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Treating Statistical Markers of Disease Is Not the Same as Treating Disease Itself

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What stands to reason is not always borne out by facts, for reality is often refractory to human wishes. There was a good illustration of this unfortunate principle in a recent edition of the New England Journal of Medicine.

It has long been known that low concentrations of high-density lipoproteins (HDL) and high concentrations of low-density lipoproteins (LDL) are associated, in a more or less linear fashion, with cardiovascular disease such as strokes and heart attacks. It would seem to stand to reason, therefore, that raising the HDL and lowering the LDL would lead to fewer cardiovascular "events," as strokes and heart attacks are called.

One way to achieve this wished-for biochemical change is to treat patients at risk of such events with niacin, a B vitamin, in addition to the statins that they are already taking. The largest placebo-controlled trial of niacin ever undertaken, with 25,673 patients who had already had a stroke or heart attack, has shown that the addition of niacin, though it does indeed increase HDL and decrease LDL, has no effect on the rate of heart attack or stroke. Worse still, it gave rise to serious side effects, such as worsening of diabetes and unpleasant gastrointestinal, musculoskeletal and dermatological effects. One of the most unexpected findings of the trial was the excess of infections in people treated by niacin. If anything, the overall death rate in the niacin-treated group was higher than that in the placebo control group, though the difference was not statistically significant (which is not quite the same thing as saying that it was not real). The patients were followed up, on average, for nearly four years and at no time was treatment with niacin superior to that with placebo. 

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Niacin, though a vitamin, and therefore in the popular imagination natural and ipso facto good for you, is not only useless in these circumstances, it seems, but harmful.

The result of the trial was important for itself, for many patients have been treated with niacin on the grounds that it made "sense" to do so; but it was also important because it points to a general lesson, namely that treating statistical markers of disease is not the same as treating disease itself. This should be obvious, but in practice it isn’t. Doctors increasingly treat risk factors as if they were disease, with the result that they could sometimes be doing more harm than good. Of course, there is a long medical tradition of this.

Furthermore, the trial offers presumptive evidence against the high-LDL, low-HDL theory of the causation of cardiovascular disease. The statistical association with these measurements has appeared so strong that the relationship has been taken as a causative one. But in this trial, treatment with niacin should have reduced the "event" rate by about 10 percent if the causative relationship were a true one. It is the contention of those who oppose the lipoprotein theory of cardiovascular disease that its original propounders did so, either accidentally or deliberately (though of course they believe in their hearts that it was deliberately), on the basis of highly selective data.   

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Needless to say, believers in niacin could argue that the trial in the NEJM was one of secondary rather than of primary prevention, that is to say prevention of further rather than of first cardiovascular events. But it would be a very brave, not to say foolhardy and indeed unethical investigator who mounted a trial of niacin in people who had not yet had strokes or heart attacks, but who for some reason were likely to have one, given the very considerable harms done to patients by niacin in this trial.

Interestingly, the authors of the report of the trial did not mention the general lesson which would be profoundly disconcerting for many a practitioner (to say nothing of his patients).

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image illustrations via shutterstock /  Lightspring / Robert Kneschke / Zerbor