refused or discontinued statins. There were, you know, practical and
Speaker 1: logistical considerations, so concern about taking multiple medications, polypharmacy burden,
Speaker 1: financial barriers, you know, having to drive to the clinic
Speaker 1: to get low cost statins, things like that.
Speaker 2: That's so annoying because they're all generic and not, especially
Speaker 2: in this country, be high costpits that they are, and.
Speaker 3: There should be you know, by mail et cetera.
Speaker 1: Yeah, yeah, yeah, pregnancy and breastfeeding is another sort of
Speaker 1: practical reason or preferring lifestyle modifications over a daily pill,
Speaker 1: like I'm not gonna be able to take a pill
Speaker 1: every single day, I'm gonna forget that. There were also
Speaker 1: preconceptions about side effects or impact on someone's identity, so
Speaker 1: people reported negative side effects or a fear of negative
Speaker 1: side effects, and others felt that taking statins was like
Speaker 1: giving up, that it signified sickness, and that they didn't
Speaker 1: want to be on a medication for the rest of
Speaker 1: their life. They didn't want to be dependent on this
Speaker 1: drug for health. And then there was another big reason
Speaker 1: or another big theme was mistrust in medicine and kind
Speaker 1: of a lack of understanding or belief in the drugs
Speaker 1: and how they worked, so some questioned their utility. Like
Speaker 1: I have high cholesterol. The doc says, I have high cholesterol,
Speaker 1: but I don't feel bad. Statins doesn't make me feel
Speaker 1: any different or it makes me feel worse.
Speaker 2: Right, I have this side effect that came from it,
Speaker 2: I think, And I didn't feel bad to begin with, right, exactly,
Speaker 2: why would I be on a medicine forever?
Speaker 1: People didn't also understand how statins lowered cholesterol, so it
Speaker 1: was just sort of like, well, I don't understand how
Speaker 1: they work, so I don't know that they do work.
Speaker 1: And many people also questioned the motives of doctors in
Speaker 1: prescribing the medication, like big Pharma has a hand in this,
Speaker 1: and they felt that over prescribing was an issue, especially
Speaker 1: with levels being revisited every so often and being like,
Speaker 1: now we recommend that you're you know, you didn't recommend
Speaker 1: me last year when my ELDALE.
Speaker 2: Was the same exactly. Now we need your LDAL to
Speaker 2: be less than seventy. Now we needed to be less
Speaker 2: than fifty five now, yeah, without a good explanation. They
Speaker 2: just updated the guidelines in March of this year, so
Speaker 2: they're changed yet again.
Speaker 1: Right, So there's this sort of fear of like diagnostic creep.
Speaker 1: Is that happening with cholesterol and statins or is there
Speaker 1: evidence to support this shifting of the levels and the recommendations.
Speaker 1: But often with all of these different reasons, it was
Speaker 1: a combination of things that led people to either refuse
Speaker 1: statins or stop taking them.
Speaker 3: Within two years, roughly.
Speaker 1: Forty percent of people who were taking them for primary
Speaker 1: prevention and twenty five percent of people on statins for
Speaker 1: secondary prevention end up stopping the medication. So to say
Speaker 1: that these negative attitudes towards statins are worrisome, I think
Speaker 1: is quite an understatement. It could have serious, even fatal consequences.
Speaker 1: So what do we do about it? The first step
Speaker 1: is understanding why, you know, where are these attitudes these
Speaker 1: beliefs coming from. Many of the reasons that people give
Speaker 1: for not taking or discontinuing statins can be attributed in
Speaker 1: part to misinformations or negative beliefs promoted across social media.
Speaker 1: When statins first came on the market in the late
Speaker 1: nineteen eighties, the cholesterol heart disease link had not yet
Speaker 1: been fully embraced by the general public, and in fact,
Speaker 1: there were some highly publicized front page stories written by
Speaker 1: vocal deniers controversy cells, consensus doesn't yes. And so all
Speaker 1: of a sudden, you go to the doctor. Your doctor
Speaker 1: is telling you should take this drug for your cholesterol.
Speaker 1: But just that morning you read how the cholesterol heart
Speaker 1: disease link is overblown so that big Pharma can rake
Speaker 1: in the dough and get people on meds for life.
Speaker 3: Why would you do this?
Speaker 1: Right? And it would take years after statins were introduced
Speaker 1: to put together those big data sets that show the
Speaker 1: life saving benefits of the drugs and the relatively low
Speaker 1: rate of side effects. And so doubt has really been
Speaker 1: sewn into statins from the very beginning, along with a
Speaker 1: mistrust in how the pharmaceutical industry is involved.
Speaker 3: And I get it, like.
Speaker 1: There is some truth to this involvement, especially early drug
Speaker 1: trials being designed by pharmaceutical companies. Many researchers in this
Speaker 1: area hold board positions or received funding from these companies
Speaker 1: or have a patent for these drugs, and they're trying,
Speaker 1: you know, like there is there are financial ties that
Speaker 1: are undeniable.
Speaker 2: One hundred percent, one hundred percent. And I will say
Speaker 2: like in today's day in age, not just with pharmaceutical companies,
Speaker 2: also with radiology companies and imaging companies and genetic testing companies,
Speaker 2: and so as our guidelines shift to incorporate more of these,
Speaker 2: like it is very valid to question these conflicts of interests,
Speaker 2: whether they are real or perceived, Like they.
Speaker 1: Matter, they matter, they do matter, And I think that
Speaker 1: this is, like you said, as these as these guidelines
Speaker 1: are shifting, there's these questions around like who, what's what's
Speaker 1: behind these guidelines, is there evidence for it?
Speaker 3: Et cetera.
Speaker 1: At the same time, decades of statin research. These drugs
Speaker 1: have been around for almost forty.
Speaker 2: Years forty years now.
Speaker 1: Yeah, decades of research have proven the value of statins,
Speaker 1: and that research is not solely conducted by industry, but
Speaker 1: large scale work being done across the globe, not just
Speaker 1: within pharmaceutical sectors in the United.
Speaker 3: States, but across the globe.
