You wouldn’t normally think there was much overlap between cholesterol denialism and anti-vaccination rhetoric. But there is. People who doubt the benefits of cholesterol-lowering medications, like statins, infamously tend to believe the Covid-19 vaccines killed thousands of people and will hijack BBC interviews in order to make that point. Both positions are unsupported by the science. But the interesting thing is, when it comes to cholesterol, that wasn’t always the case.
Cholesterol holds a special place in the popular imagination that sets it apart from the many other cardiac risk factors we talk about. Nobody thinks diabetes is good for you, and nobody dismisses the dangers of high blood pressure. Nobody today is under the delusion that smoking is harmless, or that our increasingly sedentary lifestyle is serving us well. But cholesterol remains a source of doubt for many in the media, the general public and, sadly, amongst physicians too.
While it is easy to pour scorn on this position, not that long ago it was actually somewhat justifiable. In September 1989, The Atlantic’s cover proclaimed: “The Cholesterol Myth: lowering your cholesterol is next to impossible with diet, and often dangerous with drugs – and it won’t make you live longer.” And they weren’t actually wrong.
It is possible to write a definitive history of cholesterol research because it only spans roughly the past 100 years. For those interested, Daniel Steinberg wrote a comprehensive 5-part series on the history of the cholesterol controversy for the Journal of Lipid Research, which was then adapted into a book: “The Cholesterol Wars: the Skeptics vs. the Preponderance of Evidence.” As unsettling as that title may be for the readership of this august publication, the point Steinberg makes in the series is that the initial skepticism was not only appropriate but also fundamental to the scientific process. But eventually the weight of the evidence became impossible to ignore, and what was once valid caution crossed over into denialism and pseudoscience.
Since I was told a 10,000 word article would not be appreciated by the readership, the history of the cholesterol controversy can be summarised in a few broad strokes. If there is a beginning to this story, that beginning was in 1913 when Nikolai Anitschkow fed rabbits purified cholesterol and demonstrated that they developed atherosclerosis in their arteries. In theory, this should have been definitive evidence, but Anitschkow faced a number of criticisms. The main problem was that his findings could not be replicated in other laboratory animals, like rats and dogs. We now understand that this happens because different animals handle cholesterol differently, but at the time it was felt that this must be some quirk specific to rabbits and was therefore irrelevant to human health. Had you been alive at the time, you might have said the same. What’s true in animals is not necessarily true in humans.
Fast forward to the 1940s and 1950s and researchers were trying to determine what could be done about the skyrocketing rates of heart disease in the early 20th century. This was the time of the Seven Countries Study by Ancel Keys, which has become a lightning rod for arguments in recent years, largely because of books like “The Big Fat Surprise” and others. Others have pointed out issues with the many criticisms levelled at Keys’ work. Broadly, we can make two points. First, the Seven Countries study was not the only study published on the subject. The Framingham Heart Study also drew associations between cholesterol and heart disease, so focusing solely on Keys essentially ignores all the other large contemporary studies of the time. Secondly, these large studies were about identifying risk factors for heart disease.
An important caveat, though, is that these weren’t diet studies or randomised trials. If you want to see whether lowering cholesterol reduces heart disease, you have to design a trial that lowered cholesterol and measured hard clinical endpoints. Had you been alive at the time, you might have said the same.
In the 1960’s researchers did exactly that. In the absence of any effective medications, they tested a series of dietary interventions in studies like the Oslo Diet-Heart study and the Finnish Mental Hospital Study, which did show a reduction in coronary heart disease. But three large trials in Britain tested corn oil, a low-fat diet, and soya-bean oil as potential therapies. While they lowered cholesterol, they didn’t affect the risk of heart disease. This prompted many like Sir John McMichael to argue against cholesterol as a cardiac risk factor and to doubt the validity of the lipid hypothesis. Had you been alive at the time, you might have said the same. If lowering cholesterol didn’t reduce cardiovascular events, then cholesterol wasn’t the thing to focus on.
In retrospect, the dietary studies were not failures per se. Many did lower cholesterol, and some did reduce cardiovascular events. But the benefits were small enough to be inconsistent and the skepticism of many was not unjustified. The hope was going to be that the new cholesterol medications would do a better job. The 1970s and 1980s saw the publication of studies on clofibrate and cholestyramine. The biggest of these, the Coronary Primary Prevention Trial, was in some ways definitive. There was a significant reduction in cholesterol which translated into a significant reduction in cardiovascular events.
