Over 26 million Americans are taking statin drugs. Some people think they should be available over-the-counter without a prescription, and it has even been facetiously suggested that they should be added to our drinking water. The protective effect of statins in cardiovascular disease and in high-risk patients with high cholesterol levels is well established. But what about people with no heart disease and normal cholesterol levels – can they benefit too?

The New England Journal of Medicine has pre-released an important new study on statins online prior to its planned publication date of November 20, 2008. It is certain to stir up a lot of controversy, and the International Network of Cholesterol Skeptics will not be happy, because it contradicts some of their favorite arguments. They have claimed that statins do more harm than good, that reducing cholesterol levels is harmful to health, that the benefits of statins and/or cholesterol lowering do not extend to women and the elderly, and that studies showing benefits of statins are meaningless because they do not show reduction of overall mortality. This study indicates otherwise.

The JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) study looked at people with low levels of LDL cholesterol but high levels of C-reactive protein (CRP). CRP is a marker for inflammation, and elevated levels are a risk factor for cardiovascular disease. Since statins reduce CRP levels, the hypothesis was that statins would prevent heart attacks in these patients.

JUPITER was a well-designed study with nearly 18,000 subjects in 1315 sites in 26 countries. It was randomized, placebo-controlled, and double blind. It found that rosuvastatin significantly reduced the rate of cardiovascular events as well as the overall death rate.

They selected subjects with care to eliminate possible confounding factors, and they even did a 4-week placebo run-in trial to eliminate subjects who were not compliant about taking the pills. Subjects were men over the age of 50 and women over the age of 60 who had no history of cardiovascular disease, who had LDL cholesterol levels of 130 mg per deciliter or lower (usually considered normal), and who had elevated CRP levels of 2.0 mg per liter or greater. The primary endpoint was the occurrence of a first major cardiovascular event such as a heart attack or stroke. Secondary endpoints looked at specific individual events like nonfatal MI, and included overall death rate from any cause.

The results were overwhelming. 20 mg of rosuvastatin a day produced:

• LDL cholesterol 50% lower than with placebo
• CRP 37% lower
• Reduction of first major cardiovascular event from 1.36 per 100 person-years to 0.77.
• Reduction of MI from 0.37 to 0.17
• Reduction of stroke from 0.34 to 0.18
• Reduction of revascularization for unstable angina from 0.77 to 0.41
• Reduction of all-cause death rate from 1.25 to 1.0

These were all highly significant, from p=0.02 to p=0.00001. Effects were similar for all subgroups evaluated:

These effects were consistent in all subgroups evaluated, including subgroups customarily considered to be at low risk, such as people with Framingham risk scores of 10% or less, those with LDL cholesterol levels of 100 mg per deciliter or less, those without the metabolic syndrome, and those with elevated levels of high-sensitivity C-reactive protein but no other major risk factor. The trial also showed robust reductions in cardiovascular events with statin therapy in women and black and Hispanic populations for which data on primary prevention are limited.

The rate of reported side effects was similar for both the rosuvastatin and the placebo group. Muscle side effects including rhabdomyolysis have been a great concern of statin critics, but in this study there was no difference between the statin and placebo groups and there was only one case of rhabdomyolysis and that was in a 90-year-old subject with febrile influenza, pneumonia, and trauma-induced myopathy. Some critics have claimed that statins cause cancer, but in this study there were fewer new diagnoses of cancer and significantly fewer cancer deaths in the rosuvastatin group (p=0.02). The only adverse finding was a higher rate of physician-reported diabetes in the rosuvastatin group; but there was no significant difference in blood glucose levels between the groups.

So rosuvastatin is effective and safe for primary prevention of heart disease in patients with normal cholesterol levels. Does that mean we should give it to everybody or put it in the drinking water? NO!

• They estimated that 95 people would have to take rosuvastatin over 2 years or 25 people would have to take it over 5 years to prevent one new major cardiovascular event.
• If I did the math right, 400 people would have to take it for a year to prevent one death.
• Rosuvastatin costs $3.45 a day. That would add up to over half a million dollars for each death prevented. Who will pay?
• This study only involved patients with high CRP levels. We don’t know if it would benefit those with normal CRP levels.
• This was a short-term study and we don’t know what the long-term effects of rosuvastatin might be.
• LDL cholesterol levels dropped to an average of 55 mg per deciliter – this is very low and we don’t know what the long term consequences of such low levels might be.
• It studied a select group with no confounding factors; the results in the general population and in younger patients might be quite different.
• We still don’t know the role of CRP and it’s not recommended as a screening test for the general population.
• We can’t be sure we’d get the same results from other statins as from rosuvastatin.
• We don’t know whether the benefits are due to lowered cholesterol or whether lowered cholesterol is a marker for other benefits of the drug.

In a thoughtful accompanying editorial, Mark Hlatky, MD says,

At this point, the current guideline for measurement of high-sensitivity C-reactive protein remains reasonable: a measurement may be obtained in asymptomatic individuals who have an intermediate level of risk, as estimated on the basis of standard clinical risk markers, if the decision to initiate drug treatment might change depending on the high-sensitivity C-reactive protein level. In my view, the evidence still favors this selective strategy for measuring high-sensitivity C-reactive protein, not routine measurement.

This study sounds almost too good to be true, and the drug company will inevitably be accused of trying to drum up business. Rosuvastatin is marketed by AstraZeneca under the brand name Crestor. The study was admittedly funded by the manufacturer, but 1315 separate sites were involved and AstraZeneca “played no role in the conduct of the analyses or drafting of the manuscript and had no access to the unblinded trial data until after the manuscript was submitted for publication.” It seems unlikely that they could have done anything to bias the results.

I hope this study doesn’t just encourage doctors to indiscriminately hand out more pills. Prevention should address all modifiable risk factors and should start with lifestyle changes like smoking cessation and exercise. In my view, this study is not enough to justify wholesale statin treatment, but it does give us more confidence that statins are safe and effective. And it shoots down some of the claims of anti-statin activists. It will be interesting to see if this study will change practice guidelines. The NEJM is conducting a poll to see if readers think it should. You can cast your vote here.