Is the cholesterol hypothesis dead?

Is there any life left in the cholesterol hypothesis (a.k.a. the lipid hypothesis)? Is there anything left for serious scientists to cling to or is time for its mouldering corpse to end up on the trash heap of medical history, alongside lobotomy, bloodletting and the theory of the four humors? I was asked this question by a reader of this blog recently, and as it happens, a systematic review was recently published in Evidence Based Medicine (my favorite medical journal, mainly because it is edited by the brilliant Dr. Carl Heneghan) that definitively answers this question, so I thought it would be interesting to go through what the evidence says together.

As many readers will be aware, the cholesterol hypothesis is the idea that cardiovascular disease is caused by high levels of cholesterol in the blood stream. The hypothesis harks back to the early part of the twentieth century, when a Russian researcher named Nikolai Anitschkow fed a cholesterol rich diet to rabbits and found that they developed atherosclerosis (hardening of the arteries, the process which in the long run leads to cardiovascular disease). Of course, rabbits and humans are very different species, with very different dietary preferences. Rabbits, being herbivores, normally have very little cholesterol in their diets, while humans, being omnivores, generally consume quite a bit of cholesterol. Regardless, the data was suggestive, and led to the hypothesis being formulated.

In the 1940’s and 1950’s an American researcher named Ancel Keys carried out a number of studies which supposedly showed a correlation between cholesterol intake and heart disease in humans. The most famous of these was the “Seven Countries Study”, which was an observational study carried out in, as the name implies, seven different countries, and which found that people in countries with a high intake of saturated fat had high blood levels of cholesterol, and were much more likely to develop heart disease than people in countries with a low intake of saturated fat. This lead to the hypothesis that saturated fat intake leads to high blood cholesterol levels which leads to atherosclerosis which leads to cardiovascular disease and premature death.

As we’ve discussed before, observational studies cannot draw any conclusions about causation, they can only show correlation. And there is also a question why these seven specific countries were chosen (the reader will be aware that there are in fact closer to two hundred countries) – they certainly weren’t chosen at random. If the populations in a study aren’t chosen at random, that creates a significant risk of cherry picking of data (and makes it impossible for the researchers carrying out a study to refute that accusation).

In spite of these limitations, the cholesterol hypothesis became heavily hyped, leading to official dietary recommendations around the world, which are still very much unchanged, that recommend low intakes of saturated fat and cholesterol, and of foods rich in these substances, such as red meat.

The hypothesis also resulted in pharmaceutical companies investing huge sums in research to find a drug that would lower cholesterol levels in the blood. A number of drugs were discovered, but unfortunately, although they could lower cholesterol levels, none of them seemed to have any effect on mortality. People were dying at the same rate even with these drugs, sometimes even at higher rates. That was the first hit against the cholesterol hypothesis.

Then came statins, and everything changed. Statins are molecules that in nature are produced by certain types of fungi. Among other biological functions that aren’t completely understood, they inhibit an enzyme called HMG-CoA-reductase. This enzyme is central to the body’s ability to produce cholesterol. When it is blocked, cells are unable to produce their own cholesterol and have to find it from elsewhere. This causes them to express receptors on their surfaces that allow them to suck up cholesterol from the blood stream. This effect is most noticeable in the liver, since the liver is the body’s main cholesterol factory, and is the organ primarily responsible for recycling the molecules that transport cholesterol in the blood stream (cholesterol is a vital part of cell membranes so all cells in the body have the capacity to produce their own cholesterol). Since cholesterol is hoovered up from the blood stream, the cholesterol level in the blood drops. Yay!

The reason I say everything changed with statins is that they actually seemed to work. For the first time a drug had been discovered that lowered cholesterol and that also seemed to decrease mortality. Ancel Keys seemed to have been vindicated. Anyone suggesting that the cholesterol hypothesis was dead in the water was derided as a nut.

Now, as time has gone by, the cholesterol hypothesis has actually grown more complex, which is why doctors don’t really talk about cholesterol so much any more. Instead they talk about LDL, which stands for Low Density Lipoprotein. LDL is a transport molecule that is used to transport cholesterol in the blood stream (cholesterol is a lipid and as such is not soluble in blood, so it needs to be transported in a special transport molecule). This is important, because in the updated version of the hypothesis, it’s not the cholesterol itself that’s bad, it’s the LDL. Basically, the idea is that LDL that’s moving around in the body can become oxidized. Oxidized LDL can get stuck in artery walls, and start an inflammatory process that leads to atherosclerosis. So what statins actually do is cause the liver to hoover up LDL molecules from the blood stream, which prevents them from becoming oxidized in the tissues and causing atherosclerosis.

