The Amazing Journey to JUPITER

Abstract & Commentary

By Jonathan Abrams, MD Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque Dr. Abarams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.

Source: Ridker PM, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207.

JUPITER, a trial first presented november 9, 2008, at the American Heart Association meeting in New Orleans, was clearly "the bell of the ball," with multiple television, newspaper, and medical journal reports. This remarkable study was designed to ask the question of whether healthy older patients with high C-reactive protein (CRP) but elevated LDL cholesterol would benefit from high-dose statin treatment. The study involved 18,000 older, healthy men and women with LDL cholesterol levels less than 130 and a CRP level greater than 2.0, who were randomized to rosuvastatin 20 mg daily or placebo. The cohorts were followed for multiple endpoints of major cardiac events, including myocardial infarction, stroke, revascularization, hospitalization for unstable angina, or CV-related death. The trial was stopped after a median of 1.9 years because of a marked reduction in events in the statin-treated patients. Also, LDL levels were reduced by 50% and high sensitivity CRP reduced by 37%! The primary endpoints in the placebo-treated patients were much more frequent than with active drug, with a hazard ratio for rosuvastatin of 0.56 (p < 0.00001), as well as a 0.46, p = 0.0002 hazard ratio for myocardial infarction. Stroke and revascularization were reduced by approximately 50%. There was an overall reduction in the combined endpoint of MI, stroke, or CV death of 47%. Overall deaths from any cause were decreased with rosuvastatin (hazard ratio 0.80, p = 0.02). The results were consistent in all subgroups, even with those who had a very low Framingham risk score of 10% or less, or baseline LDL levels of 100 mg or less. Statin therapy was effective in women, African-Americans, and Hispanic populations.

No significant adverse effects were noted in the statin-treated patients compared to those on the placebo, even in those individuals whose LDL cholesterol dipped below 55 mg, which occurred in half the participants, and even below 44 mg in 25%! There was no excess in myopathy or other medical problems, including new cancers. Of note, there was a small increase in new diabetes in the statin group (270 patients vs 216 in the placebo, p = 0.01). There was no difference in the number of individuals who had intracranial hemorrhage. In conclusion, subjects in the JUPITER trail who received rosuvastatin, all of whom had high CRP levels at baseline, had a significant reduction in the incidence of major cardiovascular events when compared to placebo treatment. The robust reduction in CV events occurred rapidly and without obvious harm that could be attributed to powerful LDL cholesterol lowering.

Commentary

This remarkable study, carried out in 26 countries and 1,315 sites, is very exciting. It needs to be stressed that the degree of LDL lowering was most substantial (approximately 50% reduction), greater than in any clinical trial yet reported. Rosuvastatin, currently the most potent statin available, was given to normal cholesterol, healthy older individuals, with a 50% reduction in all adverse events seen in the active treatment group, which is quite remarkable. Caveats are many.

A variety of commentaries have been published on the web regarding this study, which received enormous press coverage. The concept that atherosclerosis is, in part, an inflammatory disease that involves LDL cholesterol is consistent with the role of rosuvastatin in these patients, who were not dyslipidemic by current definitions and had no clinical evidence of vascular disease at the time of entry to the study. The authors point out that statins have been shown to reduce cardiovascular events in a number of trials, including those in healthy individuals, those with stable CAD, and those with acute coronary syndrome. Also, the magnitude of the benefits associated with statin therapy correlates with the high-sensitivity CRP level results.

JUPITER raises major practical questions, in addition to whether or not this trial should provide a definite role for high-dose statins in older individuals with no overt cardiovascular disease. All were associated with a "hyper inflammatory state," as suggested by a high CRP. The median CRP levels at baseline were 4.2, range of 2.2-7.1, equal in both statin-treated and placebo subjects. One year after entry, CRP levels had fallen to 2.2, clearly a robust reduction in the statin group. One wonders about the nature of individuals who have no clinical cardiovascular disease but do have a high CRP. Is the CRP truly a marker for higher risk, as it would appear from this data? It is not certain why CRP is elevated in otherwise healthy individuals. The results of JUPITER are provocative, and certainly open the door to a more widespread use of statins, possibly even when LDL cholesterol does not exceed present lipid guidelines. The many commentary reports about this study are of considerable interest, confirming the fact that lipids and the inflammatory hypothesis are now firmly part of our attack against cardiovascular ischemic events of all types.

There appears to be little downside risk in these otherwise healthy patients. The remarkable finding of optimal major reduction event rates in less than two years suggest that the trial was more positive than Ridker et al speculated in their initial design and discussion. There is a hint of an increase in diabetes, as well as elevated glycated hemoglobin. These findings have also been found in other statin trials, raising the interesting question of whether statin therapy may induce a problem in glucose metabolism; follow-up data in these patients suggested no diabetic hazard, however. Ridker et al comment that the trial stopping at a median follow-up of less than two years would clearly mask the effects of long-term therapy with high-dose statin.

What should physicians do with these data? This a multibillion dollar question. Clearly, high cholesterol itself was once not believed by many to be risky or significant in the development of atherosclerosis. In only a relatively few years, since the advent of statins approximately 20 years ago, has the concept of aggressive lipid lowering emerged. JUPITER adds to this dialogue, introducing a large number of questions of where we should go from here. Certainly, the use of very high-dose statin, which can be readily achieved with the current drugs, should be reconsidered with respect to individuals demonstrating increased risk because of elevated CRP. The idea of treating a healthy person with a potentially problematic drug, which is costly, certainly will raise the hackles of many. Nevertheless, I believe, along with many others, that JUPITER has far exceeded our expectations, and that treatment for high-risk individuals (men older than 50, women older than 60) should now include the consideration of statin therapy. Dr. Paul Ridker, the putative father of CRP, can be congratulated for his one-man exploration of the impact of CRP elevation and its reduction, which surely will result in great benefits for individuals and new targets for potential statin use.