The story could have ended there. But there were caveats. Cholestyramine as a medication was poorly tolerated because of its many side effects. Also, there was a reduction in cardiovascular events, but no significant drop in mortality. Some argued that there was no point treating people for a problem if they didn’t live longer. Reducing mortality is what really matters. Had you been alive at the time, you might have said the same.
And so we come to the inflection point and the Atlantic cover of 1989. “Lowering your cholesterol is next to impossible with diet, and often dangerous with drugs – and it won’t make you live longer.” It was technically correct. But for the first time you had a divergence in the debate. You could argue that the current medications were not effective at changing outcomes, and in retrospect they weren’t. They were terrible by modern standards. But if you look back objectively at the history of the research, it was pretty clear that cholesterol was involved in the process of atherosclerosis. Every time you lowered it significantly, people had fewer heart attacks. We just lacked the tools to make a major dent in people’s serum lipid profile.
In the 1990s, everything changed. Statins entered the market and the 4S study with simvastatin showed that the medication lowered cholesterol, reduced heart attacks, and also reduced cardiovascular and all-cause mortality. Twenty-six randomised studies later, it became clear that statins did what they promised. They reduced cholesterol and prevented cardiovascular disease. But the deniers still had one last redoubt. Maybe it wasn’t about cholesterol. After all, previous cholesterol trials had been disappointing. Maybe there was something special about statins and they prevented heart disease via a mechanism independent of cholesterol. Had you been alive at the time, you might have said the same. I was, and I did.
As long as statins were the only useful cholesterol medications available, you could maybe convince yourself the benefits were unique to that drug class. But they aren’t the only medication out there anymore. The development of ezetimibe (which blocks cholesterol absorption in the intestine) and PCSK9 inhibitors (which act on the cholesterol receptor in cells) have made that argument unsustainable.
The amazing thing about cholesterol medication is that their benefit is very linear. If you plot out all the studies of cholesterol medications (both statin and non-statin treatments), they fall along a very straight line. The point is a medication’s cardiovascular benefit is proportional to how much it lowers cholesterol. Dietary interventions have a small impact whereas the newer injectable cholesterol medications called PCSK9s have a huge cardiovascular risk reduction. In the end, there’s nothing special about statins. It’s the degree of cholesterol lowering that matters.
You will hear people argue that statins are too expensive, that the benefits are too marginal in a general low risk population, or that they don’t want to endure the side effects. It’s worth pointing out that statins are now off-patent, and no pharmaceutical company is lobbying for their use. The benefits of statins are inherently higher in high-risk populations and lower in low-risk ones. All medications work this way. But even in patients without cardiovascular disease, there is a cardiovascular benefit. It just isn’t as marked as what you see in patients who have a history of heart attack or stroke.
As for the side-effects, they are over-represented in the media, and many of the subjective symptoms people suffer are due to the nocebo response. What’s more, anyone who doesn’t want to use statins to lower cholesterol is free to use any of the newer (albeit more expensive) cholesterol medications on the market now. Just don’t think you can get away with natural therapies like fish oil, cinnamon, garlic, turmeric, or red yeast. These have been tested head-to-head against rosuvastatin, and the statin came out on top.
You can argue that there are better ways to measure cholesterol beyond the simple characterization of good (HDL) cholesterol versus bad (LDL) cholesterol. You can argue that, in low-risk populations, the cost of therapy outweighs the benefit. You can argue that we should be doing more to encourage lifestyle change and healthy eating habits, especially among children. All of these are interesting arguments, but they are questions of policy, not science.
Steven Nissen from the Cleveland Clinic called statin denial an “Internet-driven cult with deadly consequences.” That’s because negative news stories about statins lead to medication discontinuation and, ultimately, more heart attacks.
Not that long ago, many people had good arguments against the “lipid hypothesis.” Had you been alive at the time, you might have said the same. But, at some point, you would have had to do the thing that is oh so hard to do. You would have had to change your mind. Not everyone can pull it off.
A lot of the anti-cholesterol talking points were valid arguments decades ago. It was once valid to argue that Betamax was better than VHS. Had you been alive at the time, you might have said the same. But if you bring that up now, you would no longer be relevant.
The “lipid hypothesis” is not really a hypothesis anymore, in the same way that the Theory of Evolution is not really a theory (in the common use of the word). It’s pretty clear to everyone that cholesterol is involved in the pathogenesis of heart disease. The only way you can deny it is by denying the evidence and recycling arguments from the past. And that’s how cholesterol denialism became a pseudoscience.
Does Coffee Cause Cancer, And 8 More Myths About The Food We Eat by Dr Christopher Labos is out now, published by ECW Press.