Now, unfortunately for the pharmaceutical companies, there are patent laws, which mean that after a couple of decades, their drugs go off-patent and they are no longer able to make big profits. Which is why they have developed newer types of cholesterol lowering drugs. There is ezetimibe, which works by inhibiting the uptake of cholesterol from the intestine. Most recently there are the PCSK9-inhibitors, which increase the liver’s uptake of LDL by preventing it from recycling the LDL-receptors on its surface, which results in more receptors on the surface and therefore a higher uptake of LDL from the blood stream.

Since there has been such widespread agreement that the cholesterol hypothesis is true, and that drugs that lower LDL also lower heart disease, cardiologists’ organizations around the world have set targets for LDL levels in the blood stream. For example, the American Heart Association and the American College of Cardiologists have set a target LDL reduction of 50% for people at high risk of cardiovascular disease, and 30% for people at moderate risk. Basically, people at high or moderate risk should be started on one cholesterol lowering drug, and if this drug doesn’t have a big enough effect on their LDL levels, then a second drug should be added. If enough effect still isn’t seen, then a third drug can be added, and so on until the target is reached.

Clearly, if the cholesterol hypothesis is true, then the amount of benefit seen from lowering LDL should stand in direct proportion to the amount by which LDL is lowered, right? Anything else would be illogical.

This brings us nicely to the recent systematic review in Evidence Based Medicine. The review looked at all randomized controlled trials involving either a statin, ezetimibe, or a PCSK-9 inhibitor, in which data was provided on both the level of LDL-reduction and mortality, and in which the treatment period was at least one year. The authors declared no conflicts of interest and received no outside funding in order to carry out the review.

In total, 35 trials were included in the review, with the smallest trial containing 249 participants, and the largest trial containing 27,564 participants. The total number of participants across all the trials was over 230,000. 29 of the 35 trials had over 1,000 participants. Basically, these were for the most part large, high quality studies. That should certainly be enough data to tell us definitively whether the cholesterol hypothesis is dead or alive.

The trials were sorted based on whether they were treating people with moderate risk of cardiovascular disease or people with high risk, and then further grouped based on whether the participants on average met the official American LDL targets (at least a 30% reduction in LDL for people with moderate risk, and at least a 50% reduction for people with high risk).

Here’s what they found:

Of the 13 trials that successfully met the LDL targets, only one was able to find a beneficial effect on mortality. Of the 22 trials that did not meet the LDL targets, four reported a mortality benefit. So, overall, only 5 out of 35 trials were able to find a mortality benefit, and four of those that did find a benefit did not lower LDL to the target level.

Furthermore, some trials that saw significant LDL reductions (over 50%) were not able to show any effect on mortality, while other trials in which LDL only dropped by 11-15% did see a significant effect on mortality. Basically, less LDL-lowering actually seemed to be better in terms of mortality than more LDL-lowering.

So, what can we conclude?

Firstly, yes, the cholesterol hypothesis is dead, dead, dead. There is no correlation between effect on LDL and effect on mortality. Anyone who still chooses to cling to the cholesterol hypothesis in spite of this is consciously refusing to see what a vast amount of high quality scientific evidence is putting right in front of their eyes.

Secondly, as an interesting aside, only 5 out of 35 trials found a mortality benefit, which means that 30 out of 35 did not find any benefit. And yet somehow statins are one of the most widely prescribed drugs in the world. Personally, if I look at an entire evidence base consisting of 35 trials, with a total of 230,000 patients, and 30 of those trials, with 195,000 people, fail to find a mortality benefit, then that’s going to make me think the treatment doesn’t work. At least not if the point of the treatment is to make people live longer.

So what are the practical implications for you as a patient? As I mentioned in an earlier article, there is no point getting your cholesterol levels tested, because they tell you nothing about your risk of cardiovascular disease. If you are already on a cholesterol lowering drug, and intend to continue for whatever reason, there is no point doing annual check-ups of your cholesterol levels, because there is no correlation between how much the drug lowers those levels and your risk of future cardiovascular events. And there is certainly no point in trying to reach a “target” LDL level.

You might also enjoy my article about whether it makes sense to treat high blood pressure aggressively, or my article about whether salt is bad for your health.

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Author: Sebastian Rushworth, M.D.

