Ep 218 The Lowdown on Statins

Summary

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This Podcast Will Kill You

Ep 218: The Lowdown on Statins

Hosts: Dr. Erin Welsh & Dr. Erin Allmann Updyke
Date: August 4, 2026

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Overview of the Episode

In this episode, Erin Welsh (Ph.D.) and Erin Allmann Updyke (MD, Ph.D.) tackle the biology, history, controversies, and current state of statins—blockbuster drugs used for lowering cholesterol. Picking up from last week's foundational episode on cholesterol, this deep-dive explores the discovery of statins, how they work, their effect on cardiovascular disease, the public’s complicated relationship with these drugs, and the landscape of alternatives and guidelines today. The hosts emphasize evidence, dispel common misconceptions, and candidly discuss the discord between scientific consensus and public trust.

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Key Discussion Points & Insights

1. The Historical Context of Cholesterol & Heart Disease

• Early Understanding (11:16 – 13:50)
  • Seven decades of research (1910s–1980s) pieced together the link between cholesterol and cardiovascular disease.
  • Notable studies: Anichkow’s rabbit experiments, Framingham Heart Study, Brown & Goldstein’s work on the LDL receptor.
• Slow Integration into Clinical Practice
  • In 1983, half of US internists recommended no therapy unless cholesterol was over 300 mg/dL; 27% would never recommend drug therapy.

2. The Need for Effective Treatment

• Landmark Study (16:18 – 18:31)
  • 1980s: The Coronary Primary Prevention Trial showed that lowering cholesterol reduced heart attacks.
  • Cholestyramine, a sandy-tasting powder with GI side effects, was the first tested cholesterol-lowering drug—clearly needed improvements.

3. The Discovery of Statins (19:49 – 24:11)

• Akira Endo’s Logic Leap
  • Inspired by penicillin, Endo hypothesized that fungi might produce compounds inhibiting cholesterol synthesis (HMG CoA reductase).
  • After screening 6,000 microbes, he discovered compactin (mevastatin) from Penicillium citrinum—the first statin.
  • Quote:

    "[Endo] was like, fungi is all I knew. So that's where I looked. But it also, like, that logic is very clear. But it had no direct support from any studies." – Erin Welsh (21:12)

  • Pharmaceutical companies soon raced to develop their own statins (Merck's lovastatin, Simvastatin).

4. Statins’ Blockbuster Arrival & Evidence Base (23:10 – 26:03)

• Effectiveness
  • Statins shown to dramatically reduce LDL and cardiac events; Simvastatin reduced death rate by 42%.
  • By the late 1980s, statins were widely available.
  • In 40 years, deaths from cardiovascular disease have fallen >75% in some industrialized nations—statins are a key contributor, alongside diagnostics and lifestyle shifts.

5. The Controversy and Barriers to Statin Uptake (26:03 – 31:32)

• Why Aren’t More People Taking Them?
  • Practical Reasons: pill burden, financial barriers despite generics, logistical access.
  • Side Effect Fears: muscle symptoms (myopathy), GI upset, identity issues (“being on meds for life”).
  • Mistrust: doubts about efficacy, perception of pharmaceutical profiteering, shifting guidelines causing skepticism.
  • Misinformation: Media, social media and influencers play significant roles in sowing doubt about both cholesterol itself and statin safety.
• Notable Quote:

  "Controversy sells, consensus doesn't." – Erin Welsh (29:20)

6. Side Effects: Reality vs. Nocebo (32:13 – 35:32)

• Side Effects Are Real (But Also Complex)
  • After 2001’s cerivastatin recall, warnings increased and patients became hyperaware, amplifying the nocebo effect.
  • Studies show similar rates of muscle aches in statin and placebo groups; most muscle symptoms not directly caused by statins, but symptoms are still very real.
• Quote:

  "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." – Erin Welsh (34:21)

7. Wider Cultural and Technological Impacts (35:33 – 39:45)

• Social media and generative AI compound misinformation, with influencers sometimes financially motivated to push alternatives.
• Lack of provider-patient connection, insurance, and rising appointment/medication costs further impede effective care.

8. Statins in Practice: Mechanism and Options (43:03 – 56:02)

• How Statins Work
  • Statins block HMG CoA reductase, the rate-limiting step in liver cholesterol synthesis, forcing cells to pull cholesterol from the bloodstream by upregulating LDL receptors.
  • There may also be an anti-inflammatory effect, reducing plaque buildup risk.
• Differences Between Statins
  • Vary by potency (“intensity”) and in side-effect profile (though no clear favorite for fewer muscle symptoms).
• Efficacy
  • Massive evidence base: meta-analyses show statins are highly effective at lowering LDL and preventing events.
  • Quote:

    "Statins are like, like pound for pound, I guess… incredibly effective and like just so much good data to support them." – Erin Almond Updyke (51:36)

• Adverse Effects
  • Muscle symptoms are most reported, but large studies indicate <10% of muscle complaints are attributable to statins.
  • More severe effects (e.g., rhabdomyolysis): 4 excess cases per 10,000 on high intensity regimens.

