Which is More Important, the Level of the LDL Cholesterol or the C-reactive Protein?

Abstract & Commentary

Synopsis: The CRP and the LDL-C are independent predictors of cardiovascular risk.

Source: Ridker PM, et al. N Engl J Med. 2005;352:20-28.

Statins lower the levels of C-reactive protein (CRP) as well as the levels of LDL cholesterol (LDL-C). Whether lowering the CRP affects the clinical outcomes of statin therapy has not previously been investigated.

The study population was derived from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombosis in Myocardial Infarction 22 study (PROVE IT-TIMI 22), performed between November 2000 and February 2004; it involved 4162 patients who had been hospitalized in the preceding 10 days with acute coronary syndromes.

In this study, patients in whom statin therapy resulted in LDL-C levels of less than 70 mg/dL had lower event rates than those with higher levels (2.7 vs 4.0 event per 100 person years; P = 0.008). However, virtually an identical difference was observed between those who had CRP levels less than 2 mg/L after statin therapy and those who had higher levels (2.8 vs 3.9 events per 100 person-years; P = 0.006), an effect present in all levels of LDL-C achieved.

For patients with post-treatment LDL-C levels of more than 70 mg/dL, the rates of recurrent events were 4.6 per 100 person-years among those with CRP levels of more than 2 mg/L and 3.2 events per 100 person-years among those with CRP levels of less than 2 mg/L. Although atorvastatin was more likely than pravastatin to result in low levels of LDL-C and CRP, meeting these targets was more important than the specific choice of therapy. Patients who had LDL-C levels of less than 70 mg/dL and CRP levels below 1 mg per liter after statin therapy had the lowest rate of recurrent events (1.9 per 100 person years).

Ridker and colleagues concluded that patients who have low CRP levels after statin therapy have better clinical outcomes than those with higher CRP levels, regardless of the resultant level of LDL-C. Strategies to lower the cardiovascular risk with statins should include monitoring CRP as well as cholesterol.

Comment by Ralph R. Hall, MD, FACP

In a second article in the same issue of The New England Journal of Medicine,1 Nissen and associates add support to the individual contributions of lipid lowering and the CRP.

Nissen et al performed ultrasonography on 502 patients with angiographically documented coronary disease. Patients were randomly assigned to receive pravastatin 40 mg daily or atorvastatin 80 mg/d. Ultrasonagraphy was repeated after 18 months to measure progression of atherosclerosis. Lipoprotein and CRP levels were measured at base line and at follow-up.

They found a reduced rate of progression of atherosclerosis associated with the more intense atorvastatin therapy than with pravastatin. These findings were significantly related to both the lower lipid levels and the CRP. They suggested that "the level of CRP may ultimately represent an important therapeutic target."

The relationship between CRP and lipid levels is complex. Treating inflammatory rheumatoid arthritis with prednisone or methotrexate results in improvement in the lipid profiles of the patients who have significant clinical improvement and who are not receiving lipid- lowering drugs. It has recently been reported that second-hand smoke will raise the CRP.2

A number of questions remain, as these are secondary prevention studies. What is the precise role of CRP levels in primary prevention? Is the age of the patient important when we prescribe intensive statin therapy? The mortality rate of older patients in intensive care units has been reported to be increased in those with lower lipid levels.3 What is the role of exercise and diet in controlling CRP levels? Observational studies are conflicting as to the role of exercise in lowering the CRP.

The evidence is growing that we should add the CRP to our assessment of patients’ risk. The evidence is at least as strong for intensive lipid lowering for patients with risk factors to control both the lipids and the CRP.

Dr. Hall, Emeritus Professor of Medicine University of Missouri- Kansas City School of Medicine, is Associate Editor of Internal Medicine Alert.

References

1. Nissen SE, et al. N Engl J Med. 2005;352:29-38.

2. Onder R. Am J Med. 2003;115:265-271.

3. Panageotakos DC. Am J Med. 2004;116:145-150.