Reuters (and former Newsweek) science reporter Sharon Begley has written a highly readable and informative article in the May/June issue of the Saturday Evening Post on the risk and benefits of statins, the controversial cholesterol-lowering drugs.

Currently, as Begley points out, these drugs are being taken by an astounding number of Americans: one-fourth of everybody aged 45 and older.

No wonder, as Begley also reports, that U.S. sales of statins, which include brand names like Lipitor and Crestor, topped $14 billion in 2009.

Yet, despite the ubiquitousness of these drugs, more than a dozen studies have shown that when used for primary prevention — in other words, by otherwise healthy people with no personal history or symptoms of heart disease — statins do very little, if anything, to prevent a heart attack or stroke. (The story is very different when people who have had a previous heart attack or stroke take the drugs. Statins can decrease their risk of dying within the next five years by as much as a third, one expert tells Begley.)

Making sense of the data

Begley does a terrific job of putting the risk-benefit data regarding statins into perspective for readers:

Consider two of the most rigorous and widely cited clinical trials of statins: In one, three people of every 100 without pre-existing heart disease but with high cholesterol who took a placebo pill suffered a heart attack; two of every 100 such people taking the best-selling Lipitor did. In the other trial, four of every 100 volunteers taking placebo had a non-fatal heart attack or stroke while two of every 100 taking Crestor did. These results are typical of the findings of other studies.

As [cardiologist Dr. Eric] Topol notes, the bottom line is that the most popular statins reduce the risk of having a heart attack or stroke from three or four percent to two percent.

That benefit is barely significant, says Begley, especially when compared with the health risks associated with statin use, which include muscle pain or weakness (in about 5 percent of people who take the drugs) and, most worrisomely, diabetes. “One person in 167 who takes a statin for five years will develop diabetes,” reports Begley.

That means, as an expert tells her, “that among people taking statins for primary prevention, the risk of diabetes is greater than the benefit of stroke reduction.”

A ‘stratospheric’ number

Another useful way to consider the risk-benefit data regarding statins, says Begley, is to look at something called the “number needed to treat” (NNT):

NNT simply means how many people must be given a medication, undergo surgery, have a diagnostic test, or have any other medical intervention in order for a single one of them to benefit from it. That number can be surprisingly high even for interventions with unquestioned benefits. For instance, 16 people with open fracturers need to receive antibiotics for one to benefit; eight people need to take inhaled steroids during an asthma attack to prevent one from going to the hospital. In each case the vast majority of people would not have developed infections or needed a trip to the ER, respectively, even without the intervention. The NNT in these cases is 16 and eight.

Statins for primary prevention have a stratospherically higher NNT. Sixty people would have to take a statin for five years for one to avoid a heart attack; 60 is the NNT for avoiding this outcome. And 268 people without heart disease would need to take a statin for five years for one person to be saved from a stroke; 268 is therefore the NNT for avoiding this outcome.

A paradigm shift?

As Begley explains, the ineffectiveness of statins for primary prevention makes sense when we realize that “cholesterol levels are not as strongly predictive of cardiovascular disease as once thought.” “This has shocked everyone,” states Dr. David Newman, an emergency clinician and director of clinical research at Mount Sinai Medical Center in New York, in the article. “Cholesterol levels are actually a fairly weak predictor of who will have a heart attack.”

But the debate goes on. Medical paradigms take a notoriously long time to shift.

Just this month, the authors of a new meta-analysis published in the journal Lancet reported that statins did save lives when prescribed to low-risk individuals. They recommended that the drugs be even more broadly prescribed.

But as Newman points out on his website, the findings of that meta-analysis shouldn’t be compared with the other earlier — and more relevant — ones that found no benefit from statins:

Why? It is the way they calculated their numbers. This meta-analysis, like [an] earlier one from the same group, reports outcomes per-cholesterol-reduction. The unit they use is a “1 mmol/L reduction in low density lipoprotein (LDL),” in common U.S. terms, a roughly 40-point drop in LDL.

That’s the magic: each of the benefits reported in the paper refers to patients with a 40-point cholesterol drop. Voilá. One can immediately see why these numbers would look different than numbers from reviews that asked a more basic question: did people who took statins die less often than people taking a placebo? (The only important question.) Instead, they shifted the data so that their numbers corresponded precisely to patients whose cholesterol responded perfectly.

Patients whose cholesterol drops 40 points are different than others, and not just because their body had an ideal response to the drug. They may also be taking the drug more regularly, and more motivated. Or they may be exercising more, or eating right, and more health conscious than other patients. So it should be no surprise that this analysis comes up with different numbers than a simple comparison of statins versus placebo pills. Ultimately, then, this new information tells us little or nothing about the benefits someone might expect if they take a statin. Instead it tells us the average benefits among those who had a 40-point drop in LDL.

You can read Begley’s article on the Saturday Evening Post website. You can read Newman’s response to the Lancet meta-analysis at his SmartEm (Science, Medicine and Research Translation) blog.