9. Alternative Therapies and New Frontiers (59:57 – 65:44)

• Other Meds:
  • Ezetimibe: limits cholesterol absorption, ~10% LDL reduction.
  • PCSK9 Inhibitors: monoclonal antibodies or siRNA (e.g., inclisiran) that prevent breakdown of LDL receptors, allowing even greater cholesterol clearance; offer potent LDL reduction but are expensive and less studied.
• Supplements & "Natural" Alternatives
  • Phytosterols & red yeast rice lack regulation, have variable efficacy, and may pose risks.
  • Quote:

    "Most brands…have no detectable levels of that actual compound. Right. There's no regulation on the composition of those particular supplements." – Erin Almond Updyke (69:08)

• On Guidelines and Conflicts of Interest
  • Many involved in writing cholesterol guidelines have ties to pharma, imaging, or genetics industries; the evidence base is massive, but trust issues are understandable.

10. Global Perspective & Call to Action (70:29 – 72:59)

• Global Impact
  • Cardiovascular disease causes ~19 million deaths/year; 600 million people worldwide live with it.
  • 80% of cases due to modifiable risk factors.
  • In the US, if all eligible people took statins as recommended, up to 1 million cardiovascular events could be prevented in 10 years.
• Access Disparity
  • Only 1 in 10 people needing cholesterol-lowering medication in low/middle-income countries get them.
• Lifelong Management
  • Statins and similar regimens usually required indefinitely ("Plaques weren't built in a day…").
• Quote:

  "Cholesterol… this relationship between LDL and cardiovascular disease is so incredibly clear… we really have the potential to treat [it]." – Erin Almond Updyke (71:46)

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Notable Quotes & Memorable Moments

• On Scientific Progress:

  "I also just can't believe how recent it all is." – Erin Welsh (24:26)

• On The Patient Experience:

  "Blame your parents. Like, it's probably your genetics." – Erin Almond Updyke (47:24)

• On Prevention:

  "Rebrand these drugs for what they are. Heart attack prevention, stroke prevention, a way to extend your life, your quality of life…" – Erin Welsh (39:10)

• On Public Health:

  "It's such a huge bummer that there are so many people who do not have access to this." – Erin Almond Updyke (71:38)

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Timestamps for Important Segments

• [11:16] – Rise of cholesterol as a cardiovascular villain; key studies
• [16:18] – First intervention trials and guideline shifts
• [19:49] – Akira Endo’s story and the discovery of statins
• [23:10] – Statins hit the market; global impact
• [26:03] – Why people refuse or discontinue statins: practical, social, and psychological barriers
• [32:13] – Side effects, the nocebo effect, and addressing patient fears
• [43:03] – Deep dive into how statins (and other options) work; efficacy compared
• [59:57] – New alternatives and a realistic look at “natural” products
• [70:29] – Stats and global burden; how many events could be prevented
• [72:58] – Call to action and summary of the problem

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Final Thoughts

The Erins conclude that, although statins are life-saving with a vast evidence base, uptake remains stymied by misinformation, side-effect anxiety, access issues, and systemic trust deficits. They call for better education, improved patient-provider relationships, and systemic solutions to bridge the gap between known science and real-world health outcomes.

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Further Reading & Resources

• Scientific Papers & Guidelines:
  • Steinberg: ‘An interpretive history of the cholesterol controversy’
  • Jew et al. 2018: Patient beliefs and attitudes about statins
  • Silverman et al., JAMA 2016: Meta-analysis of LDL lowering and cardiovascular risk
  • Wreath et al., Lancet 2022: Muscle symptoms meta-analysis
  • 2023 Global Burden of Disease Study

Links and more resources can be found at thispodcastwillkillyou.com under the episodes tab.

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Next Week

A book club episode featuring Deborah Cohen, author of “Bad Influence,” examining misinformation and the wellness industry—with a segment on statins.

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End of Summary

Transcript

[Erin Almond Updike]

This is exactly right.

[Kal Penn]

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[Narrator/Trailer Voice]

Class.

[Kal Penn]

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[Erin Almond Updike]

None of these words have anything to

[Kal Penn]

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[Erin Almond Updike]

Barbara in the house.

[Kal Penn]

Hope you guys aren't too drunk. Already now in theaters.

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[Kal Penn]

Oh, so it couldn't have been a woman sexist?

