Elsevier

The Lancet

Volume 373, Issue 9670, 4–10 April 2009, Pages 1175-1182
The Lancet

Fast track — Articles
Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial

https://doi.org/10.1016/S0140-6736(09)60447-5Get rights and content

Summary

Background

Statins lower high-sensitivity C-reactive protein (hsCRP) and cholesterol concentrations, and hypothesis generating analyses suggest that clinical outcomes improve in patients given statins who achieve hsCRP concentrations less than 2 mg/L in addition to LDL cholesterol less than 1·8 mmol/L (<70 mg/dL). However, the benefit of lowering both LDL cholesterol and hsCRP after the start of statin therapy is controversial. We prospectively tested this hypothesis.

Methods

In an analysis of 15 548 initially healthy men and women participating in the JUPITER trial (87% of full cohort), we prospectively assessed the effects of rosuvastatin 20 mg versus placebo on rates of non-fatal myocardial infarction, non-fatal stroke, admission for unstable angina, arterial revascularisation, or cardiovascular death (prespecified endpoints) during a maximum follow-up of 5 years (median 1·9 years), according to on-treatment concentrations of LDL cholesterol (≥1·8 mmol/L or <1·8 mmol/L) and hsCRP (≥2 mg/L or <2 mg/L). We included all events occurring after randomisation. This trial is registered with ClinicalTrials.gov, number NCT00239681.

Findings

Compared with placebo, participants allocated to rosuvastatin who achieved LDL cholesterol less than 1·8 mmol/L had a 55% reduction in vascular events (event rate 1·11 vs 0·51 per 100 person-years; hazard ratio [HR] 0·45, 95% CI 0·34–0·60, p<0·0001), and those achieving hsCRP less than 2 mg/L a 62% reduction (event rate 0·42 per 100 person-years; HR 0·38, 95% CI 0·26–0·56, p<0·0001). Although LDL cholesterol and hsCRP reductions were only weakly correlated in individual patients (r values <0·15), we recorded a 65% reduction in vascular events in participants allocated to rosuvastatin who achieved both LDL cholesterol less than 1·8 mmol/L and hsCRP less than 2 mg/L (event rate 0·38 per 100 person-years; adjusted HR 0·35, 95% CI 0·23–0·54), versus a 33% reduction in those who achieved one or neither target (event rate 0·74 per 100 person-years; HR 0·67, 95% CI 0·52–0·87) (p across treatment groups <0·0001). In participants who achieved LDL cholesterol less than 1·8 mmol/L and hsCRP less than 1 mg/L, we noted a 79% reduction (event rate 0·24 per 100 person-years; HR 0·21, 95% CI 0·09–0·52). Achieved hsCRP concentrations were predictive of event rates irrespective of the lipid endpoint used, including the apolipoprotein B to apolipoprotein AI ratio.

Interpretation

For people choosing to start pharmacological prophylaxis, reduction in both LDL cholesterol and hsCRP are indicators of successful treatment with rosuvastatin.

Funding

AstraZeneca.

Introduction

Present guidelines for statin therapy emphasise the need to achieve specific goals for LDL cholesterol to maximise clinical outcomes.1, 2 However, statin therapy has greatest efficacy in the presence of inflammation,3, 4 and several studies show that statins reduce the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) largely independently of LDL cholesterol.5, 6, 7, 8 Furthermore, in both the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT–TIMI 22)9 and Aggrastat-to-Zocor (A to Z)10 trials of patients with acute coronary ischaemia treated with statin therapy, the best clinical outcomes were in those who not only achieved LDL cholesterol less than 1·8 mmol/L (<70 mg/dL), but who also achieved hsCRP less than 2 mg/L. These findings are consistent with the pathophysiological understanding that atherothrombosis is a disorder of both hyperlipidaemia and inflammation11 and that statins have anti-inflammatory and lipid-lowering properties.12, 13

Despite the consistency of these results, whether achieving lower concentrations of hsCRP after initiation of statin therapy is associated with improved clinical outcomes, in a similar manner to that associated with achieving lower concentrations of LDL cholesterol, remains controversial. We prospectively tested this hypothesis in the large-scale JUPITER (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial.14

Section snippets

Patients and procedures

The study population was derived from JUPITER—a randomised, double-blind, placebo-controlled trial that was designed to investigate whether rosuvastatin 20 mg daily decreased the rate of first cardiovascular events compared with placebo in apparently healthy men and women with LDL cholesterol less than 3·37 mmol/L (<130 mg/dL) who are at increased vascular risk due to hsCRP concentration of 2 mg/L or more. Full details of the trial protocol and procedures have been previously presented.14 The

Results

Table 1 shows baseline characteristics of the study population in the placebo and rosuvastatin groups according to achieved LDL cholesterol and achieved hsCRP concentrations. Baseline age, blood pressure, HDL cholesterol, triglycerides, glucose, and haemoglobin A1c were much the same between groups (table 1).

As expected, baseline LDL cholesterol values were lower in particpants given rosuvastatin who subsequently achieved LDL cholesterol less than 1·8 mmol/L compared with those who did not;

Discussion

In healthy men and women starting rosuvastatin therapy in the JUPITER trial, achievement of target concentrations of LDL cholesterol less than 1·8 mmol/L and hsCRP less than 2 mg/L was associated with improved event-free survival compared with achievement of neither target or with achievement of reduced LDL cholesterol alone. The differential outcomes that we recorded on the basis of achieved concentrations of LDL cholesterol and hsCRP remained significant and unchanged in magnitude after

References (22)

  • C Arnaud et al.

    Toward immunomodulatory and anti-inflammatory properties of statins

    Trends Cardiovasc Med

    (2005)
  • G De Backer et al.

    European guidelines on cardiovascular disease prevention in clinical practice

    Eur Heart J

    (2003)
  • SM Grundy et al.

    Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines

    Circulation

    (2004)
  • PM Ridker et al.

    Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators

    Circulation

    (1998)
  • PM Ridker et al.

    Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events

    N Engl J Med

    (2001)
  • MA Albert et al.

    Effect of statin therapy on C-reactive protein levels: the Pravastatin Inflammation/CRP Evaluation (PRINCE), a randomized trial and cohort study

    JAMA

    (2001)
  • PM Ridker et al.

    Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators

    Circulation

    (1999)
  • PM Ridker et al.

    Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia

    Circulation

    (2001)
  • I Jialal et al.

    Effect of hydroxymethyl glutaryl coenzyme A reductase inhibitor therapy on high sensitive C-reactive protein levels

    Circulation

    (2001)
  • PM Ridker et al.

    C-reactive protein levels and outcomes after statin therapy

    N Engl J Med

    (2005)
  • DA Morrow et al.

    Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial

    Circulation

    (2006)
  • Cited by (877)

    • Systemic inflammation in psoriasis: Sequel of metabolic syndrome

      2023, Metabolic Syndrome: From Mechanisms to Interventions
    • High-Sensitivity C-Reactive Protein

      2023, Clinical Lipidology: A Companion to Braunwald's Heart Disease
    View all citing articles on Scopus
    View full text