Speaker 1: And while yes, of course pharmaceutical companies love a drug
Speaker 1: that someone has to take for long periods of time,
Speaker 1: many statins today are available in a generic form, and
Speaker 1: so they're not as profitable as they once were. In
Speaker 1: any case, your primary care doc is not getting a
Speaker 1: kickback from prescribing these drugs. They simply don't want you
Speaker 1: to die from heart disease.
Speaker 2: It's so truely Arian, that's true.
Speaker 3: It's true. Okay.
Speaker 1: Another big reason that people cited was side effects, including
Speaker 1: or specifically muscle symptoms. This is one of the top
Speaker 1: reasons that people stop taking or never start taking statins.
Speaker 1: Side Effects are real and important to take seriously because
Speaker 1: they can truly impact quality of life. But the story
Speaker 1: of side effects when it comes to statins is complicated.
Speaker 3: Until two thousand.
Speaker 1: And one, there were very few reports of tolerability or
Speaker 1: safety concerns for people taking statins, but that year a
Speaker 1: statin seruvastatin, was removed from the market due to safety concerns,
Speaker 1: specifically for rahpdomiel issis, which occurred at a rate of
Speaker 1: zero point zero one percent in people.
Speaker 3: Taking it okay.
Speaker 1: Promptly after its removal from the market, all information sheets
Speaker 1: included warnings about all for all statins included warnings about
Speaker 1: muscle symptoms, and physicians counseled patients to report muscle aches
Speaker 1: as an early warning sign of rahpdomiel issis. This issue
Speaker 1: was highly publicized, as it should have been. You know,
Speaker 1: this is a potentially serious side effect, and so let's
Speaker 1: you know, make sure you look out for this. And
Speaker 1: many patients who felt muscle aches often would interpret them
Speaker 1: as myopathy or go to their doctor with concerns about myopathy.
Speaker 1: They would stop taking statins and their symptoms improved, which
Speaker 1: reinforced the belief that these statins might be dangerous, right,
Speaker 1: or the cause of that the cause of that? Right,
Speaker 1: And certainly these muscle symptoms were and are real, But
Speaker 1: there is also something called the nocibo effect that seems
Speaker 1: to be at play here, at least to some degree.
Speaker 3: So the nocebo effect is the opposite of the placebo effect.
Speaker 1: It's anticipation of negative symptoms that leads you to experience them.
Speaker 1: Studies on statins have shown that when both researcher and
Speaker 1: patient don't know whether someone is getting medication statin or placebo,
Speaker 1: both control and treatment groups experience similar rates of muscle aches,
Speaker 1: which suggests that it might not be the statins themselves
Speaker 1: directly responsible for those symptoms.
Speaker 3: Right, At least in all.
Speaker 1: Cases, the symptoms are absolutely real. The nocibo effect does
Speaker 1: not mean that it's all in your head. You're experiencing
Speaker 1: these symptoms. They just might not always be caused by
Speaker 1: the drug itself.
Speaker 2: Right. It's not like there's a direct mechanistic link between
Speaker 2: the drug that is directly causing that muscle symptom necessarily, right.
Speaker 3: But it could be.
Speaker 1: It could like, and so this is where it's really
Speaker 1: really tricky to tease apart both the patient and provider.
Speaker 1: And so it might be just like, feel like the
Speaker 1: easiest course to go, I'm just going to stop because
Speaker 1: I don't want to feel this way. I don't want to.
Speaker 1: I'm worried about this, and this is hurting my quality
Speaker 1: of life. I'm going to stop. Other research has also
Speaker 1: shown that people who are exposed to more negative stories
Speaker 1: surrounding statins and side effects are more likely to discontinue use.
Speaker 1: And I think that what's also at play here is
Speaker 1: when we kind of touched on this, is that we
Speaker 1: don't feel high cholesterol like, we don't feel any different
Speaker 1: when our cholesterol is low, but we do expect a
Speaker 1: lot of the time that the medications we take will
Speaker 1: make us feel different. We're supposed to feel better from
Speaker 1: these medications, supposed to feel something something yeah, yeah, And
Speaker 1: so it makes sense that if you read horror stories
Speaker 1: about side effects of statins that abound on the internet,
Speaker 1: you're predisposed to expect that those bad outcomes will happen
Speaker 1: to you. And what doesn't help this is that there
Speaker 1: is a vast amount of misinformation and disinformation about statins
Speaker 1: circulating on social media and generative AI. There's a motive
Speaker 1: for people to be spreading some of this misin disinformation.
Speaker 1: So in fact, there was a recent study that showed
Speaker 1: that many generative AI models, when fed prompts asking about statins,
Speaker 1: especially if those prompts were leading sort of like what
Speaker 1: can I take things?
Speaker 2: Isn't there some evidence of these side effects with statins
Speaker 2: like those kinds of questions.
Speaker 1: Yeah yeah, or like what should I take that's safer
Speaker 1: than statins? Like what natural product should I take that
Speaker 1: are that's safer than statins. But many of these models
Speaker 1: gave inappropriate and inaccurate answers.
Speaker 2: That doesn't surprise me at all, right.
Speaker 1: Right, the sheer amount of misinformation that's out there and
Speaker 1: just sort of the overall decline or disregard of expertise
Speaker 1: that's happening around the globe.
Speaker 3: Yeah there.
Speaker 1: And then there are the people who are very vocal
Speaker 1: in their opposition to statins, that at the same time
Speaker 1: are telling you don't go on statins, buy my red
Speaker 1: yeast rice supplement instead, or buy this diet book, or
Speaker 1: they're trying to make money off of you in some way,
Speaker 1: you know, subscribe to my sub stack that says, you know,
Speaker 1: day one diet with me, and right, I'll tell you
Speaker 1: throw away your statins, Yeah yeah, And that the thing
Speaker 1: is like I also understand why that's appealing when you've
Speaker 1: been dismissed by your physician, or your physician is saying
Speaker 1: it's not the statin causing this, just like that simply
Speaker 1: across the board, or if you can't even afford to
Speaker 1: go see a doctor, right, this this information is out there,
Speaker 1: and that is filling a hole that you want.
Speaker 2: And it feels like you're being taken seriously for the
Speaker 2: first time when you're like I went to my doctor
Speaker 2: with these concerns and you were totally dismissed or they
Speaker 2: were like, oh, you're fine, right, I'm not fine if
Speaker 2: I'm having symptoms, right.
