Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)—Can C-Reactive Protein Be Used to Target Statin Therapy in Primary Prevention?

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The most important action of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is their ability to lower levels of low-density lipoprotein (LDL) cholesterol. Statins have proved highly effective in reducing the risk of cardiovascular events in both primary and secondary prevention studies. However, the magnitude of risk reduction associated with statins is greater than that predicted on the basis of LDL cholesterol lowering alone. A likely explanation for this effect is the anti-inflammatory action of statins. Following the observation that high-sensitivity C-reactive protein (hs-CRP) is a powerful predictor of cardiovascular events, investigators in the Cholesterol and Recurrent Events (CARE) and Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) trials demonstrated that the magnitude of risk reduction associated with statin therapy was higher among those with elevated hs-CRP levels. In addition, there is accumulating evidence that statins lower plasma levels of hs-CRP in a manner largely independent of LDL cholesterol lowering. In contrast, little benefit has been demonstrated for statin therapy in the absence of both hyperlipidemia and inflammation. Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) is a large multinational, long-term, double-blind, placebo-controlled, randomized clinical trial designed to assess directly whether statin therapy (rosuvastatin 20 mg/day) should be given to apparently healthy individuals with low LDL cholesterol levels but elevated hs-CRP levels—a critical issue for the prevention of cardiovascular disease. Support for the concept behind the JUPITER trial is also now available from several recent trials comparing different intensities of statin therapy on disease progression as well as clinical end points. These studies indicate that the hs-CRP level achieved after initiation of statin therapy may be as important as the LDL cholesterol level achieved. All of these data raise the possibility that hs-CRP could be used to target high-risk patients who may benefit from early statin use. Ongoing work will determine whether hs-CRP reduction, independent of LDL cholesterol reduction, results in a net clinical benefit.

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Role of Inflammation in Cardiovascular Disease

Multiple large-scale prospective studies performed in a variety of populations have demonstrated that hs-CRP is a strong and independent predictor of CVD events, including myocardial infarction (MI), ischemic stroke, sudden cardiac death, and diabetes mellitus.11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 In the Physicians’ Health Study, an epidemiologic study of >22,000 healthy middle-aged men with no clinical evidence of disease, increasing levels of hs-CRP at study entry were associated

C-Reactive Protein–Lowering Effects of Statins in Acute Coronary Syndromes

Until recently, it was not known whether the hs-CRP–lowering action of statins provided any clinical benefit beyond their LDL cholesterol–lowering action. In 2 studies published recently—the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) and the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) studies—the strongest evidence to date is provided for the independent cardiovascular benefits associated

Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)

Because inflammation is an integral part of the underlying pathophysiology of atherosclerosis and hs-CRP is a useful clinical marker of this inflammatory process, an important unresolved question is whether hs-CRP screening combined with traditional lipid screening would provide an improved strategy for statin use in primary prevention of CVD. The JUPITER trial was designed to answer this question. Several factors governed the design. First, statin therapy has been repeatedly demonstrated to

Conclusion

The JUPITER trial is the first large-scale, multinational, double-blind, placebo-controlled clinical trial to investigate the effects of statins in the primary prevention of cardiovascular events in individuals with low levels of LDL cholesterol who may be at risk because of their elevated hs-CRP levels. Trial results could provide an evidence base for the use of hs-CRP in addition to LDL cholesterol to guide statin therapy in primary prevention. Because of its potential impact on public

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  • Cited by (0)

    Paul M Ridker is listed as a co-inventor on patents held by the Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease.

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