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JUPITER to Earth: A statin helps people with normal LDL-C and high hs-CRP, but what does it mean?

Cleveland Clinic Journal of Medicine. 2009 January;76(1):37-44 | 10.3949/ccjm.75a.08105
January 1, 2009|Cleveland Clinic Journal of Medicine
Mehdi H. Shishehbor, DO, MPH;Stanley L. Hazen, MD, PhD
Author and Disclosure Information

Mehdi H. Shishehbor, DO, MPH
National Institutes of Health CTSA-KL2 Scholar, Department of Interventional Cardiology, Heart and Vascular Institute, Cleveland Clinic

Stanley L. Hazen, MD, PhD
Head, Section for Preventive Cardiology and Rehabilitation; Director, Center for Cardiovascular Diagnostics and Prevention; Department of Cell Biology; and Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic

Address: Stanley L. Hazen, MD, PhD, Department of Preventive Cardiology, C51, Cleveland Clinic, 9500 Euclid Avenue, C51, Cleveland, OH 44195; e-mail hazens@ccf.org

Dr. Hazen has received fees as a consultant or speaker for AstraZeneca, BG Medicine, Biophysical, Merck, Merck/Schering-Plough, Pfizer, PrognostiX, and Wyeth Pharmaceuticals corporations. He has the right to receive royalty payments for inventions or discoveries related to Abbott Laboratories, Biosite, Frantz Biomarkers, and Siemens corporations. And he may receive future financial benefits from Cleveland Clinic for inventions or discoveries related to PrognostiX corporation.

ABSTRACTThe JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) (N Engl J Med 2008; 359:2195–2207) compared rosuvastatin (Crestor) 20 mg daily vs placebo in apparently healthy people who had levels of low-density lipoprotein cholesterol (LDL-C) lower than 130 mg/dL but elevated levels (≥ 2 mg/L) of high-sensitivity C-reactive protein (hs-CRP). Rosuvastatin treatment lowered LDL-C levels by 50% and hs-CRP levels by 37%, accompanied by a 44% relative risk reduction in the composite end point of unstable angina, revascularization, and confirmed death from cardiovascular causes. In absolute terms, 95 people had to be treated over 2 years to prevent one event. There was, however, a higher incidence of diabetes in the rosuvastatin group.

KEY POINTS

  • LDL-C is the current gold standard diagnostic marker of risk, and elevated values should be aggressively treated in both primary and secondary prevention.
  • The optional LDL-C goal of 70 mg/dL for patients at high risk may need to be extended to others at higher global risk, such as those with elevated hs-CRP.
  • Although elevated hs-CRP may identify some people with low LDL-C who are nevertheless at higher global risk, more sensitive and specific markers of risk are needed.

STUDY RESULTS

Patient recruitment and eligibility

Between February 4, 2003, and December 15, 2006, a total of 89,890 people were screened. Of these, 17,802 met the inclusion and exclusion criteria and were included in the study. Of the 72,088 people who were excluded, 25,993 (36.1%) had an hs-CRP level below 2 mg/L and 37,611 (52.2%) had an LDL-C level of 130 mg/dL or higher.

A not-so-healthy population

The aim of the investigators was to include relatively healthy people. The median age was 66 years, about 16% of participants were current smokers, about 11% had a family history of heart disease, and about 41% met the criteria for metabolic syndrome, all conditions that are associated with elevated hs-CRP.25 Of note, the median hs-CRP level was 4.2 mg/L, a level indicating higher global risk according to the American College of Cardiology/American Heart Association consensus statement.26

Reduction in lipid levels and hs-CRP

By 12 months, in the rosuvastatin group, the median LDL-C level had fallen by 50% (from 108 to 55 mg/dL), and the median hs-CRP level had fallen by 37% (from 4.2 to 2.2 mg/L). Additionally, the triglyceride level had fallen by 17%. The high-density lipoprotein cholesterol levels did not change significantly.

Impact on end points

The rosuvastatin group had a 44% lower incidence of the primary end point, 142 vs 251 events (P < .00001). The authors calculated that 95 people would need to be treated with rosuvastatin for 2 years to prevent one event. Rosuvastatin was also associated with a significant reduction in each component of the primary end point. More importantly, significantly fewer people died of any cause in the rosuvastatin group (Table 1). Rosuvastatin was beneficial in all subgroups studied (Figure 1).