Speaker 1: Yeah, And I mean again, like all of this, I
Speaker 1: think what it does is it speaks to a need
Speaker 1: to more closely examine the side effects that people report,
Speaker 1: not just muscle symptoms, but the other side effects that
Speaker 1: people report, and how best to address them, how best
Speaker 1: to measure them, How can we make it so that
Speaker 1: people can take drugs that will lower cholesterol and potentially
Speaker 1: save their lives. So again, what do we do about it?
Speaker 1: And I think that as a start, we can look
Speaker 1: at the reasons people take statons. So that same systematic
Speaker 1: review that I mentioned earlier also showed many people have
Speaker 1: positive sentiment towards these drugs. They trust their efficacy, like
Speaker 1: look how much my bad cholesterol dropped and my good
Speaker 1: cholesterol rose. They report that their health anxiety has eased
Speaker 1: thanks to the drugs, reporting an enhanced peace of mind,
Speaker 1: and they view them also as a way of taking
Speaker 1: control and ensuring a better, healthier future. Rebrand these drugs
Speaker 1: for what they are heart attack prevention, stroke prevention, a
Speaker 1: way to extend your life, your quality of life, and
Speaker 1: spend more time with the people you love, accomplishing all
Speaker 1: the things.
Speaker 3: You want to do.
Speaker 1: These drugs might not make you feel any better instantaneously,
Speaker 1: but they will make it more likely that you're around
Speaker 1: to feel and do things ten years from now. Having
Speaker 1: high cholesterol it doesn't mean that you have failed. It
Speaker 1: should not be seen as shameful, as something that you
Speaker 1: should hide or feel embarrassed by, and taking these medications
Speaker 1: should make you feel like you're taking agency over your
Speaker 1: own life. Prevention is always harder, especially when the threat
Speaker 1: like a heart attack, doesn't seem imminent or is so
Speaker 1: scary that you're like, I have to think that this
Speaker 1: won't happen to me.
Speaker 2: I can't put my mind in that place.
Speaker 1: Yes, but that denial it really does not serve us well.
Speaker 1: And so with that eron, I'm going to turn it
Speaker 1: over to you to tell us about how statins actually
Speaker 1: work and where things stand with cardiovascular disease around the
Speaker 1: globe today.
Speaker 2: I would love to so knowing that statins have made
Speaker 2: such a huge impact, or have the potential at least
Speaker 2: to make such a huge impact on disease, I think
Speaker 2: we first need to understand a little bit more about
Speaker 2: how they work. So I want to go through not
Speaker 2: just statins, but the strategies overall that we use today
Speaker 2: to lower LDL cholesterol, specifically how these strategies work, and
Speaker 2: then I want to wrap up by giving us all
Speaker 2: like a reminder of why lowering cholesterol is so important,
Speaker 2: by looking at athrosclerotic heart disease kind of across the globe. Okay,
Speaker 2: And so the first thing to know is that while
Speaker 2: statins are because of how long they've been around and
Speaker 2: because of how strong the evidence is that they are
Speaker 2: extremely effective not just at lowering that cholesterol, but actually
Speaker 2: at preventing heart attack, stroke and death. They are a
Speaker 2: mainstay of therapy today for cholesterol management, but they are
Speaker 2: not the only thing that we have. And the first
Speaker 2: thing that is always recommended across the board is diet
Speaker 2: and lifestyle changes. And the thing is that we do
Speaker 2: have really decent data as far as nutrition data goes,
Speaker 2: which we all know is limited. Yep, we do have
Speaker 2: decent data that lifestyle changes can work for a lot
Speaker 2: of people. But the problem is that we also know
Speaker 2: that your total cholesterol and your LDL cholesterol, so the
Speaker 2: packages of LDL cholesterol are not entirely driven by your diet.
Speaker 2: They're not entirely driven by how much exercise you're getting, right.
Speaker 2: There are a lot of different things that go into
Speaker 2: determining what your cholesterol levels are and whether they are
Speaker 2: high or whether they are low. And one of the
Speaker 2: big things is our genetics. You talked in last week's
Speaker 2: episode AARIN about familial hypercholesterolemia. This is one or really
Speaker 2: kind of like one group of disorders that can seriously
Speaker 2: contribute to elevated cholesterol, especially LDL cholesterol. But it's not
Speaker 2: the only one. There are a whole bunch of other
Speaker 2: genetic contributions, whether that's multiple genes or things that we
Speaker 2: don't even know yet, right, Genes that we haven't even
Speaker 2: discovered yet that are associated with the ratios and amounts
Speaker 2: of cholesterol, whether that's because these genes affect how we
Speaker 2: recycle cholesterol, whether they affect how much cholesterol we produce
Speaker 2: in our liver, or whether like in familial hypercholesterolemia, they
Speaker 2: affect our LDL receptors and how good our cells are
Speaker 2: at taking that cholesterol out of our bloodstream right, right,
Speaker 2: So all of these things are going to play a
Speaker 2: role as well as our dietary factors and our lifestyle factors,
Speaker 2: and so that is usually the first thing that any
Speaker 2: physician is going to recommend if someone's cholesterol is elevated,
Speaker 2: is can we bring this down by reducing or stopping
Speaker 2: smoking if you smoke, because that has a huge effect
Speaker 2: Lowering the amount of alcohol that you drink, which is
Speaker 2: going to help to lower your cholesterol levels. Switching out
Speaker 2: saturated fats in your diet for unsaturated fats, right, switching
Speaker 2: out animal products for plant products. These are the kinds
Speaker 2: of dietary changes that we have good data to say
Speaker 2: that not only do they reduce your cholesterol levels, but
Speaker 2: they also can actually prevent cardiovascular disease. We have that data,
Speaker 2: it exists, but for many people that isn't sufficient, and
Speaker 2: so that is when it is recommended that medication is
Speaker 2: actually used, right, whether it's because somebody can't or doesn't
Speaker 2: want to change their diet or exercise, or they can't
Speaker 2: increase physical activity, or they are literally already doing the
Speaker 2: most and it's still not enough. And that happens so
Speaker 2: so so often.
Speaker 1: Right, And I think it's like, this is where I
Speaker 1: feel like it can feel like I have failed or
Speaker 1: I thought I was trying my best to do all
Speaker 1: these things and still it's not working.