I am a practicing physician in Stockholm, Sweden. I studied medicine at Karolinska Institutet (home of the Nobel prize in medicine). My main interests are evidence based medicine, medical ethics, and medical history. Every day I get asked questions by my patients about health, diet, exercise, supplements, and medications. The purpose of this blog is to try to understand what the science says and to translate the science in to a format that non-scientists can understand.

23 thoughts on “Is the cholesterol hypothesis dead?”

  1. Thank you, very interesting!

    Would you say that there are any differences between the most common hypercholesterolemia and familial hypercholesterolemia re risks and medication, or are the same results applicable for both types?

    1. Hi Åsa,

      The studies in this review have, I think, just looked at the level of cholesterol. I don’t think any have looked further to see whether the patients have familial hypercholesteremia or not.

      As dr. Malcolm Kendrick has discussed on his blog, familial hypercholesteremia is not a risk factor for heart disease. In fact, the rate of heart disease is the same regardless of whether you have familial hypercholesteremia or not. Here’s a link to one of his articles on the subject:

      https://drmalcolmkendrick.org/tag/familial-hypercholesterolaemia/

  2. Once again, very fact based, objective and logical report covering a very important and interesting subject. Well done.

    1. Luckily for me, I work in the emergency room at present, so I’m not the type of doctor who prescribes cholesterol lowering drugs to patients (that is mostly done by GP’s and cardiologists) and therefore I don’t see these types of drug reps. In Sweden, the scope for drug reps to influence doctors is more limited than in many other countries, and mostly consists of the “läkemedelslunch” or “drug lunch”, where the drug company gives the doctor a free lunch in return for sitting and listening to a presentation about the drug for an hour. Personally, I avoid going to these lunches, because studies have shown that they impact doctors prescribing patterns (of course they do, otherwise the pharmaceutical companies wouldn’t bother organizing them).

  3. So for a 37 Year old amateur who has had type 1 diabetes for over 30 years but is well controlled in diabetes but has slightly higher LDL values, is the conclusion that one do not need to start treatment for preventive purpose?

  4. Confirms what I was guessing since a long time. On top of this, our brains seem to need quite a lot of Cholesterins which needs to be transported there. Thank you very much for this article.

  5. Quite. This is seldom talked about. My husband has just died. But his mental and physical disintegration began 12 years ago when he was force-fed Lipitor, without informed consent, which suddenly, within weeks, destroyed his memory. His feedback of alarming symptoms to his female GP was met with combative comments, such as “It can’t possible be the drug… do not stop taking the drug…” It took me six months of research to persuade my husband that his prescribed statins were destroying him. But by that time the damage was done and my bright, intelligent, healthy partner (inclined towards ‘But doctor knows best…’ ) was on a downward deteriorating slide, losing his memory completely, which subsequently led to dementia. Were it not for the then VERY FEW writers and doctors speaking out, such as McKendrick, Colpo, Graveline, Ravnskov, and especially knowledge gained from the RxISK website of Dr.David Healy, I would have become insane years ago. Ill-health goes well beyond Statins, Evidence suggests that there is no such thing as the Hippocratic Oath or any ethical base to Medicine any more. A multiplicity of hidden financial agendas, not patients, are now the sole focus.

  6. Hi there
    I just recently subscribed to you email chain and am very glad I did so.
    Thank you for you clear and concise explanations that allow readers to understand and better yet, help others to understand. It seems that almost everything that we have been told about our Health over the last 40+ years is BS. The truth is just around the corner. Thank you for steering us all in the right direction. Stop the bloodletting.
    Kevin in Edmonton, Canada

  7. I have been told that in France pharmaceutical companies manage to have access to the data bases showing which doctor has prescribed how much of their medication. I guess that in other countries this works too. Which opens the door to direct rewards for turnover, nothing less that a salesman commission agreement. No wonder there are more and more patients taking 10 or more different medications each day. Especially the old people are easy targets. I wonder how long patients remain patient and confident in the light of this unhealthy system.

  8. Dr Rushworth, my greatest concern as a patient growing older is the push by the health care system to put me on medications I don’t need and won’t benefit from. You need to stand strong and you have to deal with this by yourself. I have been in the patient seat a few times, and I have to say the trust is broken. I have taken my stance; I will eventually die sometime in the future free of medicine in my body. It might be a foolish plan to say no to all pills, I may miss a possible cure, but it still seams as the most reasonable way to keep the aging body healthy and maintain a good quality of life.

    1. Hi, I think in general it makes sense to look in to the evidence on a drug before you start taking it, especially if it is a drug that you are supposed to take for the rest of your life. Polypharmacy is a huge problem in the elderly population.