Adverse events

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. Copyright 2008 Massachusetts Medical Society. All rights reserved.
Figure 1. Effects of rosuvastatin on the primary end point, according to baseline characteristics. The interaction with the primary end point was not Statistically significant for any of the variables studied.
The incidence of diabetes was higher in the rosuvastatin group (270 vs 216, P = .01). In general, rosuvastatin therapy was otherwise safe, with minimal side effects. No significant differences were seen between the treatment groups in muscle weakness, incidence of cancer, or disorders of the hematologic, hepatic, gastrointestinal, or renal systems.

WHAT DOES THIS MEAN?

Is lower LDL-C better?

The JUPITER trial is the latest of several statin trials that have shown significant reductions in major adverse cardiovascular events when LDL-C was lowered below what has been recommended by the current guidelines.27,28

In 2002, the Heart Protection Study29 showed a significant reduction in major adverse cardiovascular events in patients at high risk of coronary artery disease if they received simvastatin (Zocor), even if they had LDL-C levels lower than 100 mg/dL at baseline. Similarly, the Pravastatin or Atorvastatin Evaluation and Infection-Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI 22) trial30 showed a 16% relative risk reduction in a composite end point in patients presenting with acute coronary syndrome if they received intensive statin therapy.

These two studies led to an update by the National Cholesterol Education Program (Adult Treatment Panel III), suggesting an optimal LDL-C goal of less than 70 mg/dL in those with coronary artery disease or its risk equivalent (ie, diabetes mellitus, peripheral vascular disease). Furthermore, in support of the “lower is better” theory, a number of studies that used intravascular ultrasonography have shown regression of coronary plaque with aggressive LDL-C lowering. Notably, in a Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (the ASTEROID trial),5 rosuvastatin 40 mg daily caused significant plaque regression while lowering LDL-C to 61 mg/dL over a 24-month period.

A number of high-dose statin trials have shown that lowering LDL-C to less than 70 mg/dL significantly reduces major adverse cardiovascular events.31–39 The JUPITER trial was unique in that it extended these findings to people without known coronary disease (ie, primary prevention) or elevated cholesterol but with elevated levels of a marker of inflammation—hs-CRP. In view of the JUPITER results and of studies using intravascular ultrasonography in the primary prevention setting, it seems clear that lowering LDL-C to levels less than 70 mg/dL also reduces both atherosclerotic plaque progression and the rate of first major adverse cardiovascular events in primary prevention in patients at higher global risk.

Did the study prove that reducing hs-CRP lowers risk?

Measuring hs-CRP levels has been extensively studied in apparently healthy populations, stable angina, unstable angina, and other cardiovascular settings.18,21,40–43 It has been shown to have significant prognostic implications in a number of primary and secondary trials.44 Additionally, those with elevated LDL-C and hs-CRP levels benefit the most from statin therapy.16,45,46 Animal studies have also provided some evidence that CRP may play a role in atherogenesis.47,48 However, recent clinical and genetic studies have raised doubt about the direct causal relationship between CRP and coronary artery disease,23,49,50 and epidemiologic studies have questioned its usefulness as a marker of risk.51,52

The JUPITER study adds little to clear up the controversy about whether hs-CRP is a mechanistic participant in atherosclerotic disease. However, it also shows that this issue is somewhat irrelevant, in that selection of patients for high-potency statin therapy solely on the basis of high hs-CRP without other indications for lipid-lowering therapy clearly reduces risk and improves survival.

JUPITER did not examine whether people with higher hs-CRP levels benefited more from statin therapy than those with lower levels. The hypothesis-generating data for JUPITER came from an analysis of changes in hs-CRP and LDL-C in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).16 Thus, JUPITER did not include people with both low LDL-C and low hs-CRP because, in the AFCAPS/TexCAPS analysis, those with low LDL-C and low hs-CRP had extremely low event rates and no clinical efficacy of statin therapy, despite good LDL-C reduction. In marked contrast, those with low LDL-C but elevated hs-CRP had high event rates and large relative risk reductions— hence the need for JUPITER to prospectively test this hypothesis. Nevertheless, the initial results of JUPITER as presented do not yet make it clear that there is a dose-response relationship between higher levels of hs-CRP and a greater reduction in events, even in a cohort with elevated hs-CRP at baseline. This analysis will no doubt be forthcoming in another manuscript from Ridker and colleagues. Specifically, it will be of interest to examine whether those with the highest hs-CRP levels benefited the most from rosuvastatin on both an absolute and relative scale, and whether those with the greatest hs-CRP reduction also benefited more. With the present data available from JUPITER, a reasonable interpretation is that an elevated hs-CRP simply widens the inclusion criterion for those for whom high-potency statin therapy improves clinical outcomes.53

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