Speaker 3: And it's like.
Speaker 1: That that's okay, Like this is not your no, you're
Speaker 1: not a failure of No.
Speaker 2: Yeah, no, it's that's so true, Aaron, Like I see
Speaker 2: people in clinic all the time that this happens too,
Speaker 2: and I just say, blame your parents, like it's probably
Speaker 2: your genes. Okay. So let's then talk about what are
Speaker 2: some of the big medicines that we use and how
Speaker 2: do they actually work. Why are they working? Yes, yes, statins.
Speaker 3: So.
Speaker 2: Statins block an enzyme in our liver that's called hmg
Speaker 2: CoA reductase. The cliff Notes version is that this particular enzyme,
Speaker 2: hmg CoA reductase, this one is the rate limiting step
Speaker 2: in cholesterol synthesis in your liver, so that enzyme is
Speaker 2: necessary in our liver for our liver to make cholesterol.
Speaker 2: And remember, our liver is making over fifty percent of
Speaker 2: the cholesterol floating around in our body.
Speaker 1: Right, so you have if you have more hmg CoA reductase,
Speaker 1: then you have more cholesterol photogram in your body. If
Speaker 1: you reduce that reductase that enzyme, then you have less.
Speaker 2: And Aaron, it goes even further than that, Okay, because
Speaker 2: what happens is that by blocking this enzyme in particular,
Speaker 2: because it is the rate limiting step, meaning it's like
Speaker 2: the slowest one in the daisy chain right when you're
Speaker 2: moving stuff into our house, we dramatically reduce, not just
Speaker 2: like a little bit do we reduce how much cholesterol
Speaker 2: your liver's making. You're dramatically reducing, like putting a huge
Speaker 2: break on how much cholesterol your liver can make. And
Speaker 2: because all of our cells still need cholesterol, our cells
Speaker 2: have to get better at taking cholesterol out of our bloodstream,
Speaker 2: so they actually up regulate those LDL receptors, those velcro,
Speaker 2: sticky hands on the surface of our cells that capture
Speaker 2: our LDL cholesterol floating around in our bloodstream. So it's
Speaker 2: not just that, oh, we're not making as much cholesterol,
Speaker 2: it's that we're not making as much cholesterol and our
Speaker 2: body cells still need cholesterol, so they start vacuuming it
Speaker 2: out of our bloodstream at really high rates.
Speaker 3: Beautiful. Isn't that cool?
Speaker 2: Oh?
Speaker 3: Yeah, I love that.
Speaker 2: There's also some interesting evidence that statin's also might have
Speaker 2: a little bit of like an anti inflammatory effect as well.
Speaker 3: Yeah, and we talked.
Speaker 2: In last week's episode about how important inflammation is in
Speaker 2: the process of atherosclerosis or in the process of that
Speaker 2: cholesterol actually forming a plaque in your bloodstream. Inflammation is
Speaker 2: an integral part of that, and so there's some thought
Speaker 2: that there's also an anti inflammatory effect of statins, though
Speaker 2: we don't fully understand that mechanism there. So that's how
Speaker 2: statins work, and they're incredibly effective erin. There was a
Speaker 2: meta analysis from twenty sixteen that was really interesting, So
Speaker 2: it's kind of old now, but it looked at over
Speaker 2: fifty different studies that looked at all the different possible
Speaker 2: interventions that we had at that time and all of
Speaker 2: the randomized control trials of those different interventions and the
Speaker 2: effect of lowering LDL cholesterol on cardiovascular disease risk by
Speaker 2: these different interventions. Okay, we had twenty five trials on statins,
Speaker 2: twenty five of them compared to only four diet trials
Speaker 2: compared to only two at the time on PCSK nine
Speaker 2: in hibit which I'll get to in a second, right
Speaker 2: one on a zmib, which is another medicine that we use.
Speaker 2: And so what that means is not only do we
Speaker 2: have so much data on their effect, it also means
Speaker 2: that our confidence intervals on just exactly how effective they
Speaker 2: are are really narrow for statins. So we know, like
Speaker 2: without a doubt that statins are extremely effective at lowering
Speaker 2: our LDL cholesterol and at reducing the risk of adverse
Speaker 2: cardiovascular events.
Speaker 3: Period is that what is what did that study show?
Speaker 1: The meta analysis show in terms of like that by
Speaker 1: the numbers impact.
Speaker 2: So by the numbers, statins are the most consistent. Diet
Speaker 2: is A has a slightly less effect but still a
Speaker 2: significant effect. PCSK nines, which I'll get to in a second,
Speaker 2: have the greatest effect. They lower LDL cholesterol the most
Speaker 2: and they reduce your risk the most. But the confidence
Speaker 2: intervals are super wide because at least at that time,
Speaker 2: we just didn't have as much data on them, right, right, Yeah,
Speaker 2: and then the other ones are in between. But statins
Speaker 2: are like like pound I guess, I don't know if
Speaker 2: that's right, but like incredibly effective and like just so
Speaker 2: much good data to support them.
Speaker 1: We're really dialed in on how statins work and how
Speaker 1: well they work.
Speaker 3: Are there?
Speaker 1: What are the differences between different types of statins?
Speaker 2: Great question, So different types of statins. A lot of
Speaker 2: the difference is in their potency. So some statins can
Speaker 2: lower your LDL cholesterol to a much greater degree than
Speaker 2: other statins, the exact of like why, I don't know, okay,
Speaker 2: but that means that we have statins that vary in
Speaker 2: what we call their intensity, And by intensity we mean
Speaker 2: how much, by what percentage are we lowering your LDL cholesterol.
Speaker 2: So if I can give you a medicine that's going
Speaker 2: to lower your LDL cholesterol by at least fifty percent,
Speaker 2: that's considered a high intensity statin regimen. And if it's
Speaker 2: by less than thirty percent, then that's considered a low
Speaker 2: intensity regimen. And then there's intermediate in between. Okay, okay, yeah, moderate.
