Sebastian Rushworth, M.D. | September 8, 2020
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.