In the News
November 12, 2008
The JUPITER trial
Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin
One could hardly open a newspaper or turn on the television earlier this week without seeing some reference to the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), with most of the commentary describing it as a very important study which was going to dramatically expand the number of people taking statin medications. So here is a description of the study and what it might mean:
The JUPITER trial was a study of 17,802 healthy men and women who had two distinguishing characteristics. First, they had normal cholesterol levels specifically characterized as an LDL-cholesterol level of less than 130 mg per deciliter - a level that would not normally be considered to require cholesterol-lowering drug therapy. And second, they had a level of C-reactive protein greater than 2 mg per liter, indicating the possibility of some level of inflammation in the arteries of the heart and brain. The study only included men over 50 years of age and women over 60 years of age and there were lots of exclusions, including anyone who was a current or former user of cholesterol-lowering drugs, was on hormone replacement therapy, had evidence of liver or kidney disease, or who had diabetes or poorly controlled blood pressure. And since C-reactive protein is a relatively nonspecific marker of inflammation, individuals who had diseases known to cause inflammation, such as rheumatoid arthritis, inflammatory bowel disease, or patients on steroid therapy were also excluded.
The participants included in the trial were randomly divided into two groups: half were given a placebo (an inactive tablet), and the other half were given a tablet containing 20 mg of Crestor, to be taken daily. Crestor (rosuvastatin) is the most potent statin available and 20 mg is a substantial dose of this agent. In fact, the median LDL fell from 108 mg per deciliter at the beginning of the study to 55 milligrams per deciliter at one year, and stayed at that level as long as four years after the initiation of the study. This therapy had a fairly dramatic effect, reducing the risk of a coronary or cerebrovascular (stroke) event by 54%, a finding so impressive that the study was actually stopped after a median follow-up of only 1.9 years of what had been planned to be a five-year follow-up for everyone. So does this mean that large numbers of people who are not now being treated with cholesterol-lowering drugs should be treated? Here are the key points to consider:
- First, this study does not apply to younger folks - men were over 50 and women were over 60 years of age.
- The median LDL achieved using 20 mg of Crestor was 55 mg per deciliter. At the present time the national guidelines suggest that individuals who already have coronary disease or who are at high risk because of diabetes, or a combination of multiple risk factors such as smoking and high blood pressure along with elevated cholesterol, should have an LDL level that is at least less than 100 mg per deciliter, and although many of us think that such individuals should have LDL levels less than 70 mg per deciliter the guidelines still list this latter goal as being "reasonable" but not yet "recommended". It is quite a leap to go from these guidelines for patients who are already at high risk to a suggestion that healthy individuals should have their LDL level reduced to a considerably greater extent.
- Although the reduction in risk is striking, this is a group whose baseline risk is not exceptionally high. As a consequence, it was necessary to treat 95 individuals for two years to prevent one event (an event could not only be a death, but also non-fatal heart attacks or strokes, or hospitalization for cardiac symptoms such as increasing chest pain), or 31 individuals for four years. The cost per event prevented works out to between $150,000 and $200,000, given the three dollars plus cost of Crestor.
- Of course, these days few of the third-party payers are going to pay for Crestor - they will substitute a weaker drug. What the efficacy is of an agent that lowers LDL to a lesser degree is unknown.
- In this study Crestor was not associated with any harmful events - it was just as likely that participants on the placebo medication would develop muscle aches or other problems that might have been attributed to the active medication. The only difference was that more subjects on Crestor were reported to become diabetic by their physicians, although laboratory tests for diabetes were essentially not different in the two groups. But the study, because it was stopped early, had an average duration of follow-up of less than two years. There is no evidence that having a very low cholesterol is in any way harmful, but of course it is also true that we have not followed healthy individuals on high dose lipid-lowering therapy for the several decades that individuals may be on such therapy.
- It is very important to remember that C-reactive protein is highly variable and can go up 100 or even 1000 fold from a viral infection. So if C-reactive protein is low, that's great but if it is high it should be repeated before deciding on a course of action. Here is a link to a fuller discussion of C-reactive protein.
- This is of course one more study that says that for LDL lower is better, and in doing so fits in with a continuous trend over the last decade. In fact, we are beginning to approach recommended levels that human beings were actually intended to have and that nonindustrialized and vegan populations actually do have.
- The study was paid for by Astra-Zeneca, the company that makes Crestor. But they had no role in analyzing or interpreting the data.
So the bottom line is that this study again demonstrated the powerful effect of these cholesterol-lowering drugs to prevent cardiac and stroke events. It was restricted to men over 50 and women over 60 who were relatively healthy, had high levels of C-reactive protein, and did not have other complicating illnesses or risk factors such as diabetes or poorly controlled blood pressure. If you fall into this group, it may very well be appropriate to have your C-reactive protein level measured and to have a discussion with your physician about appropriate therapy.
Here are links to the actual paper and to an accompanying editorial, both published in the New England Journal of Medicine.
http://content.nejm.org/cgi/content/abstract/NEJMoa0807646v1 (the JUPITER article)
http://content.nejm.org/cgi/content/extract/NEJMe0808320?resourcetype=HWCIT (the accompanying editorial)