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The Great Cholesterol Debate

In the great cholesterol debate that has been going for the better part of a hundred years, there have been so many issues regarding how to measure it, how to treat it, and whether to treat it at all. The latest issue: does particle size vs. particle number matter, and should you be paying money to private labs to find out?

Before we can talk about cholesterol and how to measure it we need to get some things straight. Cholesterol is absolutely tied to heart disease even though convincing people of that fact has been surprisingly difficult. The cholesterol hypothesis for heart disease dates back to the early 1900’s when Russian physician Nikolay Anichkov demonstrated that feeding rabbits a high cholesterol diet led to the fatty deposits in coronary arteries that cause heart disease. Unfortunately, his work garnered little notice at the time, and to be fair rabbits and humans are very different. But by the 1950’s rising rates of cardiovascular disease sparked new interest in this poorly understood molecule called cholesterol. Work by John Gofman and Donald Fredrickson determined the different types of cholesterol and how they were handled by the liver. But the real milestone in the link between cholesterol and heart disease came from the Framingham Heart study. Starting in 1960, a series of publications from the Framingham Heart Study would link cholesterol, blood pressure, smoking, obesity, and lack of exercise to heart disease. It is largely because of the Framingham Heart study that we identified what we call the traditional cardiac risk factors.

However, using total cholesterol was good but imperfect tool for predicting cardiac risk. Cholesterol after all is a general term that encompasses a number of different molecules called lipoproteins. Lipoproteins are generally characterized according to their density. Going from lowest to highest they are:

  1. chylomicrons: very  large particles that carry fat absorbed from the intestine
  2. very low density lipoprotein (VLDL): which carry mostly triglycerides
  3. Intermediate density lipoprotein (IDL): which carry a mixture of cholesterol esters and triglycerides
  4. Low density lipoprotein (LDL): which are the major blood cholesterol carriers
  5. High density lipoprotein (HDL): which carry cholesterol back to the liver to be either excreted or used to synthesize other molecules.

We tend to reduce our discussion of cholesterol between the “bad” LDL cholesterol and the “good” HDL cholesterol even though cholesterol is much more complex. Even the above breakdown is a bit simplistic. But the distinction between HDL and LDL was useful. Two people might have high cholesterol, but one might have high HDL (and therefore be at low cardiac risk) and the other might have high LDL (and therefore be at high cardiac risk).

In recent years, studies have questioned whether the good HDL hypothesis was actually valid. Niacin used to be used quite commonly to boost HDL but trials like AIM-HIGH and HPS2-THRIVE have shown that raising HDL with niacin did not prevent heart attacks. Another class of medications called CETP inhibitors were developed and tested but they too raised HDL without reducing heart attacks. The rather poor performance of HDL raising medications has led to a gradual revision of the idea that HDL is good for you.

Conversely, the data is fairly unequivocal that LDL is bad for you. As early as 1995, studies showed that lowering LDL cholesterol with statins reduced the risk of heart attacks and cardiac deaths. Over the years there have been many trials showing the benefit of statins. A recent meta-analysis examining 25 statin trials demonstrated that the more a statin reduces your LDL cholesterol the greater the cardiovascular benefit. In fact, you see the same benefit even with other types of non-statin medications like ezetimibe (brand name ezetrol) or PCSK9 inhibitors that also lower LDL cholesterol. Given the wealth of data on the issue, it is hard to understand how anyone could claim that LDL cholesterol has nothing to do with cardiac disease.

But LDL too is not a perfect tool for assess cardiac risk. While it is possible to measure it directly, it is most often calculated using a formula called the Friedewald formula. Although the formula is generally speaking quite accurate, it can be thrown off when triglyceride levels are very high. Many people are told to fast before doing blood tests to measure their cholesterol, even though there is actually little data that it makes a difference when it comes to LDL measurements.

The issue with LDL is that we are measuring the concentration of LDL in the blood not the actual number of particles. There is in fact good evidence that the number of particles matters, such that having a large number of small particles is worse than having a small number of large particles.

Measuring the number of particles can be done with nuclear magnetic resonance testing but can also be achieved very easily by measuring an apolipoprotein called ApoB. ApoB is a molecule found on the cholesterol particles that cause heart disease. Since each of these lipid molecules has one ApoB molecule on their surface, measuring ApoB levels provides a good measure of the number of particles in the blood.

There are a certain number of people whose LDL levels might seem normal but who have an excess number of small particles and would therefore have a higher ApoB level. These people would likely be in line for more aggressive treatment to lower their risk even further. The percentage of people misclassified in this way has varied in different studies. Studies have shown it to be as low as 8.6% and as high as 25% depending on the type of patients being studied. Suffice it to say, there is likely a non-negligible portion of the population that is being undertreated if only LDL is used as a target.

Can you get your ApoB level checked? Yes, and there is no need to go to a private lab or pay some guy on the Internet to get it done. Doing so is unnecessary. It can be done at any blood-testing center and it is covered like all other blood tests. You might ask, why there has not been a wholesale switch from LDL to ApoB? Well to be fair the Canadian guidelines do recommend checking ApoB and many (but not all) of my colleagues check ApoB as well as the standard cholesterol panel. There is some debate about whether to use ApoB or non-HDL cholesterol (which is the total cholesterol minus the HDL cholesterol). Both these values seem to perform similarly well and both actually appear in guidelines as useful measurements. It is also worth pointing out that regardless of how you measure cardiovascular risk, the treatment for high cholesterol remains the same. Statins are the mainstay of cardiac treatment because, as mentioned above, they have been shown in multiple trials to reduce cardiac risk. Therefore, further screening with ApoB to measure particle number is not so much about diagnosing people but really about finding that subset of patients who might need more medication and more aggressive treatment to lower their cholesterol even further.

In the end, the “controversy” about particle size is not much of a controversy. While there is some debate about how to best measure cholesterol, no one is disputing that cholesterol matters when it comes to heart disease, and no one really disputes the importance of treating patients at high risk for heart disease.


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