The cholesterol-lowering drugs collectively known as “statins” are among the top drugs sold in the United States, and worldwide. Although current guidelines only recommend the use of statins for people with elevated cholesterol, there is new evidence that these recommendations should be expanded. The November 20, 2008 issue of the New England Journal of Medicine will report the findings of the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), which were also reported on November 9 at an American Heart Association Conference in New Orleans. The JUPITER trial studied nearly 18,000 healthy adults without high cholesterol and found that daily therapy with rosuvastatin (Crestor) significantly prevented cardiovascular events.

In addition to high cholesterol, elevated levels of C-reactive protein (CRP) — a measure of inflammation — are predictive of cardiovascular events. Since statins are known to lower CRP levels, in addition to cholesterol levels, the JUPITER trial evaluated the daily use of rosuvastatin in patients with elevated CRP, but normal to low LDL cholesterol levels. The primary endpoints assessed in the study included heart attack, stroke, heart-related deaths or hospitalizations, the need for artery-opening procedures, unstable angina, and death. The patient population included 17,802 people in the United States and 25 other countries. One-quarter of the patients were black or Hispanic, and 40% were women — a demographic significantly underrepresented in most statin trials. Men in the study were aged 50 or older, and women were aged 60 or older. None had a history of heart disease or diabetes.

The study was a double blind, placebo-controlled trial in which patients were randomly assigned to take a daily placebo or 20 mg rosuvastatin. The study, funded by the AstraZeneca, the manufacturer of Crestor, was supposed to last 5 years, but was stopped after a median length of less than 2 years when an independent review panel found that the patients in the rosuvastatin group were faring significantly better than those in the placebo group.

Overall, rosuvastatin reduced the risk of any cardiovascular event by 44%. The risk of heart attack was reduced by 54%, stroke by 48%, and the need for an artery-opening procedure by 46%. In more absolute terms, there were 136 cardiovascular events each year per 10,000 people taking placebo, and only 77 events for those taking rosuvastatin. Remarkably, every subgroup benefited from rosuvastatin.

The study is astonishing, but not without concern. Most importantly, people taking rosuvastatin had a significantly increased risk of high blood sugar levels and new-onset diabetes. Further, while no significant differences were seen in the adverse event profiles of rosuvastatin versus placebo in JUPITER, it is not known what the long-term effects of some of these statins, which can cause rare, but serious side effects, may be. Lastly, the cost of rosuvastatin is prohibitive. Rosuvastatin is currently only available as a brand-name drug at a cost of approximately $3.45 daily. Several other statins are now available as generic alternatives and are available for less than $1 daily.

Expanding the results of JUPITER to the entire adult population in the United States would call for approximately 4% of them to be treated with daily rosuvastatin. At the current market price, it would cost $9 billion annually, and prevent 30,000 cardiovascular events. More simply, 120 people would need to be treated for 2 years to prevent 1 event.

The JUPITER trial did offer confirmation that CRP levels can be used to predict risk of cardiovascular events, but simply calling for every person with elevated CRP to start drug therapy may not be indicated. Prevention is certainly an important concept in health care today, but prevention should more likely include things like a sensible diet, exercising regularly, and not smoking. Popping pills to mitigate every risk factor would merely increase drug interactions, adverse drug events, and health care costs. Practitioners and patients must balance the benefits of any treatment or prevention practice with its long-term risks and costs.

References

M. A. Hlatky (2008). Expanding the Orbit of Primary Prevention — Moving beyond JUPITER New England Journal of Medicine DOI: 10.1056/NEJMe0808320

P. M Ridker, E. Danielson, F. A.H. Fonseca, J. Genest, A. M. Gotto, J. J.P. Kastelein, W. Koenig, P. Libby, A. J. Lorenzatti, J. G. MacFadyen, B. G. Nordestgaard, J. Shepherd, J. T. Willerson, R. J. Glynn (2008). Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein New England Journal of Medicine DOI: 10.1056/NEJMoa0807646