[Erin Almond Updike]

You ever see Ocean's 8? Enough Super Troopers 3?

[Kal Penn]

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[Erin Welsh]

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 influen. 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. 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. Choos. 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.

[Advertisement Voice]

Sa.

[Erin Almond Updike]

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

[Erin Welsh]

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 leap that it took.

[Erin Almond Updike]

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

[Erin Welsh]

Yeah, me too. Me too. It's gonna be great. Hi, I'm Erin Welsh.

[Erin Almond Updike]

And I'm Erin Almond Updike.

[Erin Welsh]

And this is this podcast, Will Kill youl.

[Erin Almond Updike]

Welcome to Cholesterol Part two.

[Erin Welsh]

Part two, where we lower statin. Boogaloo. Yes.

[Narrator/Trailer Voice]

Good ones.

[Kal Penn]

Yeah.

[Erin Welsh]

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 disease.

[Erin Almond Updike]

I know that we're biased, but I think it's a great episode. I did, too. Haven't listened to it. Check it out. And then today, we're gonna 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 gonna be really great.

[Erin Welsh]

Yes.

[Erin Almond Updike]

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

[Erin Welsh]

It is. Once again, we are drinking Plac Attack again. Are we attacking plaque? Is plaque attacking us?

[Erin Almond Updike]

Yes. A little bit of both.

[Erin Welsh]

Yes.

[Erin Almond Updike]

What can plaque attack?

[Erin Welsh]

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

[Erin Almond Updike]

So we'll post the full recipe on our website. Podcast with Kelly.com on our social medias, which include Instagram and Blue sky and Facebook. 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.

[Erin Welsh]

Absolutely. You will.

[Advertisement Voice]

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[Erin Welsh]

You can also see a little bit of what we're up to by going to our website. This podcast will kill you. Dot com. It's got. Yeah, not. Not quite, but like, it's got. It's got resources, right?

[Erin Almond Updike]

Lots of resources.

[Erin Welsh]

Lots. We've got all of the papers for all of our episodes. It's got links to our bookshop.org affiliate page, music by Bloodmobile, links to Merch, links to Patreon. It's got a firsthand account form a Contact Us form, things that you can explore.

[Erin Almond Updike]

Everything we could think of is there.

[Erin Welsh]

Yeah.

[Erin Almond Updike]

Thank you to everyone who has rated and reviewed and subscribed on your podcatcher or YouTube of choice. Yes, yes, we appreciate it.

[Erin Welsh]

We do. We know there is 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.

[Erin Almond Updike]

I know every time someone says, they listen. I'm like, to me, to us.

[Erin Welsh]

What?

[Erin Almond Updike]

Really?

[Erin Welsh]

Yeah. It's incredible. It's incredible.

[Advertisement Voice]

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[Erin Welsh]

Thank you.

[Erin Almond Updike]

Okay, Aaron, tell me about this guy and how he came up with statins and everything else.

[Erin Welsh]

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

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[Erin Almond Updike]

Goodbye, Goodbye.

[Kal Penn]

Hey everyone, it's Kal Penn. I'm the host of Irsay The Audible and iHeart Audiobook Club. This week on the podcast, I am sitting down with Ray Porter, the narrator of Andy Weir's audiobook project, Hail Mary, massive sci fi adventure about survival and science and what happens when you wake up alone, very far from Earth.

[Ray Porter]

I really had to make a decision because I caught myself getting that frog in my throat and starting to get teary as I'm narrating some of these sections. And it's like, okay, yo, yo, yo, is this indulgent? And I really thought about it. I was like, no. At this point it would kind of be betraying the trust the author and the listener have in telling this story if I don't go through it. But there's places in this book that deeply, emotionally affected me, and I left it on the mic. That's great because it served the story. People will say like, oh my God, I cried at the end. It's like, yeah, dude, me too.

[Kal Penn]

Listen to Irsay, the Audible and iHeart audiobook club on the iHeartradio app or wherever you get your podcasts.

[Erin Welsh]

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 Anichkow's Atherosclerotic Rabbits. There were analytical ones, epidemiological ones, like the Framingham Heart Study genet and mechanistic ones like Brown and Goldstein's Nobel Prize winning work characterizing the LDL receptor. Lots of different studies, right?

[Erin Almond Updike]

Lots of different lines of evidence.

[Erin Welsh]

Yes, yes. And this week I'm gonna 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 cardiovasc vascular 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 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.

[Erin Almond Updike]

Fascinating. Total cholesterol in like the mid-80s, basically.

[Erin Welsh]

1983. Yeah.

[Erin Almond Updike]

Wow.

[Erin Welsh]

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

[Erin Almond Updike]

Yeah, 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.

[Advertisement Voice]

Yep.

