Cholesterol and Heart Disease – A Quick Look Beyond

The word cholesterol is inherent to heart disease. Just like Paris is the capital of France and the Moon orbits the Earth, so cholesterol is associated with heart disease.

And common knowledge extends further. Most people know that cholesterol is measured in blood and that there’s is supposed to be both good and bad cholesterol. Bad cholesterol may clog arteries, so by all means make sure it’s low.

Cholesterol and Heart Disease - A Quick Look Beyond

Of course, most of us know there is only one type of cholesterol. The “good” and “bad” has to do with the lipoproteins that carry cholesterol molecules in our bloodstream.

A standard lipid panel provides numbers for total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C) (1) and high-density lipoprotein cholesterol (HDL-C)(2).

LDL-C is often termed “the bad cholesterol” because high levels are associated with increased risk of heart disease.

On the other hand, HDL-C is usually nicknamed “the good cholesterol” because high blood levels are associated with less risk of heart disease and low levels are associated with increased risk.

Recently many experts and non-experts have cast doubt on the role of cholesterol as a causative factor for cardiovascular disease (CVD). The internet is flooded with articles and books have been published with titles such as the “Cholesterol Conspiracy” and “The Great Cholesterol Myth”. Some have suggested that the fat hypothesis is the biggest lie in medicine.

The opposite view is usually found among medical professionals. Cholesterol is regarded as a key player when it comes to cardiovascular disease;dietary recommendations aim at lowering LDL-C and cholesterol lowering drugs are often prescribed.

In a paper (3) published 2010 in the American Journal of Cardiology, William C. Roberts, editor-in-chief of the American Journal of Cardiology for the last 33 years wrote: “The lower the LDL cholesterol, the better, and this principle has been established repeatedly despite voices of the anticholesterol, antistatin fallacy mongers! It’s the cholesterol, stupid!

I believe healthy scepticism is the lifeblood of modern science. It is not about choosing teams and ignoring evidence that contradict our believes. Dogmatic assertions may get in the way of scientific progress.

So, let’s have a quick look at recent scientific results that may strengthen our understanding of the role of lipid measurements in assessing the risk of cardiovascular disease.


Lipid Combinations

It is well known that high levels of LDL-C, low levels of HDL-C and high levels of triglycerides (TG) are each by itself a major risk factor for developing CVD (4,5,6).

But what about lipid combinations. What if both LDL-C and HDL-C are high? Will high HDL-C wipe out the risk associated with high LDL-C? And what about TG? How do they affect the mixture?

Interestingly these questions have not been addressed until lately. A paper published in the American Heart Journal in December 2014 (7) reports results from the Framingham Heart Study Offspring Cohort where the association between different lipid combinations and the long-term risk of cardiovascular disease was studied.

The study addressed 3,501 healthy middle-aged individuals without any history of cardiovascular disease who were followed for a median of 20 years.

Cholesterol and Heart Disease - A Quick Look BeyondThe authors defined levels of high LDL-C as >130 mg/dL (3.4 mmol/L), high TG as > 150 mg/dL (1.7 mmol/L), and low HDL-C as < 40 mg/dL (1.0 mmol/L).

The participants were grouped into eight distinct groups according to “normal”, or “low” or “high range” values of LDL-C, HDL-C, and TG.

The group with normal LDL-C, normal HDL-C and normal TG had a 5.9% risk  of cardiovascular events (age- and sex-adjusted 10 year CVD incidence) compared to 18.4% in the group with high LDL-C, low HDL-C and high TG.

Evidently, lipid combinations can tell us quite a lot about the risk of developing CVD.

What Is Most Important, LDL-C, HDL-C or TG?

Interestingly, low HDL-C alone or in combination with a high LDL-C and/or high TG was the category associated with the greatest risk of CVD.

When compared with HDL-C, LDL-C alone was associated with only a marginally increased risk of CVD. For example, the hazard ratio for the group with low HDL-C but normal LDL-C and normal TG was 1.93 while the group with high LDL-C but normal HDL-C and normal TG had a hazard ratio of 1.28.

In contrast to HDL-C or LDL-C alone, no increase in CVD risk was associated with high TG alone.

In my opinion, the most interesting finding of this study is that a lipid combination with low HDL-C is associated with a much higher risk than a lipid combination with high LDL-C. If HDL-C is low, it makes a little difference whether LDL-C is high or not.

On the other hand, it can be argued that lowering LDL-C with statins seems to reduce CVD risk while raising HDL-C has not been found to be helpful.

How can this discrepancy be explained?

HDL-C and Insulin Resistance

The authors of the above paper cite two recent studies that suggest that HDL-C is a surrogate marker (8,9). This may imply that low HDL-C is not problematic in itself but is associated with some other factor that can increase risk. But, where is the missing link?

It is known that low HDL-C and high TG commonly occur together. In fact, the TG/HDL-ratio (10) is strongly associated with the incidence (11) and the extent (12) of coronary artery disease.

Low HDL-C and high TG are very often related to obesity and metabolic syndrome. These situations are characterised by the phenomenon we call insulin resistance.

Insulin resistance is a condition in which cells fail to respond to the normal actions of insulin. Most people with this condition have high levels of insulin in their blood. Insulin resistance appears to play an important role in CVD and is associated with increased mortality (13).

Interestingly, previously published data from the Framingham Heart Study have shown that the risk associated with low HDL-C or high TG is increased only in the presence of insulin resistance (14) .

Another study showed the benefit of fibrate therapy was much less dependent on levels of HDL-C or TG than on the presence or absence of insulin resistance (15).

Accordingly, there is evidence that in the absence of insulin resistance, low HDL-C is much less relevant as a marker of risk than when insulin resistance is present. Therefore, insulin resistance may be the missing link between low HDL-C and the risk of CVD.

So, possibly, to reduce the risk of low HDL-C, we should aim at reducing insulin resistance instead of targeting low HDL-C in itself.

Should These Findings Affect Modern Dietary Advice?

For fifty years, dietary advice has aimed at lowering LDL-C. Therefore, a low-fat diet rich in fruits, vegetables, nuts, legumes, whole grains, low-fat dairy products, fish, and lean cuts of meat is recommended to lower the risk of CVD.

But what if low HDL-C is a stronger marker of risk than LDL-C as suggested by the above study. Should we approach individuals with low HDL-C with the same dietary approach? Is a “Prudent” low-fat diet best for individuals with insulin resistance?

Today there is abundant evidence available suggesting that carbohydrate restriction is more effective than a low-fat approach to treating insulin resistance (16).

Therefore, modern dietary recommendations have to take into account recent scientific evidence suggesting that a low fat approach may not always be the best advice to cut the risk of CVD.

Don’t misunderstand me though. I’m not suggesting we should skip fresh foods such as fruits, vegetable, fish and nuts.

However, evidence suggests we have to abandon the fat phobia, the fear of saturated fat, and the view that preferring carbs rather than fat is always the best option to reduce the risk of CVD.

But, should we abandon LDL-C and the low-fat approach? Absolutely not. There are situations when lowering LDL-C is of prime importance.

But, it is time we broaden our perspective.


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