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Let me introduce myself. My name is Mark Sisson. I’m 63 years young. I live and work in Malibu, California. In a past life I was a professional marathoner and triathlete. Now my life goal is to help 100 million people get healthy. I started this blog in 2006 to empower people to take full responsibility for their own health and enjoyment of life by investigating, discussing, and critically rethinking everything we’ve assumed to be true about health and wellness...

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March 27, 2017

Dear Mark: That New Cholesterol-Lowering Drug Study

By Mark Sisson
21 Comments

Inline_Dear_MarkFor today’s edition of Dear Mark, I’m answering one question. It’s a good one. A reader (many, actually) wrote in to get my opinion on the latest blockbuster cholesterol-lowering drug. A new study appears to show that the drug in question—Repatha—reduced LDL to unprecedented levels and protected patients against the primary cardiovascular disease endpoints they were measuring. What does it all mean? Should we all start taking Repatha?

Let’s dig into it:

Hi Mark,

What’s your take on this study of a new heart disease drug called Repatha? Apparently it was able to reduce LDL levels to an unprecedented degree, and the lower the LDL the lower the heart attack risk.

Yeah, I saw this. Here’s an article about it in the NY Times. Here’s the actual study. The Times article is positively gushing, recounting that the drug “significantly reduced the chance” of a “heart attack or stroke” in “men and women who had exhausted all other options.”

What’d they take? Repatha is an PCSK9 inhibitor. PCSK9 binds to LDL receptors and prevents them from taking up LDL particles. More PCSK9 activity, fewer available LDL receptors, more LDL particles in the blood.

Given that I’ve spoken about the importance of having good LDL receptor availability and the likely causative role of oxidized LDL particles in heart disease, this doesn’t sound too bad. After all, all else being equal, shouldn’t we want fewer LDL particles? At least Repatha isn’t cutting off a major enzymatic pathway with multiple downstream effects, which is what statins do.

Who took it? High-risk patients with heart disease, about 27.5k of them split into two groups. One got Repatha. One got placebo. Everyone was on statins, so there was no true placebo.

What happened? As the NY Times mentions, the drug did lower the chance of the primary endpoint.

Except the endpoint wasn’t just one event. The endpoint was a composite endpoint. That is, they grouped different events together. The endpoint wasn’t just “did the person have a stroke?” It was “did the person have a stroke, heart attack, hospitalization due to unstable angina or coronary revascularization, or cardiovascular death?”

There’s a big problem with composite endpoints: they assume the constituent events are of equal signifiance. Everyone can agree that death deserves “primary endpoint status.” I’d rather not die of a heart attack (or anything). I imagine most people feel the same way. Not everyone would put “ended up in the hospital because of chest pain” on equal footing as “died from a heart attack”—particularly the people taking the drug. But the success of the Repatha study depends on the two being equally undesirable.

Other “benefits” included reducing LDL levels to an average of 30. A quarter of subjects taking Repatha got their LDL levels down to 19! You’d think with LDL that low they’d be totally impervious to heart attacks and fast approaching demi-god status if not outright immortality.

They weren’t. When you shatter the composite endpoints and examine the individual events, you notice that Repatha didn’t actually help people avoid fatal heart attacks or death from other causes. In fact, the Repatha group had slightly higher death rates from heart attacks (251 vs 240) and other causes (444 vs 426), though it didn’t reach statistical significance.

Furthermore, this study was supposed to last 4 years. They ended it after a little more than 2 years. Drug companies don’t cut studies short if they’re going great. They cut studies short when things start trending south. Were the deaths piling up? Were the initial gains in primary endpoints showing signs of reversal? We just don’t know. But it looks bad if you ask me.

What’s the purpose of PCSK9, though? It can’t be “to give us heart disease.” It’s got to be there for some reason or another, even if that reason is an “outdated relic” of our ancestral past.

It probably evolved as an anti-infectious disease adaptation. LDL is anti-microbial; it can protect against viruses, bacteria, and parasites. In environments with high parasite loads or rampant infectious disease, high PCSK9 activity could enable protective levels of LDL to circulate. 

Another role of LDL is to “soak up” oxidants and other inflammatory agents in the blood. Sure enough, inflammation also increases PCSK9 activity.

Are there any other ways to inhibit PCSK9 that don’t involve spending thousands a month on a potentially-risky drug?

Berberine inhibits PCSK9. It even performs favorably against cholesterol-lowering drugs.

Fasting inhibits PCSK9. In one study, fasting humans achieved the lowest levels of PCSK9 at the 36 hour mark.

Those appear to be safer options. They at least have more history than Repatha.

Overall, I’m not sure what to say. Clearly, the gushing media coverage is misleading. The drug helped reduce non-fatal cardiovascular events, but failed to reduce fatal ones (and even slightly increased them). Furthermore, they cut the study short, which suggests the possibility of worsening mortality and/or other undesirable trends.

I’m not writing it off completely. PCSK9 inhibition might help certain people with confirmed heart disease at high risk of having another attack, like those with familial hypercholesterolemia. Maybe they work better if you’re not taking a statin. Maybe PCSK9-inhibitor+statin is just too much LDL reduction. And maybe there are other, safer ways to inhibit the enzyme.

With the massively positive response from the industry, I’m sure we’ll be getting more research in the coming years. Hopefully, it pans out. But don’t be too surprised if it doesn’t.

That’s it for today, folks. Did you hear about the study? What do you think about the results?

Take care.

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21 Comments on "Dear Mark: That New Cholesterol-Lowering Drug Study"

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KidPsych
KidPsych
1 month 2 days ago

Excellent write up, as always. It is disturbing how glowingly the media reported the study.

