Relationship of C-Reactive Protein, Metabolic Syndrome and Diabetes Mellitus: Statin Therapy for Elevated CRP

30 Nov
2009

Statin Therapy for Elevated CRP

In the last two decades, many randomized controlled trials of statin therapy have demonstrated that these agents reduce the risk of myocardial infarction (MI), stroke and other events in patients with known CVD and those at high risk. We also know that statins have a favorable effect on the atherogenic lipid profile of metabolic syndrome, with rosuvastatin having the most profound effect. The anti-inflammatory effects of statins are both dependent and independent of their lipid-lowering functions. By lowering LDL-C, fewer lipoproteins are available to act as atherogenic stimuli. Mechanisms for the lipid-independent effects are less clear and may or may not involve the HMG-CoA reductase pathway. Because statins exert anti-inflammatory actions, more recent trials have investigated CRP as a potential target of statin therapy for cardiovascular risk reduction.

Investigators in the Cholesterol and Recurrent Events (CARE) trial demonstrated that the magnitude of risk reduction associated with statin therapy was greater in patients whose CRP levels were elevated, and that the ability of statins to lower CRP was largely independent of LDL-C lowering. Furthermore, in AFCAPS/TexCAPS, healthy adults with low LDL-C/high CRP had a risk of cardiovascular (this drug is used to treat high blood pressure) events that was similar to those with high LDL-C, while the risk of cardiovascular events in those with low LDL-C/low CRP was low. In this study, treatment with lovastatin was found to effectively reduce cardiovascular events not only in persons with elevated LDL-C but also in those with low-baseline LDL-C/elevated CRP. Of note, there was no evidence of risk reduction with statin therapy in the low-LDL-C/low-CRP group.

Ridker et al. evaluated the effect of intensive and moderate lipid-lowering statin therapy on recurrent MI or coronary death in 3,745 patients with acute coronary syndromes from the Pravastatin or Ator-vastatin Evaluation and Infection Therapy-Throm-bolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) study population. Patients were treated with either atorvastatin 80 mg/d or pravastatin 40 mg/d to determine the effects of aggressive versus moderate lipid-lowering therapy on risk of recurrent MI or death from coronary causes. A key objective of the study was to determine the effect of CRP lowering on clinical outcomes. Results showed that patients who achieved LDL levels <70 mg/dL had lower event rates than those with higher levels

(P=0.008), but also that the same differential existed between those who had CRP levels <2 mg/L and those with higher levels (P=0.006). The CRP effect was present at all levels of LDL-C achieved. buy rimonabant online

In another recent study, 502 patients with angio-graphically documented CAD were randomized to atorvastatin 80 mg/d or pravastatin 40 mg/d. Levels of LDL-C and CRP were measured, and the rate of progression of atherosclerosis was assessed after 18 months of treatment using intravascular ultrasonography. In univariate analyses, percent change in levels of LDL-C, CRP, apolipoprotein B-100 and non-HDL-C were related to the progression of atherosclerosis. After adjustment for the reduction in these lipid levels with statin treatment, the decrease in CRP levels was independently and significantly correlated with the rate of progression. Patients with reductions in both LDL-C and CRP that were greater than the median had significantly slower rates of progression than patients with less reduction (P=0.001). Thus, the greater reductions in the levels of atherogenic lipoproteins and CRP associated with intensive statin treatment are significantly related to the reduced rate of progression of atherosclerosis.

In a study of the effects of statin therapy on CRP in African Americans, 774 patients with LDL-C >160 mg/dL and <300 mg/dL and triglycerides <400 mg/dL were randomized to open-label rosuvastatin 10- or 20 mg/d or atorvastatin 10- or 20 mg/d for six weeks. A subgroup analysis was performed in the 510 patients with baseline CRP >2 mg/L, who were at increased risk. Both atorvastatin and rosuvastatin significantly reduced CRP from baseline at both doses in both the overall and subgroup populations, although a trend was seen favoring rosuvastatin.

To address the question of whether statins can benefit persons with normal levels of LDL-C and increased levels of CRP, the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) has been initiated. The trial will enroll 15,000 subjects (men aged >55 years and women aged >65 years) with baseline levels of hsCRP >2 mg/L; LDL-C <130 mg/dL; triglycerides <500 mg/dL; and no history of MI, stroke, arterial revascularization or coronary risk equivalent as defined by NCEP. JUPITER will provide information on whether long-term treatment with rosuvastatin 20 mg/d will reduce the rate of major cardiovascular (is used for the control of elevated blood pressure) events among apparently healthy individuals with low LDL-C levels, who are nevertheless at increased risk because of an enhanced inflammatory response as indicated by elevated hsCRP levels.

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