Speaker 2: There's also differences in like some of them are more lipophilic,
Speaker 2: so they're more like fats, and some of them are
Speaker 2: more hydrophilic, so they're more like They act more like
Speaker 2: proteins in that they're more like soluble in water, and
Speaker 2: so that might differ in how much they build up
Speaker 2: in different tissues in your body. But there's not great
Speaker 2: data that says that one is more or less likely
Speaker 2: to cause side effects than the other. And that's the
Speaker 2: next thing I want to briefly talk about because it's
Speaker 2: an important part of the statin story and you mentioned
Speaker 2: it as well Erin it is not the case that
Speaker 2: side effects don't exist. Any medication, any therapy really has
Speaker 2: the potential to cause side effects. And like you mentioned, Aaron,
Speaker 2: the most cited side effect that causes people to stop
Speaker 2: taking a statin medication is muscle symptoms, and that's a
Speaker 2: really general term. It's often muscle pain or muscle aches,
Speaker 2: or sometimes muscle weakness. Now there's also other things like
Speaker 2: gastro intestinal side effects or liver enzymes can increase, which
Speaker 2: is usually transient and can be completely reversed either by
Speaker 2: going down on the dose or stopping the statin. But
Speaker 2: muscle effects are like the big one, right and there
Speaker 2: was a recent meta analysis that looked at data from
Speaker 2: randomized control trials from over one hundred and fifty thousand
Speaker 2: people and twenty three different studies that were comparing either
Speaker 2: statins versus place EBO or different intensity as a statin,
Speaker 2: so that high intensity versus low intensity therapy. And what
Speaker 2: they found is not that muscle symptoms were never reported
Speaker 2: by any means, but that by comparing all these different regimens,
Speaker 2: what they estimated was that less than ten percent of
Speaker 2: all of the reports of muscle symptoms could actually be
Speaker 2: directly attributed to statins themselves.
Speaker 3: Does that make sense, I think so.
Speaker 1: So the it's not talking about the rate of side
Speaker 1: effects that happen, No, how much of those side effects
Speaker 1: are statin's directly responsible for cause exactly? And is this
Speaker 1: based on like do we understand mechanism?
Speaker 2: Oh, such a good question.
Speaker 1: We don't.
Speaker 2: We don't. Because the vast majority of these, even the
Speaker 2: side effects that could be attributed to statins are considered mild.
Speaker 2: A lot of people actually will continue their statin and
Speaker 2: the amount of people who report symptoms after the first
Speaker 2: year actually goes down. So it's usually in that first
Speaker 2: year of therapy. Realistically, it's usually within the first few
Speaker 2: weeks or months of starting a statin medicine that people
Speaker 2: are more likely to have effects directly related to the statin.
Speaker 2: But no, we don't understand exactly the mechanism. But most
Speaker 2: of them are mild and they do not result in
Speaker 2: actual damage to the muscle, tissue or myopathy. Now that
Speaker 2: does not mean that they can't ever, Right, there are
Speaker 2: more serious events like rhabdomyolysis, and that is estimated to
Speaker 2: occur about four excess cases per ten thousand people if
Speaker 2: you're on a high intensity statin. Does that mean there's
Speaker 2: only four But like some people get rabdo that has
Speaker 2: nothing to do with statins, So statins will call its
Speaker 2: four excess cases for every ten thousand people on a
Speaker 2: high intensity statin.
Speaker 3: Is it more common? Okay you were about to say yes.
Speaker 2: Yeah, and one per ten thousand on less intensive So
Speaker 2: it does go up, like the chances of side effects
Speaker 2: and the chances of more severe side effects go up
Speaker 2: with intensity. So sometimes just going down from a high
Speaker 2: intensity regimen to a lower intensity regimen takes away side
Speaker 2: effects entirely for people, and that's enough and then you're
Speaker 2: still getting some benefit, just maybe not quite as much
Speaker 2: as you were on a high intensity regimen.
Speaker 1: Okay, question about that meta analysis. You said that ten
Speaker 1: percent of the side effects experience are directly attributable to statins.
Speaker 3: What is the ninety percent? Where does that get attributed to?
Speaker 2: I don't know, I don't We don't have an answer
Speaker 2: to that.
Speaker 3: Just the hyper didn't suggest anything.
Speaker 2: No any answers, Okay, no, I mean some of it.
Speaker 2: They're like, is it just aging, is it just no
Speaker 2: stibo effect? Is it like a bunch of different possible things,
Speaker 2: but not like a clear answer. No.
Speaker 1: And so this was like by looking at people who
Speaker 1: are on placebo are still experiencing these side effects and
Speaker 1: we don't know what's causing that, Okay.
Speaker 2: Right, So then you're looking at like how many excess cases,
Speaker 2: how many excess reports will you get? It was estimated
Speaker 2: like eleven reports of muscle pain or weakness per one
Speaker 2: thousand people on statins in that first year were from statins. Okay,
Speaker 2: eleven per one thousand.
Speaker 3: Right, So it's tricky.
Speaker 2: It's really really really tricky because it's not that these
Speaker 2: symptoms are not real, right, And and if you are
Speaker 2: one of those people who has that severe side effect, right,
Speaker 2: one of four per ten thousand. That's a very real
Speaker 2: effect for you. And so it is always a tricky
Speaker 2: thing to balance because when we are talking about treating
Speaker 2: and preventing, especially when we're talking about preventing cardiovascular disease,
Speaker 2: we are talking both about population level reductions and risk,
Speaker 2: and we're also talking about an individual risk benefit calculation,
Speaker 2: right and so, and those are not the same calculations
Speaker 2: on a population scale versus on an individual scale.
Speaker 3: Yeah, and yeah.
Speaker 2: It doesn't help when people's symptoms are completely ignored, or
Speaker 2: when they're told oh, it's absolutely not from this, or
Speaker 2: when they're told from wellness influencers online that this medication
Speaker 2: that they've been on safely for ten years is now
Speaker 2: causing the symptoms that they're having, right yeah, yeah, yeah, yeah,
Speaker 2: which I see all the time.
Speaker 1: I mean I think that what is a real challenge too,
Speaker 1: is like how do you balance saying Okay, these are
Speaker 1: real symptoms, you are experiencing this, this is very real
Speaker 1: is and deciding is this caused by the statina, is
Speaker 1: this not caused by the statin? Are you going to
Speaker 1: be someone who is the point zero zero one percent
Speaker 1: are right? And then it's like what even if these
Speaker 1: side effects are not directly caused by the statin, they're
Speaker 1: still impeding your ability to say, exercise or something like that.
