What’s Cholesterol Got to Do With It?

2008-01-31

Richard Moore

http://www.nytimes.com/2008/01/27/opinion/27taubes.html

January 27, 2008
OP-ED CONTRIBUTOR
What¹s Cholesterol Got to Do With It?
By GARY TAUBES

THE idea that cholesterol plays a key role in heart disease is so tightly woven 
into modern medical thinking that it is no longer considered open to question. 
This is the message that emerged all too clearly from the recent news that the 
drug Vytorin had fared no better in clinical trials than the statin therapy it 
was meant to supplant.

Vytorin is a combination of cholesterol-lowering drugs, one called Zetia and the
other a statin called Zocor. Because the two drugs lower LDL cholesterol by 
different mechanisms, the makers of Vytorin (Merck and Schering-Plough) assumed 
that their double-barreled therapy would lower it more than either drug alone, 
which it did, and so do a better job of slowing the accumulation of fatty 
plaques in the arteries ‹ which it did not.

Heart disease specialists who were asked to comment on this turn of events 
insisted that the result implied nothing about their assumption that LDL 
cholesterol is dangerous, only about whether it is always medically effective to
lower it.

But this interpretation is based on a longstanding conceptual error embedded in 
the very language we use to discuss heart disease. It confuses the cholesterol 
carried in the bloodstream with the particles, known as lipoproteins, that 
shuttle that cholesterol around. There is little doubt that certain of these 
lipoproteins pose dangers, but whether cholesterol itself is a critical factor 
is a question that the Vytorin trial has most definitely raised. It¹s a question
that needs to be acknowledged and addressed if we¹re going to make any more 
headway in preventing heart disease.

To understand the distinction between cholesterol and lipoproteins it helps to 
know something of the history of cholesterol research.

In the 1950s, two hypotheses competed for attention among heart disease 
researchers. It had been known for decades that cholesterol was a component of 
atherosclerotic plaques, and people who have a genetic disorder that causes 
extremely high cholesterol levels typically have clogged arteries and heart 
attacks. As new technology enabled them to look more closely at lipoproteins, 
however, researchers began to suspect that these carrier molecules might play a 
greater role in cardiovascular disease than the cholesterol inside them. The 
cholesterol hypothesis dominated, however, because analyzing lipoproteins was 
still expensive and difficult, while cholesterol tests were easily ordered up by
any doctor.

In the late 1960s, biochemists created a simple technique for measuring, more 
specifically, the cholesterol inside the different kinds of lipoproteins ‹ 
high-density, low-density and very low-density. The National Institutes of 
Health financed a handful of studies to determine whether these ³cholesterol 
fractions² could predict the risk of cardiovascular disease. In 1977, the 
researchers reported their results: total cholesterol turned out to be 
surprisingly useless as a predictor. Researchers involved with the Framingham 
Heart Study found that in men and women 50 and older, ³total cholesterol per se 
is not a risk factor for coronary heart disease at all.²

The cholesterol in low-density lipoproteins was deemed a ³marginal risk factor² 
for heart disease. Cholesterol in high-density lipoproteins was easily the best 
determinant of risk, but with the correlation reversed: the higher the amount, 
the lower the risk of heart disease.

These findings led directly to the notion that low-density lipoproteins carry 
³bad² cholesterol and high-density lipoproteins carry ³good² cholesterol. And 
then the precise terminology was jettisoned in favor of the common shorthand. 
The lipoproteins LDL and HDL became ³good cholesterol² and ³bad cholesterol,² 
and the lipoprotein transport vehicle was now conflated with its cholesterol 
cargo. Lost in translation was the evidence that the causal agent in heart 
disease might be abnormalities in the lipoproteins themselves.

The truth is, we¹ve always had reason to question the idea that cholesterol is 
an agent of disease. Indeed, what the Framingham researchers meant in 1977 when 
they described LDL cholesterol as a ³marginal risk factor² is that a large 
proportion of people who suffer heart attacks have relatively low LDL 
cholesterol.

So how did we come to believe strongly that LDL cholesterol is so bad for us? It
was partly due to the observation that eating saturated fat raises LDL 
cholesterol, and we¹ve assumed that saturated fat is bad for us. This logic is 
circular, though: saturated fat is bad because it raises LDL cholesterol, and 
LDL cholesterol is bad because it is the thing that saturated fat raises. In 
clinical trials, researchers have been unable to generate compelling evidence 
that saturated fat in the diet causes heart disease.

The other important piece of evidence for the cholesterol hypothesis is that 
statin drugs like Zocor and Lipitor lower LDL cholesterol and also prevent heart
attacks. The higher the potency of statins, the greater the cholesterol lowering
and the fewer the heart attacks. This is perceived as implying cause and effect:
statins reduce LDL cholesterol and prevent heart disease, so reducing LDL 
cholesterol prevents heart disease. This belief is held with such conviction 
that the Food and Drug Administration now approves drugs to prevent heart 
disease, as it did with Zetia, solely on the evidence that they lower LDL 
cholesterol.

But the logic is specious because most drugs have multiple actions. It¹s like 
insisting that aspirin prevents heart disease by getting rid of headaches.

One obvious way to test the LDL cholesterol hypothesis is to find therapies that
lower it by different means and see if they, too, prevent heart attacks. This is
essentially what the Vytorin trial did and why its results argue against the 
hypothesis.

Other such tests have likewise failed to confirm it. A recent trial of 
torcetrapib, a drug that both raises HDL and lowers LDL cholesterol, was halted 
midstream because the drug seemed to cause heart attacks and strokes rather than
prevent them. Estrogen replacement therapy also lowers LDL cholesterol, but it 
too has failed to prevent heart disease in clinical trials. The same goes for 
eating less saturated fat.

So it is reasonable, after the Vytorin trial, to question the role of LDL 
cholesterol in heart disease. Not whether statins help prevent heart disease, 
but whether they work exclusively, or at all, by this mechanism.

There are numerous other ways in which statins might be effective. They reduce 
inflammation, which is now considered a risk factor for heart disease. They act 
to keep artery walls healthy. And statins act on lipoproteins as much as on the 
cholesterol inside them. They decrease the total number of low-density and very 
low-density lipoproteins in the blood, including the smallest and densest form 
of LDL, which is now widely believed to be particularly noxious.

Because medical authorities have always approached the cholesterol hypothesis as
a public health issue, rather than as a scientific one, we¹re repeatedly 
reminded that it shouldn¹t be questioned. Heart attacks kill hundreds of 
thousands of Americans every year, statin therapy can save lives, and skepticism
might be perceived as a reason to delay action. So let¹s just trust our 
assumptions, get people to change their diets and put high-risk people on 
statins and other cholesterol-lowering drugs.

Science, however, suggests a different approach: test the hypothesis rigorously 
and see if it survives. If the evidence continues to challenge the role of 
cholesterol, then rethink it, without preconceptions, and consider what these 
other pathways in cardiovascular disease are implying about cause and 
prevention. A different hypothesis may turn out to fit the facts better, and one
day help prevent considerably more deaths.

Gary Taubes is the author of ³Good Calories, Bad Calories: Challenging the 
Conventional Wisdom on Diet, Weight Control and Disease.²

Copyright 2008 The New York Times Company
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