  9. About 25 years ago I heard a discussion on BBC Radio 4 (the serious channel) between a cardiologist and a general physician. The cardiologist claimed that cholesterol-lowering drugs reduced deaths from heart disease. The physician countered by saying that the same drugs did not lower overall mortality as the death rates from other conditions, such as cancer, rose.

    1. Hi Sherard,
      That is exactly right. Cardiovascular deaths is a nonsense statistic that says nothing. The only thing that mattets is overall mortality. Patients usually don’t care about which cause of death is listed on their death certificate. If a drug makes you less likely to die of heart disease but as much more likely to die of something else, then that is a pointless drug to take (unless the drug has some other useful effect, like for example relieving symptoms of some kind).

  10. Thank you! I was diagnosed with familial hypercholesterolemia earlier this year and put on Rosuvastatin and Ezetimib, so this is very interesting information. Not that I’m sure what I should do about it yet though. 🙂

  11. Franz,

    Starting at about 1980 [in a quarter, a neighbourhood, or a district] any pharmacist received a monthly visit from a pharmaceutical employee.
    Computers were appearing and the employee took from the pharmacy all information he could. About his company and about other rival companies.
    Everything in a Cassette. Quantities and names of doctors included.
    They pay the favour with several boxes of antibiotics and other legal drugs ‘offered’ to the pharmacy without any papers at all.
    Later Diskettes were replace by CDs and now all goes by the Internet.
    The “drug lunch” was (and is) common.
    I think I was clear.
    In Europe…

  12. 1. There were conflict of interest stated in the systematic review (the coauthor favours a specific diet). Like all analyses, also meta analyses are not objective and simply “true”. Results depend on the selection and quality of included trials (e.g. have they been plannend and powered for the outcome of interest?) and the way the data is summarized, presented and how the findings are placed within the context of exisitng evidence. As a experienced statistician I can assure you, that also in these analyses you can push the evidence (at least slightly) in the preferred direction. For instances, if you have 30 trials and none of them was initially powered for the outcome long-term mortality, likely all of these 30 trials will not find a harmful or beneficial impact of a treatment on mortality. This doesn’t mean that there is no effect. It just means, we do not have enough data to show it.

    2. I am honestly interested what you think about the Lancet consensus paper on this topic:
    https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31357-5/fulltext

    1. Hi Frederik,
      1. As to your first point, what you say about power is true. But the problem with saying a study wasn’t powered for a result is that you can have it powered for one result, say “cardiovascular deaths”, which I’m sure you will agree is a nonsense statistic, since people don’t care about what cause of death is listed on their certificate, without being powered for “overall death”, which is what actually matters. This allows the people doing the study to claim that the drug works, even though they actually don’t know whether it does or doesn’t.

      People don’t take statins to avoid dying from heart attacks, they take them to avoid dying. And the people doing the study can also lump a bunch of different things together in to an overall outcome metric, that involves things like “frequency of PCI”, which is a decision taken by a doctor and isn’t remotely a patient oriented outcome, and then they can perhaps claim a positive effect on the overall outcome metric of death and frequency of PCI. Which most people will interpret as a positive effect on mortality, even if the entire positive effect comes from lowering the frequency of PCI.

      Almost all of these studies had several thousand participants and followed them for multiple years. If a study with that many participants carried on for that long isn’t powered to detect an effect on mortality, then the effect on mortality is so small that I would argue it isn’t worth caring about. As to the selection of trials – this meta-analysis included all published randomized controlled trials of cholesterol lowering that did at least one year of follow-up and that had data on both cholesterol lowering and mortality. All the big famous cholesterol lowering trials were included, most of which were funded by the pharmaceutical companies producing the respective drugs themselves.

      2. Like the systematic review described above shows, there is no correlation between likelihood of effect and size of LDL-lowering, so the authors of that paper are wrong on that point. And also note how they never claim that statins decrease mortality, only that they decrease “vascular events”. I think that speaks volumes. If statins decrease cardiovascular deaths but increase deaths from other causes (which is perfectly possible), then that would make them a pretty pointless drug to take.

  13. „Do not trust any statistic you did not fake yourself…. „ is apparently not by Churchill, but nevertheless true. In my main field, finance, I can confirm that I have not seen a non-biased statistic in the last 30 years. I guess it is the same when it comes to pharmaceuticals.

  14. You might have a look at Dr. Kendrick’s blog. He has a long series of articles in which he tries to get to the bottom of what causes CVD. Spoiler: he’s pretty certain that cholesterol has absolutely nothing to do with it.

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