Speaker 1: And so it's like, gona be helpful for your health, right,
Speaker 1: it's a mess. I'm very curious to hear suggestions on
Speaker 1: how out of a question.
Speaker 2: I mean, I don't know, Like I really think that
Speaker 2: what it always has to come down to is a
Speaker 2: good relationship with a physician or provider that you trust, right,
Speaker 2: who knows you, who you know, who can explain these
Speaker 2: things to you. And like, it's why I don't think
Speaker 2: AI can take over for all doctors Aaron. But maybe
Speaker 2: that's my bias.
Speaker 1: Well it's not, but I think it is the way
Speaker 1: that medicine is going, and like the and has been
Speaker 1: trending in.
Speaker 3: The last twenty years, more.
Speaker 1: Expensive, shorter visits, yep, more video visits that don't always
Speaker 1: necessarily feel like you're having a connection with someone, right,
Speaker 1: it all is just standing in the way of forming
Speaker 1: these relationships.
Speaker 2: I know, because they're the most important thing in my
Speaker 2: highly biased opinion. Ah okay, but we have more options too.
Speaker 2: Some people are gonna have side effects from statins or
Speaker 2: they're just like no, I will not take a statin. Cool,
Speaker 2: don't worry. We have other options now, and I'm not
Speaker 2: going to go through every single one, but I'm going
Speaker 2: to call out two that are probably like the two
Speaker 2: biggest groups that we use. One is called zetimibe, and
Speaker 2: this is a drug that blocks a protein that's in
Speaker 2: the cell membranes of our guts and our bile ducts.
Speaker 2: So what this does is it blocks the amount of
Speaker 2: cholesterol that we are absorbing and reabsorbing. So this one,
Speaker 2: it doesn't have as huge of an effect by any means,
Speaker 2: but it can still lower cholesterol, often by like ten percent.
Speaker 2: We're talking LDL cholesterol. It can lower you. So that's
Speaker 2: not nothing to shake a stick at. So now let
Speaker 2: me talk about the one that people are so excited about.
Speaker 2: And then I said multiple times that is a non
Speaker 2: since we're called PCSK nine inhibitor skin. Okay. PCSK nine
Speaker 2: is the shorthand name for a protein that I'm not
Speaker 2: going to tell you the name of because I don't
Speaker 2: know it. It's too long. But this is a protein
Speaker 2: that our liver makes. It's really interesting. Its job this
Speaker 2: protein is to degrade break down LDL receptor proteins. Okay,
Speaker 2: so this protein is kind of like an anti recycler
Speaker 2: of this protein, of this receptor who usually collects the
Speaker 2: LDL in our bloodstream. Okay, yeah, Why does this protein
Speaker 2: do this, I don't know right now, but that is
Speaker 2: what it does. So if you can block this enzyme,
Speaker 2: this protein, then you will have more LDL receptors available
Speaker 2: to be reused and recycled to be collecting our LDL
Speaker 2: cholesterol in our bloodstream.
Speaker 1: So this is like a velcro glove thief, this this protein.
Speaker 2: The protein. Yeah, PCSK nine exactly, it's a velcro glove thief.
Speaker 1: Then the velco gloves are numerous to catch all those
Speaker 1: tennis balls of LDL.
Speaker 2: I really like this analogy, by the.
Speaker 3: Way, it's a really good analogy. I'm yeah, thanks.
Speaker 2: You know, I don't always come up with good ones.
Speaker 1: So I mean the best I get it was Bill Buckner.
Speaker 1: So I've really.
Speaker 2: Enjoyed that so much more than I can say. Yeah,
Speaker 2: So that is how PCSK nine inhibitors work. The main group, Like,
Speaker 2: there's a couple different medicines that we use that are
Speaker 2: mostly monoclonal antibodies. They're really interesting because a lot of times,
Speaker 2: Like they're not a pill that you have to take
Speaker 2: every day. It's like an injectable medicine that you take
Speaker 2: every week or two weeks, depending on the medicine. There's
Speaker 2: also something called in chlyserin, which is a small interfering
Speaker 2: RNA molecule okay, that binds to this protein's PCSK nine's
Speaker 2: m and degrades it. So it's also affecting that same system,
Speaker 2: it's just not blocking the receptor itself. Isn't that so cool?
Speaker 3: Wow?
Speaker 2: And the data on all of these medicines that affect
Speaker 2: PCSK nine it is incredibly strong. So we talked about
Speaker 2: that that meta analysis from ten years ago or so.
Speaker 2: PCSK nine inhibitors reduce your LDL drastically and can drastically
Speaker 2: also reduce cardiovascular events, especially in people who are very
Speaker 2: high risk, meaning people that we are doing secondary prevention
Speaker 2: who already have you know, cardiovascular dues, who have maybe
Speaker 2: already had a heart attack or a stroke and we
Speaker 2: really need to lower that cholesterol, or people who are
Speaker 2: just very high risk. Right, So in those populations is
Speaker 2: mostly where it's been studied, and so cardiologists love this medicine.
Speaker 2: The biggest issues are as with all new drugs, especially
Speaker 2: ones that are fancy things like siRNA and monoclonal antibodies.
Speaker 2: They are expensive as heck, especially in this country. We
Speaker 2: also just don't have nearly as much data on them
Speaker 2: as we do for statins, so the error bars on
Speaker 2: their benefit is still messier, even though they still have
Speaker 2: a really good effect.
Speaker 3: Do we have information about side effects?
Speaker 2: It's a great question. I should have looked into it more.
Speaker 2: There definitely can be side effects, but I honestly just
Speaker 2: did not do a good job of looking into them
Speaker 2: as much. So I will get back to you on that. Okay.
Speaker 1: I'm not to have a question sort of like about lowering.
Speaker 1: So we've talked about lowering and the importance of having
Speaker 1: lower levels, but there is such a thing as too low.
Speaker 3: What are consequences of that?
Speaker 2: That's a great question. I don't have a number for you, Okay.
Speaker 2: What the data shows is that the higher your individual
Speaker 2: risk of cardiovascular disease, right, Because cardiovascular disease is not
Speaker 2: only cholesterol.
Speaker 3: No, no, no, I hope that I.