[Erin Almond Updike]

So that. Oh, it's just so interesting.

[Erin Welsh]

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

[Erin Almond Updike]

340.

[Erin Welsh]

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

[Erin Almond Updike]

For cholesterol.

[Erin Welsh]

For cholesterol, 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?

[Erin Almond Updike]

Yeah.

[Erin Welsh]

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

[Erin Almond Updike]

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. Tell me Evidence Based Medicine.

[Erin Welsh]

Yeah. Okay.

[Erin Almond Updike]

Because that is a really new thing.

[Erin Welsh]

Wait, wait, wait.

[Advertisement Voice]

What do you mean by that?

[Erin Welsh]

It's a really new thing?

[Erin Almond Updike]

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.

[Erin Welsh]

And it would be really interesting. Humoral theory has tons of support, Aaron.

[Erin Almond Updike]

So anyway, sorry, to sidetrack.

[Erin Welsh]

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

[Erin Almond Updike]

Yes, I know.

[Erin Welsh]

Just like.

[Erin Almond Updike]

Yeah, there's too long of a list.

[Erin Welsh]

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

[Erin Almond Updike]

It is. We're in the 80s.

[Erin Welsh]

We're in the 80s.

[Erin Almond Updike]

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

[Erin Welsh]

Right. And the cardiologists or the 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.

[Erin Almond Updike]

Right.

[Erin Welsh]

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

[Erin Almond Updike]

Okay.

[Erin Welsh]

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 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.

[Erin Almond Updike]

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

[Erin Welsh]

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

[Erin Almond Updike]

For causation, exactly. Yeah.

[Erin Welsh]

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, cholestyramine. Statins weren't yet approved at this point, and all participants were instructed to follow a cholesterol lowering diet.

[Erin Almond Updike]

Okay.

[Erin Welsh]

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.

[Erin Almond Updike]

Right.

[Erin Welsh]

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 the treatment to a T, like the the cholestyramine 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.

[Erin Almond Updike]

Right.

[Erin Welsh]

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 import importance of cholesterol.

[Erin Almond Updike]

I love that.

[Erin Welsh]

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%.

[Erin Almond Updike]

So, like in 1986, only like, 34%

[Erin Welsh]

said your LDLs would be like, yeah, okay, okay, 95. And then it was 75% in 1995. Yeah.

[Erin Almond Updike]

Better than before.

[Erin Welsh]

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, cholestyramine, 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 this or something like that.

[Erin Almond Updike]

No one's chased that.

[Erin Welsh]

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, stuff like that.

[Advertisement Voice]

Yeah.

[Erin Welsh]

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.

[Erin Almond Updike]

Okay.

[Erin Welsh]

In 1971, the firsthand account provider for this episode, Dr. Akira Endo, was working as a research biochemist at the Japanese pharmaceutical company Sankyo 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 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.

[Erin Almond Updike]

No, Right, right, right.

[Erin Welsh]

It's part of the. The ecology of their penicillium. 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.

[Narrator/Trailer Voice]

Cholesterol.

[Erin Almond Updike]

Because cholesterol is so essential for life.

[Erin Welsh]

Yeah.

[Erin Almond Updike]

Fascinating.

[Advertisement Voice]

Yeah.

[Erin Almond Updike]

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

[Erin Welsh]

Fleming did this. Maybe there's something.

[Erin Almond Updike]

I can find something here. Because cholesterol is so important.

[Erin Welsh]

Yes.

[Advertisement Voice]

And he was.

[Erin Welsh]

I mean, part of the thing too. He was like. He was like, fungi is all I knew. So that's where I looked.

[Erin Almond Updike]

Huh.

[Erin Welsh]

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.

[Erin Almond Updike]

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

[Erin Welsh]

Right?

[Advertisement Voice]

Yeah.

[Erin Welsh]

And he found it.

[Erin Almond Updike]

And he was right.

[Erin Welsh]

He found it. Yeah. I mean, so 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. It's like searching for a needle in a haystack, really.

[Narrator/Trailer Voice]

Wow.

[Erin Welsh]

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, another penicillium, and they named it compactin, also known as Mevastatin later on.

[Erin Almond Updike]

Okay. Yeah. Okay.

[Erin Welsh]

And this was the first statin. Wow.

[Advertisement Voice]

Yeah.

[Erin Welsh]

So over the next several years, Endo and other researchers at Sankyo tested compactin 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 gonna look for our own statin in the same way they had to kiss. Way fewer frogs. Only 18 before they found their prints in Lovastatin in 1978. Ugh.

[Erin Almond Updike]

Competition.

[Erin Welsh]

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.

[Erin Almond Updike]

Okay.

[Erin Welsh]

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? Right, you betcha.

