The medical community has struggled with two important questions for the past 10 years: When it comes to the low-density lipoprotein cholesterol (LDL-C) level, how low should one go and at what cost? And are there other markers of risk that can identify a higher-risk subpopulation in relatively healthy people? The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) provided partial answers for these questions by finding that a highly potent statin lowered the risk of cardiovascular events in patients with “normal” LDL-C but elevated levels of high-sensitivity C-reactive protein (hs-CRP). 1
In this article, we will critically evaluate the methods, results, and conclusions of the JUPITER trial. Additionally, we will discuss its limitations and areas of uncertainty.
The LDL-C-lowering drugs called statins have revolutionized cardiovascular medicine. 2 They are beneficial in both the primary prevention setting and in acute coronary syndromes, stable angina, and unstable angina and can halt the progression of coronary artery disease—in some cases even resulting in modest regression of plaque. 3–6
Many experts have credited the reduction in LDL-C as being the sole factor responsible for the decrease in major adverse events seen with statin therapy. 7 However, statins have other, non-lipid-lowering properties, including anti-inflammatory and antioxidant effects, that may also contribute to their benefits. 8–15
One of the anti-inflammatory actions of statins is evidenced by lower levels of the acute-phase reactant CRP. 10,11,15,16 Measuring systemic CRP levels with a highly sensitive assay (yielding the so-called high-sensitivity or hs-CRP level) provides significant clinical prognostic value across a spectrum of clinical situations, ranging from risk screening in apparently healthy people to stable and unstable angina. 17–22 People with higher hs-CRP levels are, on average, at higher risk of adverse cardiovascular events. However, controversy remains as to whether hs-CRP plays a mechanistic role in plaque formation and acute complications. Indeed, recent genetic studies argue strongly that hs-CRP lies outside the mechanistic path of atherosclerosis. 23 Nonetheless, an overwhelming amount of data indicates that hs-CRP serves as a marker of disease. 17–21
Nissen et al 10 showed that the rate of progression of atherosclerosis is lower when the levels of atherogenic lipoproteins and hs-CRP are both lowered with statin therapy. Simultaneously, Ridker et al 11 showed that patients who have lower hs-CRP levels after statin therapy have better clinical outcomes than those with higher hs-CRP levels, regardless of their achieved level of LDL-C.
Collectively, these studies and others have led some to believe that, in people with relatively low LDL-C but persistently elevated hs-CRP, statin therapy may reduce the rate of events. 15,24 The JUPITER trial was undertaken to test this hypothesis.
JUPITER STUDY DESIGN
JUPITER was designed to see whether highly potent statin therapy is beneficial in people with elevated hs-CRP who otherwise do not meet the criteria for lipid-lowering therapy. The study was conducted at 1,315 sites in 26 countries. It was sponsored by AstraZeneca, the maker of rosuvastatin (Crestor).
Inclusion and exclusion criteria
All participants had to be free of known cardiovascular disease, have an LDL-C level lower than 130 mg/dL, and have an hs-CRP level of 2.0 mg/L or greater. Patients were excluded if they were previous or current users of lipid-lowering drugs; had severe arthritis, lupus, or inflammatory bowel disease; or were taking immune-modulating drugs such as cyclosporine (Sandimmune, others), tacrolimus (Prograf), azathioprine (Azasan, Imuran), or long-term oral corticosteroids.