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Rosuvastatin, inflammation, C-reactive protein, JUPITER, and primary prevention of cardiovascular disease--a perspective - PubMed

  • ️Fri Jan 01 2010

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Rosuvastatin, inflammation, C-reactive protein, JUPITER, and primary prevention of cardiovascular disease--a perspective

Richard Kones. Drug Des Devel Ther. 2010.

Abstract

The major public health concern worldwide is coronary heart disease, with dyslipidemia as a major risk factor. Statin drugs are recommended by several guidelines for both primary and secondary prevention. Rosuvastatin has been widely accepted because of its efficacy, potency, and superior safety profile. Inflammation is involved in all phases of atherosclerosis, with the process beginning in early youth and advancing relentlessly for decades throughout life. C-reactive protein (CRP) is a well-studied, nonspecific marker of inflammation which may reflect general health risk. Considerable evidence suggests CRP is an independent predictor of future cardiovascular events, but direct involvement in atherosclerosis remains controversial. Rosuvastatin is a synthetic, hydrophilic statin with unique stereochemistry. A large proportion of patients achieve evidence-based lipid targets while using the drug, and it slows progression and induces regression of atherosclerotic coronary lesions. Rosuvastatin lowers CRP levels significantly. The Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial was designed after the observation that when both low density lipoprotein and CRP were reduced, patients fared better than when only LDL was lowered. Advocates and critics alike acknowledge that the benefits of rosuvastatin in JUPITER were real. After a review, the US Food and Drug Administration extended the indications for rosuvastatin to include asymptomatic JUPITER-eligible individuals with one additional risk factor. The American Heart Association and Centers of Disease Control and Prevention had previously recognized the use of CRP in persons with "intermediate risk" as defined by global risk scores. The Canadian Cardiovascular Society guidelines went further and recommended use of statins in persons with low LDL and high CRP levels at intermediate risk. The JUPITER study focused attention on ostensibly healthy individuals with "normal" lipid profiles and high CRP values who benefited from statin therapy. The backdrop to JUPITER during this period was an increasing awareness of a rising cardiovascular risk burden and imperfect methods of risk evaluation, so that a significant number of individuals were being denied beneficial therapies. Other concerns have been a high level of residual risk in those who are treated, poor patient adherence, a need to follow guidelines more closely, a dual global epidemic of obesity and diabetes, and a progressively deteriorating level of physical activity in the population. Calls for new and more effective means of reducing risk for coronary heart disease are intensifying. In view of compelling evidence supporting earlier and aggressive therapy in people with high risk burdens, JUPITER simply offers another choice for stratification and earlier risk reduction in primary prevention patients. When indicated, and in individuals unwilling or unable to change their diet and lifestyles sufficiently, the benefits of statins greatly exceed the risks. Two side effects of interest are myotoxicity and an increase in the incidence of diabetes.

Keywords: C-reactive protein; Framingham risk score; HMG CoA reductase; JUPITER study; Reynolds risk score; cardiovascular risk; carotid intima-media thickness; cholesterol; coronary artery calcification; coronary heart disease; diabetes; dolichol; dyslipidemia; high-density lipoprotein; hypertension; inflammation; low-density lipoprotein; metabolic syndrome; mevalonate; obesity; pleiotropic; prenylation; primary prevention; rosuvastatin; statin drugs; statin myopathy.

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Figures

Figure 1
Figure 1

A picture of C-reactive protein (CRP) from 1B09.pdb made using pymol. CRP is a pentameric molecule containing a recognition face that binds phosphocholine and calcium ions, and on the opposite side, an effector face that contains a C1q-binding site. Function depends upon Ca2+-dependent ligand binding. See text for details. Reproduced by permission of Skolstoe through Wikipedia commons.

Figure 2
Figure 2

Cholesterol is synthesized via the mevalonate pathway. Acetyl-CoA forms 3-hydroxyl-3-methylglutaryl CoA (HMG-CoA) in several steps. The conversion of 3-hydroxy-3-methylglutaryl (HMG)-CoA to mevalonate, the rate-limiting step in cholesterol synthesis, is catalyzed by HMG-CoA reductase (HMGR), an enzyme within the endoplasmic reticulum. Rosuvastatin is an efficient competitive inhibitor of HMGR, reducing not only mevalonate levels, but also prenylated downstream products. The post-translational process of prenylation is needed for the function of small G proteins, including geranylgeranylation of Rho, Ras, and Rab, necessary for cellular signaling, transduction, and intermembrane translocation. As beneficial as statins are, there are obligatory molecular consequences inherent in their use, some related to their beneficial pleiotropic actions, but also to their side effects. Many steps and enzymes are omitted for clarity.

Figure 3
Figure 3

The structure of rosuvastatin, uniquely containing sulfur, a fluorophenyl group, and a modified hydroxyglutaric acid moiety. The IUPAC name of rosuvastatin is (E,3R,5R)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan- 2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid.

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