[Erin Almond Updike]

Yeah.

[Erin Welsh]

You betcha.

[Advertisement Voice]

Yeah. Yeah.

[Erin Welsh]

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.

[Erin Almond Updike]

Simvastatin. We still use it today.

[Erin Welsh]

Yeah.

[Narrator/Trailer Voice]

Wow.

[Erin Welsh]

Yeah. Statins looked to be the next blockbuster drug. And soon every pharmaceutical company wanted in on the action, of course. And by the last year of the 1980s, three statins were approved and available on the market.

[Advertisement Voice]

Wow.

[Erin Welsh]

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.

[Erin Almond Updike]

Right.

[Erin Welsh]

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

[Erin Almond Updike]

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

[Erin Welsh]

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

[Erin Almond Updike]

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

[Erin Welsh]

I know.

[Erin Almond Updike]

And I'm just like, what?

[Ray Porter]

I.

[Erin Welsh]

There's a lot. There's a lot. And we're gonna, we're gonna get into it in a second. But. Yeah, 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.

[Erin Almond Updike]

Correct.

[Erin Welsh]

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. 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?

[Advertisement Voice]

Why?

[Erin Welsh]

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.

[Erin Almond Updike]

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

[Erin Welsh]

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

[Erin Almond Updike]

Right? Yeah, yeah.

[Erin Welsh]

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

[Erin Almond Updike]

Right.

[Erin Welsh]

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.

[Erin Almond Updike]

Yeah.

[Erin Welsh]

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.

[Erin Almond Updike]

Right.

[Erin Welsh]

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

[Erin Almond Updike]

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

[Erin Welsh]

Right. Exactly.

[Erin Almond Updike]

Why would I be on a medicine forever?

[Erin Welsh]

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. 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.

[Erin Almond Updike]

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, in March of this year. So they're changed yet again.

[Erin Welsh]

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 of 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 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 informations 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. 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 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.

[Erin Almond Updike]

Yeah.

[Erin Welsh]

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 sewn 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.

[Erin Almond Updike]

100%. 100%. And I will say, like in today's day and age, not just with pharmaceutical companies, Also with radiology companies and imaging companies and genetics 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.

[Erin Welsh]

They matter. They do matter. And 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. At the same time, decades of statin research. These drugs have been around for. For almost 40 years.

[Erin Almond Updike]

40 years now.

[Advertisement Voice]

Yeah.

[Erin Welsh]

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.

[Erin Almond Updike]

It's so true, Erin. It's true.

[Erin Welsh]

It's true.

[Erin Almond Updike]

Okay.

[Erin Welsh]

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, cerevastatin, was removed from the market due to safety concerns, specifically for rhabdomyolysis, 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. All statins 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.

[Erin Almond Updike]

Right. Were the cause of that.

[Erin Welsh]

The cause of that cause.

[Advertisement Voice]

Right.

[Erin Welsh]

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 like 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.

[Erin Almond Updike]

Right.

[Erin Welsh]

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.

[Erin Almond Updike]

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

[Erin Welsh]

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

[Erin Almond Updike]

We're supposed to feel something.

[Erin Welsh]

Something.

[Erin Almond Updike]

Yeah, yeah.

[Erin Welsh]

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, disinformation. 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 Isn't

[Erin Almond Updike]

there some evidence of these side effects with statins? Like those kinds of questions.

[Erin Welsh]

Yeah, yeah. Or like, what should I take that's safer than statins? Like, what natural products should I take that's safer than statins?

[Erin Almond Updike]

Okay.

[Erin Welsh]

But many of these models gave inappropriate and inaccurate answers.

[Erin Almond Updike]

That doesn't surprise me at all.

[Erin Welsh]

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.

[Advertisement Voice]

Yeah.

[Erin Welsh]

There. And 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. 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, and I'll tell you, 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.

[Narrator/Trailer Voice]

Right.

[Erin Welsh]

This. This information is. Is out there, and that is filling a hole that you want.

[Kal Penn]

Yeah.

[Erin Almond Updike]

Right. 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.

[Erin Welsh]

Right.

[Erin Almond Updike]

I'm not fine if I'm having symptoms.

[Advertisement Voice]

Right.

[Erin Welsh]

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. 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. 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.

[Erin Almond Updike]

Right?

[Advertisement Voice]

Right.

[Erin Almond Updike]

I can't. I can't put my mind in that place.

[Erin Welsh]

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.

[Erin Almond Updike]

I would love to

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[Kal Penn]

Hey, everyone, it's Cal Penn. I'm the host of Irsay The Audible and iHeart Audiobook Club. This week on the podcast, I am sitting down with Ray Porter, the next narrator of Andy Weir's audiobook project, Hail Mary massive sci fi adventure about survival and science and what happens when you wake up alone, very far from Earth.

