Dear Mark: That New Cholesterol-Lowering Drug Study

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.


About the Author

Mark Sisson is the founder of Mark’s Daily Apple, godfather to the Primal food and lifestyle movement, and the New York Times bestselling author of The Keto Reset Diet. His latest book is Keto for Life, where he discusses how he combines the keto diet with a Primal lifestyle for optimal health and longevity. Mark is the author of numerous other books as well, including The Primal Blueprint, which was credited with turbocharging the growth of the primal/paleo movement back in 2009. After spending three decades researching and educating folks on why food is the key component to achieving and maintaining optimal wellness, Mark launched Primal Kitchen, a real-food company that creates Primal/paleo, keto, and Whole30-friendly kitchen staples.

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21 thoughts on “Dear Mark: That New Cholesterol-Lowering Drug Study”

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    1. 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!!

  1. 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!

    1. 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.

  2. 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.

  3. 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 any drug propaganda since reading much of their info!

    1. + 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. )

  4. 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.

  5. 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 study was stopped early due to the development of some of these adverse side effects? Maybe people’s fasting glucose and A1Cs were starting to trend up? Maybe there were some subtle signs of neurocognitive decline? I can’t imagine the potential for some of the metabolic disturbance from being on two potent cholesterol lowering medications (statin + PCSK9).

    As a side rant, I’m about sick of all this cholesterol discussion (by conventional medicine). As a nurse practitioner for 10 years now with extensive background in cardiovascular disease I can attest that standard cholesterol measurements mean nothing in regards to the patients I have cared for who suffer from cardiovascular/atherosclerotic events. If ANY of the standard lipid measurements seems to show any prediction for cardiovascular events it would be the TRIG/HDL ratio. The only common finding I frequently see in patients with cardiovascular disease is a low HDL often accompanied by an elevated triglyceride level. From my anecdotal experience, LDL level means absolutely nothing. Of course these people have never had any advanced lipid profiles completed and usually have other metabolic risk factors or have the presence of metabolic disease. To think that preventing cardiovascular disease is a simple as prescribing some medication to lower LDL is way too simplistic and I wish the traditional medical community would quit looking at things through such a narrow lens.

  6. 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. Cardiovascular outcomes trials are almost always results-based and do not have well-defined timelines. That is, they go until they reach enough MACE events to draw statistical significance, then stop. Drug companies will have some idea of how long this should take, based on their knowledge of patients with this disease. Without seeing the protocol I don’t know about the timelines here, but I would expect that they reached their endpoints early. Clinical trials are massively expensive and companies aren’t going to keep running a trial once they get to a level where data is statistically significant.

    Ending a study early doesn’t necessarily indicate poor outcomes related to study drug. It could mean that they have reached the designated number of endpoints in the control group. More importantly, it could actually indicate that their treatment is so effective that it’s unethical to keep giving patients a placebo or comparator. This happened with a cancer drug that I was working on – it was so clear that the drug was extending lives that FDA didn’t feel it was ethical to withhold the treatment from the other group. I doubt that’s what happened here, but it does happen and ending a study early isn’t damning on its own. In fact, Amgen is about to enroll on a long term, open label extension of this study to examine potential adverse events, so I highly doubt that this was stopped early due to safety concerns.

    Otherwise, I agree with you that it didn’t improve mortality and therefore is not a huge deal. Wall Street also agreed, and Amgen stock took a hit, even with positive results.

    1. Wildrover, thanks for your feedback. It’s helpful to have an insider’s perspective, and the additional points you make about study discontinuation round out the discussion for sure. And, yes, Wall Street did have its say on the matter. Grok on!

  7. 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 a diet is a much better path than a pharmaceutical that decreases LDL in the blood?

  8. 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.

  9. 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?!

  10. 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?

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

  12. 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

  13. 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.

  14. 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.

    1. Terry, thanks for the feedback. I’m glad you enjoyed the study analysis and am especially pleased that you’re liking The New Primal Blueprint. I put big commitment and the wisdom of MDA readership into that book, and I appreciate knowing it’s making a difference for folks. Grok on!