Speaker 2: Have made that clear. It is not by any means
Speaker 2: only cholesterol, but lower in cholesterol is one of the
Speaker 2: big ways that we have to reduce the chances that
Speaker 2: you're going to develop or have really bad outcomes like
Speaker 2: a heart attack or a stroke or death from cardiovascular disease.
Speaker 2: And so what we know is that the higher your
Speaker 2: individual risk based on all of your other risk factors,
Speaker 2: age whether or not you smoke, how much alcohol you drink,
Speaker 2: your BMI, your blood pressure, whether you're on a blood
Speaker 2: pressure medicine, your kidney function, based on all of those things,
Speaker 2: the higher your risk, the lower we need to push
Speaker 2: your cholesterol to really lower your risk of bad outcomes.
Speaker 2: So people who are very high risk, in the newest guidelines,
Speaker 2: people who are very high risk, the recommendation is to
Speaker 2: reduce their LDL to less than fifty five. And that's
Speaker 2: very low, and we haven't seen any bad outcomes from that,
Speaker 2: meaning we haven't found a number that is too low
Speaker 2: for those people who are very high risk, okay, but
Speaker 2: for other people, we haven't necessarily shown that there is
Speaker 2: a benefit to pushing them that low. And so for
Speaker 2: most other people, the recommendation is going to be either
Speaker 2: less than seventy or less than one hundred, depending again
Speaker 2: on what your risk is of cardiovascular disease development.
Speaker 1: Huh, yeah, So prolonged use of statins are like long
Speaker 1: time use of statins.
Speaker 3: Basically, if your blood cholesterol.
Speaker 1: Is high enough that you need to be on a
Speaker 1: statin or you are prescribed as statin.
Speaker 2: Or another lipid lowering medicine or something like that, you
Speaker 2: are on that regimen for the rest of your life.
Speaker 2: Often yeah, often, yeah, that because again that's the data
Speaker 2: that we have, right right, And we'll talk in a
Speaker 2: second about how much atherosclerosis is. It is a disease
Speaker 2: of long term right, Yeah, it's not a short term.
Speaker 2: It's not the rabbits that just get it in a
Speaker 2: week or two. It is a long term disease kind
Speaker 2: of thing, and so that is why it requires long
Speaker 2: term management.
Speaker 1: Plaques weren't built in a just like rome wasn't built
Speaker 1: in a thing exactly.
Speaker 2: Whatever, Yeah, isn't it a day?
Speaker 1: Probably I'm terrible with like saying so I thought I
Speaker 1: cannot remember them.
Speaker 3: I mix my metaphors constantly.
Speaker 2: I love it. I want to just briefly like, shout
Speaker 2: out is not the right word upon rage about rage
Speaker 2: or how sure because there is a lot out there
Speaker 2: right now on like, oh, alternative types of medicines to
Speaker 2: lower cholesterol. And I'm not talking about lifestyle interventions like
Speaker 2: diet and exercise changes. We already talked about those. They
Speaker 2: have decent evidence they're an important part of this. But
Speaker 2: one of the things that some people use or claim
Speaker 2: to have a benefit in lowering cholesterol are phytosols, right.
Speaker 2: Those are plant based cholesterols, and it is possible, based
Speaker 2: on on some like observational data, that consuming high levels
Speaker 2: of these plant based cholesterols or plant based sterols might
Speaker 2: decrease LDL cholesterol, especially when you look at people on
Speaker 2: like vegan diets who have quite a lot of phytosterol
Speaker 2: consumption or who are taking other additives of phytosterols. But
Speaker 2: we have no randomized control trial data on these, and
Speaker 2: the data that do exist, what's really interesting is that
Speaker 2: they seem to be most effective when they're consumed with meals,
Speaker 2: meaning when you're getting it from foods rather than just
Speaker 2: a supplement or an addition. And of course, as we
Speaker 2: talk about so often on this podcast, Aaron, there are
Speaker 2: no regulations on supplements, whether we're talking about phytosterols or
Speaker 2: other nutraceuticals. And one of the big ones out there
Speaker 2: for cholesterol is red yea's rice. You mentioned it erin.
Speaker 2: The mechanism of the compound produced by this yeast that's
Speaker 2: grown on rice is that it blocks hmg CoA reductastes.
Speaker 3: It's a statin. It's a statin.
Speaker 1: But okay, because it's coming from a plan, it's extracted
Speaker 1: from a plant. Plants produce different levels of these things,
Speaker 1: and so you have no idea how much you're getting,
Speaker 1: and so it can be dangerous. You could be on
Speaker 1: very low dose, non existent dose versus high intensity or whatever.
Speaker 2: And most brands in studies that have looked at this
Speaker 2: have no detectable levels of that actual compound. Right, There's
Speaker 2: no regulation on the composition of those particular supplements. There's
Speaker 2: no regulation on how much of that compound, like you said,
Speaker 2: the yeast is actually going to produce when it's fermented.
Speaker 2: So there's batch to batch variation, there's brand to brand variation,
Speaker 2: and at the end of the day, it's an unregulated statin.
Speaker 3: It's unregulated.
Speaker 2: Yeah, And I don't want to make that sound like, oh, well,
Speaker 2: pharmaceutical companies are just the best thing ever, Right, they're not.
Speaker 2: And it's also not the case that our guidelines might
Speaker 2: not be subject to some degree of bias because, like
Speaker 2: you mentioned, of the conflicts of interests that exist within
Speaker 2: cardiology and within like I mean, all fields of medicine. Realistically,
Speaker 2: a good number of the authors and the people who
Speaker 2: were involved in the peer review process for the newest
Speaker 2: DISSIPIDYMA guidelines in the US have financial conflicts of interest
Speaker 2: not just with pharmaceutical companies, but with imaging companies, with
Speaker 2: genetic testing companies. And that doesn't mean that all of
Speaker 2: our data that we have that is so strong isn't
Speaker 2: real or isn't strong, but it just muddies these waters
Speaker 2: even more and it creates this gap where people can
Speaker 2: really exploit that uncertainty totally. And it's really really a
Speaker 2: bummer because atherosclerotic heart disease, including heart attack and stroke,
Speaker 2: kills an estimated nineteen million people worldwide every year. As
Speaker 2: of the twenty twenty three Global Burden of Diseases study. Wow, Yeah,
Speaker 2: an estimated six hundred million people are living with cardiovascular
Speaker 2: disease right now every across the globe. Cardiovascular disease is
Speaker 2: the leading cause of disability just in life years. In
Speaker 2: some countries it is a third to forty to forty
Speaker 2: five percent of all deaths, and of course, especially in
Speaker 2: this country, the estimated costs to healthcare are in the
Speaker 2: hundreds of billions of dollars and an estimated eighty percent
Speaker 2: of this disease is due to modifiable risk factors and cholesterol.