[Ray Porter]

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[Kal Penn]

Listen to Irsay the Audible and iHeart audiobook club on the iHeartradio app or wherever you get your podcasts.

[Erin Almond Updike]

So knowing that statins have made such a huge impact or has 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.

[Narrator/Trailer Voice]

Mm.

[Erin Almond Updike]

And so the first thing to know is that while statins are 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.

[Erin Welsh]

Yeah.

[Erin Almond Updike]

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

[Erin Welsh]

Yep.

[Erin Almond Updike]

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. 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, Aaron, about familial hypercholesterolemia. 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 at taking that cholesterol out of our bloodstream.

[Erin Welsh]

Right.

[Erin Almond Updike]

All 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, 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.

[Narrator/Trailer Voice]

Right.

[Erin Almond Updike]

Switching out animal products for plant products. These are the kinds of dietary changes that we have good data, data to say that not only do they reduce your cholesterol levels, 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. And it's still not enough. And that happens so, so, so often.

[Advertisement Voice]

Right.

[Erin Welsh]

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. No, you're not a failure of two.

[Erin Almond Updike]

Yeah, 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 gen. 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.

[Narrator/Trailer Voice]

Yes.

[Erin Almond Updike]

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 statistics 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.

[Erin Welsh]

So you have. If you have more HMG COA reductase, then you have more cholesterol floating in your body. If you reduce SAT reductase, that enzyme, then you have less cholesterol.

[Erin Almond Updike]

And, Aaron, 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 break 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, actually upregulate those LDL receptors, those Velcro sticky hands on the surface of their cells 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.

[Erin Welsh]

Beautiful.

[Erin Almond Updike]

Isn't that cool? Oh, yeah, I love that. There's also some interesting evidence that statins also might have a little bit of like an anti inflammatory. Well, 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. Aaron, 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 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.

[Narrator/Trailer Voice]

Right.

[Erin Almond Updike]

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 LDL cholesterol and at reducing the risk of adverse cardiovascular events, period.

[Erin Welsh]

Is that what is. What did that study show, the meta analysis show in terms of like the by the numbers impact?

[Erin Almond Updike]

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

[Erin Welsh]

Okay.

[Erin Almond Updike]

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. Data on them.

[Advertisement Voice]

Right, right.

[Erin Almond Updike]

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. Right.

[Erin Welsh]

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?

[Erin Almond Updike]

Great question. So different types of statins, a lot of the differences in their potency. So some statins can lower your LDL cholesterol to a much greater degree than other statins. Statins. The exact of like, why, I don't know.

[Advertisement Voice]

Okay.

[Erin Almond Updike]

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.

[Erin Welsh]

Okay, okay, okay.

[Erin Almond Updike]

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 and 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, Aaron. It is not the case that side effects don't exist.

[Erin Welsh]

Right.

[Erin Almond Updike]

Any medication, any therapy really has the potential to cause side effects. And like you mentioned, Aaron, 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 control trials from over 150,000 people.

[Ray Porter]

People.

[Erin Welsh]

Wow.

[Erin Almond Updike]

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 cells symptoms could actually be directly attributed to statins themselves. Does that make sense?

[Erin Welsh]

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 causing.

[Erin Almond Updike]

Exactly.

[Erin Welsh]

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

[Erin Almond Updike]

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 mil. 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 a 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 mild myopathy. Now.

[Advertisement Voice]

Right.

[Erin Almond Updike]

That does not mean that they can't ever. Right, right. There are more serious events like rhabdomyolysis, and that is estimated to occur about 4 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.

[Erin Welsh]

Right, right, right.

[Erin Almond Updike]

So statins will cause four excess cases for every 10,000 people on a high intensity statin.

[Erin Welsh]

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

[Erin Almond Updike]

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.

[Erin Welsh]

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?

[Erin Almond Updike]

I don't know.

[Erin Welsh]

Okay.

[Erin Almond Updike]

I don't. We don't have an answer to that. Just.

[Erin Welsh]

The paper didn't suggest any.

[Erin Almond Updike]

No.

[Erin Welsh]

Any answers. Okay.

[Erin Almond Updike]

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

[Erin Welsh]

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.

[Erin Almond Updike]

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. Okay, 11 per 1,000.

[Advertisement Voice]

Right.

[Erin Welsh]

So it's tricky. It's really tricky.

[Erin Almond Updike]

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

[Kal Penn]

Yeah.

[Erin Almond Updike]

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.

[Erin Welsh]

Right.

[Erin Almond Updike]

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

[Erin Welsh]

Yeah, yeah, yeah, yeah.

