Saturday, December 19, 2009

Total cholesterol and cardiovascular disease: A U-curve relationship

The hypothesis that blood cholesterol levels are positively correlated with heart disease (the lipid hypothesis) dates back to Rudolph Virchow in the mid-1800s.

One famous study that supported this hypothesis was Ancel Keys's Seven Countries Study, conducted between the 1950s and 1970s. This study eventually served as the foundation on which much of the advice that we receive today from doctors is based, even though several other studies have been published since that provide little support for the lipid hypothesis.

The graph below (source:, with many thanks to O Primitivo) shows the results of one study, involving many more countries than Key's Seven Countries Study, that actually suggests a NEGATIVE linear correlation between total cholesterol and cardiovascular disease.

Now, most relationships in nature are nonlinear, with quite a few following a pattern that looks like a U-curve (plain or inverted); sometimes called a J-curve pattern. The graph below (source also: shows the U-curve relationship between total cholesterol and mortality, with cardiovascular disease mortality indicated through a dotted red line at the bottom.

This graph has been obtained through a nonlinear analysis, and I think it provides a better picture of the relationship between total cholesterol (TC) and mortality. Based on this graph, the best range of TC that one can be at is somewhere between 210, where cardiovascular disease mortality is minimized; and 220, where total mortality is minimized.

The total mortality curve is the one indicated through the full blue line at the top. In fact, it suggests that mortality increases sharply as TC decreases below 200.

Now, these graphs relate TC with disease and mortality, and say nothing about LDL cholesterol (LDL). In my own experience, and that of many people I know, a TC of about 200 will typically be associated with a slightly elevated LDL (e.g., 110 to 150), even if one has a high HDL cholesterol (i.e., greater than 60).

Yet, most people who have a LDL greater than 100 will be told by their doctors, usually with the best of the intentions, to take statins, so that they can "keep their LDL under control". (LDL levels are usually calculated, not measured directly, which itself creates a whole new set of problems.)

Alas, reducing LDL to 100 or less will typically reduce TC below 200. If we go by the graphs above, especially the one showing the U-curves, these folks' risk for cardiovascular disease and mortality will go up - exactly the opposite effect that they and their doctors expected. And that will cost them financially as well, as statin drugs are expensive, in part to pay for all those TV ads.


Deadsunrise said...

Hi Ned, I posted a spanish translation of this article on

Hope you don't mind. I state the source with a link at the beginning of the article.

Thanks for the whole blog, it's fascinating.

Ned Kock said...

Hi Deadsunrise.

Sure, no problem. Thanks.

O Primitivo said...

Cholesterol, longevity, intelligence, and health. -

Vivek Rau said...

My guess is that one would have to correct this data for smoking and alcohol consumption (at least) before drawing conclusions about cholesterol vs cardiovascular disease. Observe some Islamic countries like Bangladesh and Saudi Arabia on the left of the graph, i.e. lower cholesterol than the U.S. but higher heart disease. The prohibition of alcohol in those countries will definitely have an impact on heart disease rates. Many of the less developed countries have higher rates of smoking and less advanced cardiac care than the U.S., so that will also affect mortality from cardiovascular disease.

O Primitivo said...

Hi Ned. Just to clarify that both those graphs were extracted from my Excel database on cholesterol mortality -

Ned Kock said...

Thanks Ricardo. I have edited the post, now indicating the original source. As always, thanks much!

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Ned Clack said...

These data are mainly gathered in populations that eat modern diets. From time to time I read low-carbers talking about trying to get their TC up beyond 200 but does anybody know where the bottom of the U is for people with paleolithic habits?

Many thanks for your work Ned

Matt Stone said...

Sorry I didn't find this earlier. This is awesome Ned!

Anonymous said...

I wanted to cite the figures you have here in a discussion r.e. cholesterol levels and mortality, but the links you include seem no longer to work, and I can't find the graphs. If you have any suggestions on how to track them down, it would be much appreciated. I don't feel comfortable citing untraceable data.

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