Malcolm Kendrick tackled the same subject with a similarly skeptical take: https://drmalcolmkendrick.org/2017/03/20/cholesterol-lowering-proven-or-not/

Lindsay @ PFM
1 month 2 days ago

Very interesting…
I thought the same thing about the media, if they are “gushing” it’s probably because of money “gushing” behind the scenes.
Always have to do your own research!!

Gypsyrozbud
1 month 2 days ago

Thanks so much for providing us with an depth CRITICAL look at this study. Too many people out there take what the media says to be the factual truth as opposed to an OPINION, which is really what it is.
Especially interesting that the study was terminated prematurely!

Shary
Shary
1 month 2 days ago

Agree. The trouble with any drug is that it inevitably comes with unwanted side effects, some of which are downright deadly. Repatha might help a few people who are in such bad shape that they would probably die otherwise. Then again, they might die anyway, with or without Repatha. The bottom line with all pharmaceuticals is PROFIT, not improved health. Once this is understood, it will also be understood that the results are probably not nearly as glowing as the surrounding hype might lead one to believe.

Flo
Flo
1 month 2 days ago

Please check Malcom Kendrick who has written a critical note on the subject as well: https://drmalcolmkendrick.org/2017/03/20/cholesterol-lowering-proven-or-not/

Time Traveler
Time Traveler
1 month 2 days ago

Mark, you are the canary in the coal mine; I love how you dissect and analyze the issues at hand and put them in perspective.

RICK
RICK
1 month 2 days ago
Personally, I don’t trust any drug testing anymore. For too many years the big pharma reps have been lying to us about their wonderful meds only to have them removed from the market a few years later when all the suffering and deaths from side effects come to light! When authorities delve deeper into the situation, they find that these deadly effects were known all along but carefully ignored until the company makes enough in sales to cover any law suits that come along. Check out the old Worst pills- Best pills publications by Public Citizen. I have never trusted… Read more »
OctoberAmy
OctoberAmy
1 month 2 days ago

+ 1. Our bodies are just a big bag of chemicals with some bones and other stuff. Every drug messes with that cocktail and I don’t believe anybody knows all the unintended consequences, I’m very suspicious of all of them (including Mark’s and all vitamins, which I do take, but sporadically. Does anybody really know what ratio the body wants, of Vit A to C or Magnesium to Manganese? And is my ratio the same as yours? Probably not. )

Marci Bowman
1 month 2 days ago

Thank you, Mark, for parsing the details and reminding us that we we’re sure of–having low LDL is great!–we’re probably not so sure of.

I, too, read the article and then the study, and wondered how the latter begat the former.

Ryan Parnham
1 month 2 days ago
As I was reading Mark’s article I was wondering about other adverse side effects of the Repatha, such as type 2 diabetes and neurocognitive side effects, given the marked decrease in LDL cholesterol, I read in the study in the “Results” section: “There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events)”. I found this a bit peculiar and ironic that they mentioned specifically what was on my mind (I doubt I’m the only one who wondered about this) but the skeptical side of me has to wonder if the… Read more »
wildrover
wildrover
1 month 2 days ago
I have worked in pharmaceutical safety for six years, and am involved in clinical trials every day. The following is my personal opinion and does not necessarily reflect the opinion of my employer. I’d just like to clarify the point about study discontinuation, since Mark points this out as a key smoking gun here. Many drugs are now tested for so called MACE (major adverse cardiac events) events – this is particularly true with diabetes drugs but is often seen with other classes including CV drugs. This really became more common after Avandia and the discovery of unintended CV events.… Read more »
Will Wilkin
1 month 2 days ago
If virtually every cell in our body needs cholesterol, and if it is essential especially to good neurology and endocrine function, isn’t LDL therefore also essential as the delivery device bringing cholesterol through the circulatory system to the cell? The problem, to my layman’s understanding, is not cholesterol and not even LDL, but rather only oxidized small-particle LDL that results from the combination of polyunsaturated vegetable oils and sugar, leading to inflammation. The larger, “fluffier” LDL produced in a very-low-carb diet high in healthy fats is actually healthful and essential. Am I wrong to think that, in most cases, such… Read more »
Dave Young
1 month 2 days ago

Damn, dude. Great analysis! I rarely have time for scientific assessments–I prefer to stick to higher-level principles instead. But they would have led me to the same conclusion. My radar is up for all the same markers as yours. Keep up the good work.

HealthyHombre
HealthyHombre
1 month 2 days ago

There are hundreds of related and synergistic chemical processes, but we’ll artificially reduce the amount of one of them, what could possibly go wrong with that?!

Clay
Clay
1 month 2 days ago

I keep kicking the table leg next to the couch. My toe is constantly sore and swollen. So I’m taking Vicodin to deal with the pain. Sure, I could just move the table, but why should have to change my lifestyle?

Susan
Susan
1 month 2 days ago

Read the great review by Dr Malcolm McKendrick cardiologist on this study. Very informative

Paley Institute
1 month 1 day ago

First of all, thanks for sharing this great blog with us! I am also very enthusiastic about fitness and love reading tips like this. I will definitely include this in my diet plan from now on. Please continue sharing this information. Thanks

Michael
1 month 1 day ago

Another FYI about the study results with this drug. The market was anticipating a much higher success rate than what was presented in the study findings and in order to appease customers (and not really appease investors), they announced that they would refund the cost of the drug if a customer had a heart attack or stroke while taking it.

Terry L Miller
Terry L Miller
1 month 1 day ago

Mark has picked another scientific paper to the bone. That’s what good science is, and that is why I have followed this blog for so long. I found the same thoroughness and critical thinking in The New Primal Blueprint, the latest iteration of an already excellent book, that I finished last night. As an added bonus, I think it qualifies as “lifting heavy things”. I recommend it.

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