[Erin Almond Updike]

Which I see all the time.

[Erin Welsh]

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. Is, and deciding is this caused by the statin? Is this not caused by the statin? Are you going to be someone who is the.001%? Are you? And then it's like, what? Even if these side effects are not direct, directly caused by the statin, they're still impeding your ability to say, exercise or something like that. And so it's like, which is going

[Erin Almond Updike]

to be helpful for your health.

[Advertisement Voice]

Right.

[Erin Welsh]

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

[Erin Almond Updike]

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 Welsh]

Aaron.

[Erin Almond Updike]

But maybe that's my bias.

[Erin Welsh]

Well, it's not, but I think it, it is the way that medicine is going and like the. And has been trending in the last 20 years. More expensive, shorter visits.

[Erin Almond Updike]

Yep.

[Erin Welsh]

More video visits that don't always necessarily feel like you're having a connection with someone.

[Narrator/Trailer Voice]

Right.

[Erin Welsh]

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

[Erin Almond Updike]

I know, because they're the most important thing in my highly biased opinion. Okay, but we have more options, too. Some people are going to 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.

[Narrator/Trailer Voice]

Yeah.

[Erin Almond Updike]

And I'm not going to go through every single one. But I'm going to 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 pretty 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 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.

[Erin Welsh]

Inhibitors, yes.

[Erin Almond Updike]

PCSK9 is the shorthand name for a protein that I'm not going to 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 receptor recycler of this protein, of this receptor who usually collects the LDL in our bloodstream. Okay.

[Advertisement Voice]

Yeah.

[Erin Almond Updike]

Why does this protein do this? Yeah, 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 recommended recycled to be collecting our LDL cholesterol in our bloodstream.

[Erin Welsh]

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

[Erin Almond Updike]

Yeah, the protein. Yeah, PCS9. Exactly. It's a Velcro glove thief.

[Erin Welsh]

Then the Velcro gloves are numerous. Catch all those tennis balls of ldl.

[Erin Almond Updike]

I really like this analogy, by the way.

[Erin Welsh]

It's a really good analogy.

[Erin Almond Updike]

I'm.

[Erin Welsh]

Yeah, thanks.

[Erin Almond Updike]

You know, I don't always come up with good ones, so I mean, the

[Erin Welsh]

best I could do was Bill Buckner.

[Erin Almond Updike]

So 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 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 inclusive glycerin, which is a small interfering RNA molecule, okay. That binds to this proteins PCSK9's MRNA and degrades it. So it's also affecting that same system. It's just not blocking the receptor itself. Isn't that so cool?

[Ray Porter]

Wow.

[Erin Almond Updike]

And the data on all of these medicines that affect PCSK9, it is incredibly strong. So we talked about that, 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 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.

[Erin Welsh]

Do we have information about side effects?

[Erin Almond Updike]

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.

[Narrator/Trailer Voice]

Okay.

[Erin Welsh]

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

[Erin Almond Updike]

That's a great question. I don't have a number for you. Okay. What the data shows is that the higher your individual risk of cardiovascular disease. Right. Because cardiovascular disease is not only cholesterol.

[Erin Welsh]

No, no, no.

[Erin Almond Updike]

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 react. 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. Cholesterol to really lower your risk of bad outcomes.

[Erin Welsh]

Okay.

[Advertisement Voice]

Okay.

[Erin Almond Updike]

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.

[Erin Welsh]

Okay.

[Erin Almond Updike]

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

[Narrator/Trailer Voice]

That low.

[Erin Almond Updike]

Okay. 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.

[Erin Welsh]

Huh?

[Erin Almond Updike]

Yeah.

[Erin Welsh]

So prolonged use of statins or like longtime 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 or, or

[Erin Almond Updike]

another lipid lowering medicine or something like

[Erin Welsh]

that, you are on that regimen for the rest of your life.

[Erin Almond Updike]

Often, yeah. Okay. Often, yeah, that, that. Because again, that's the data that we have. Right, right. And we'll talk in a second about how much atherosclerosis is. It is a disease of, of long term, right?

[Erin Welsh]

Yeah.

[Erin Almond Updike]

It's not a, it's not a short term, it's not the rabbits that just get it in a week or two. Yeah. It is a long term disease kind of thing. And so that is why it requires long term management.

[Erin Welsh]

Plaques weren't built in a. Just like Rome wasn't built in a. Whatever.

[Narrator/Trailer Voice]

Yeah.

[Erin Almond Updike]

Isn't it a day?

[Erin Welsh]

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

[Erin Almond Updike]

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

[Erin Welsh]

Or how about.