Speaker 2: This relationship between LDL cholesterol and cardiovascular disease is so
Speaker 2: incredibly clear, and it is something that we really have
Speaker 2: the potential to treat right. So it's uh, it's such
Speaker 2: a huge bummer that there are so many people who
Speaker 2: do not have access to this right. And it's not
Speaker 2: just older adults. I think that we think of cardiovascular
Speaker 2: disease as something that only happens to older people. But
Speaker 2: the more that we look at and study the like
Speaker 2: pathogenesis of cardiovascular disease, the more we understand that especially
Speaker 2: cholesterol is a long term exposure that increases your risk.
Speaker 2: So having exposure to higher levels greater than one hundred
Speaker 2: of LDL cholesterol, especially greater than one sixty younger in
Speaker 2: life and for longer periods, increases your risk more than
Speaker 2: if it just goes up over time. If that makes sense, Yes,
Speaker 2: it does make sense. And it's estimated that twelve to
Speaker 2: thirteen percent of young adults have dyslipidemia in this country.
Speaker 1: Wow.
Speaker 2: So that's not a small number, right. It's estimated that
Speaker 2: in the US, if everyone, based on guidelines, who was
Speaker 2: recommended to be on medicine to lower their cholesterol was
Speaker 2: actually on a medicine for this, like a statin, we
Speaker 2: could prevent one million cardiovascular disease events like heart attack, stroke,
Speaker 2: and death in ten years. A million. Whoa Okay, And
Speaker 2: that's just in the US, where we have much better access.
Speaker 2: In low and middle income countries, it's estimated that only
Speaker 2: one in ten people who would be recommended to be
Speaker 2: on some kind of medicine to lower their cholesterol or
Speaker 2: actually on a medicine because they don't have access. Right.
Speaker 2: So that's a lot.
Speaker 3: It's a lot, Eric, It's a.
Speaker 2: Lot, but there is. I just think it's one of
Speaker 2: those situations where medicine has come so far, right, and
Speaker 2: the data that we have is so strong, but it's
Speaker 2: also not all just one thing, and I think that
Speaker 2: that is where some of the kind of confusion and
Speaker 2: uncertainty and doubt can come from. Right, Because we look
Speaker 2: at cardiovascular disease events over time, they're still going up, right,
Speaker 2: But we have these great medicines, but they're still going up.
Speaker 2: And that's because it is so many other things that
Speaker 2: play into it. So this was not an episode just
Speaker 2: only about cardiovascular disease, but cholesterol overall. And that is
Speaker 2: what I have to say Erin.
Speaker 1: It is really complicated and it's so recent, and I
Speaker 1: think that's what contributes a lot to this. And it
Speaker 1: does go to show that you can have the data,
Speaker 1: you can have the treatments, you can have the like
Speaker 1: all of these different facets of in support of this,
Speaker 1: and that's not enough. And so figuring out that gap
Speaker 1: what will make what will be enough? How do we
Speaker 1: actually either get the treatment to people who need it,
Speaker 1: how do we actually develop better treatments.
Speaker 3: Whatever it is?
Speaker 2: Right?
Speaker 1: How do we address those gaps where we're clearly failing.
Speaker 2: Yeah, yeah, it's a great Questionnaaring.
Speaker 3: Hopefully someone figures it out.
Speaker 2: Yeah. Do you want to read so many papers about
Speaker 2: how we got all of this information? We can tell you.
Speaker 2: We can tell you.
Speaker 1: I also want to shout out real quick too, that
Speaker 1: they're speaking like on the subject of misinformation and social media,
Speaker 1: wellness influencers, health influencers, stuff like that. There is Next
Speaker 1: week's book Club episode is an interview with Deborah Cohen.
Speaker 1: It's a book called Bad Influence, and it's really a
Speaker 1: fascinating conversation.
Speaker 3: Definitely tune in.
Speaker 1: There's a whole we have a little bit about Statin's
Speaker 1: in there, so check it out. Yeah, but papers for
Speaker 1: this episode, Okay, I have a bunch more again. I'll
Speaker 1: shout out again that Steinberg series from two thousand and
Speaker 1: four in Interpretive History of the cholesterol controversy, then by
Speaker 1: jew at All from twenty eighteen patient beliefs and attitudes
Speaker 1: just taking statins, and then by Endo a gift from
Speaker 1: nature the birth statins. So that's the person who.
Speaker 2: Oh I love it. Let me tell you where you
Speaker 2: can learn more. I really liked a paper by Silverman
Speaker 2: at All from JAMA twenty sixteen that was the association
Speaker 2: between lowering LDLC which is LDL cholesterol and cardiovascular risk
Speaker 2: reduction among different therapeutic interventions, A systematic review and men analysis.
Speaker 2: That's the one that has really great graphs, honestly on
Speaker 2: like with therabars and the risk reduction. Loved it. I
Speaker 2: have links to the newest guidelines as well too. The
Speaker 2: study looking at the overall risk of cardiovascular disease and
Speaker 2: heart attack was from the Journal of American College of
Speaker 2: Cardiology from twenty twenty three, and that was one of
Speaker 2: the global Burden of Disease studies, so we have that one.
Speaker 2: There's also that twenty twenty two paper by wreath at
Speaker 2: All in the Lancet that was the effect of Statin
Speaker 2: therapy on muscle symptoms and individual participant data meta analysis
Speaker 2: of large scale, randomized double blind trials. But honestly, there's
Speaker 2: so much more there, Aaron, so you everyone can check
Speaker 2: it out on our website this pocastikadi dot com under
Speaker 2: the episode stap.
Speaker 1: Thank you to Bloodmobile for providing the music for this
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