[Erin Almond Updike]

Because there, there is a lot out there right now on like, oh, alternative types of medicine, 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 phytocerols. 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 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. Consumed with meals, meaning when you're getting it from foods rather than just a supplement or an addition. And of course, as we talk about so often on this podcast, Aaron, 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, Aaron. The mechanism of the compound produced by this yeast that's grown on rice is that it blocks HMG CoA Reductase.

[Erin Welsh]

It's a statin. It's a statin, 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 intensity, high intensity or whatever.

[Erin Almond Updike]

And most brands in studies that have looked at this have no detectable levels of that actual compound. Right. 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.

[Erin Welsh]

It's unregulated.

[Erin Almond Updike]

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

[Advertisement Voice]

Right.

[Erin Almond Updike]

No, no, 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.

[Erin Welsh]

Right.

[Erin Almond Updike]

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 unseen certainty.

[Erin Welsh]

Totally.

[Advertisement Voice]

Totally.

[Erin Almond Updike]

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.

[Narrator/Trailer Voice]

Wow. Yeah.

[Erin Almond Updike]

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 is so incredibly clear and it is something that we really have the potential to treat. Right.

[Erin Welsh]

Yeah.

[Erin Almond Updike]

So it's, it's such a huge bummer that there are so many people who do not have access to this.

[Ray Porter]

Right.

[Erin Almond Updike]

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.

[Erin Welsh]

Yeah.

[Erin Almond Updike]

So having exposure to higher levels greater than 100 of LDL cholesterol, especially great 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.

[Erin Welsh]

Yes, it does make sense.

[Erin Almond Updike]

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

[Advertisement Voice]

Wow.

[Erin Almond Updike]

So that's not a small number.

[Erin Welsh]

Yeah.

[Erin Almond Updike]

Right. It's estimated that in the US if everyone, based on guidelines, who was recommended to be on medicine to lower their clinical 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.

[Advertisement Voice]

A million.

[Ray Porter]

Whoa.

[Erin Almond Updike]

Okay.

[Erin Welsh]

And a lot.

[Erin Almond Updike]

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 Welsh]

It's a lot, Aaron.

[Erin Almond Updike]

It's a lot. 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. 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.

[Erin Welsh]

Yeah.

[Erin Almond Updike]

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, Aaron.

[Erin Welsh]

It is really complicated. And. 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 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.

[Erin Almond Updike]

Right.

[Erin Welsh]

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

[Erin Almond Updike]

Yeah, yeah, yeah. It's a great question, Erin.

[Erin Welsh]

Hopefully someone figures it out.

[Erin Almond Updike]

Yeah. Do you want to read so many papers about how we got all of this information? We can tell you.

[Erin Welsh]

We can tell you. I also want to shout out real quick too, that they're speaking like on. 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. 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. By Jew et al. From 2018, patient beliefs and attitudes, just taking statins. And then by Endo, a gift from Nature, the birth of statin. So that's the person who.

[Erin Almond Updike]

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 LDLC, which is LDL cholesterol, and cardiovascular risk reduction among different therapeutic interventions, a systematic review and meta analysis. That's the one that has really great graphs on assessment 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 the one of the global Burden of Disease studies. So we have that one. There's also that 2022 paper by Wreath et al in the Lancet that was the effect of statin therapy on muscle symptoms and individual participant data meta analysis analysis of large scale randomized double blind trials. But honestly, there's so much more there. Aaron so you everyone can check it out on our website this podcast with kitty.com under the episodes tab.

[Erin Welsh]

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

[Erin Almond Updike]

Thank you to Liana and Tom and Mark and Jessica and everyone at exactly right for everything that you do to make this podcast possible.

[Erin Welsh]

Thank you, thank you and thank you to you listeners, subscribers, watchers, et cetera. We appreciate you 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. Yeah, whatever, anyone it is. It truly means everything.

[Erin Almond Updike]

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

[Erin Welsh]

Until next time, wash your hands.

[Erin Almond Updike]

You feel the animals.

[Advertisement Voice]

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[Ray Porter]

This episode is supported by FX's the Shards, a seductive drama from executive producer Ryan Murphy. Set in 1980s Los Angeles, the series follows a group of glamorous, deeply entangled high school seniors drawn into a life of wealth, beauty, parties and excess. At its center is Brett, whose reality begins to unravel when the arrival of a new student coincides with a series of mysterious murders. FX's the Shards, now streaming on Hulu.

[Kal Penn]

Hey everyone, it's Kel Penn. I'm inviting you to join the best sounding book club you've ever heard with my podcast here, Hearsay, The Audible and iHeart Audiobook Club. Every episode, I nerd out with amazing guests and dive into the best new audiobooks available on Audible. It's the book club for your ears. Listen to Earsay, the Audible and iHeart audiobook club on the iHeartradio app or wherever you get your podcasts.