Synergistic Effect of Simvastatin and Ezetimibe on Lipid and Pro-inflammatory Profiles in Pre-diabetic Subjects

Long-term benefits of statins on prevention of cardiovascular events have been consistently shown in several populations. It has been demonstrated that, with particular regard to subjects at high risk, the lower LDL-cholesterol levels, the lower the incidence of cardiovascular outcomes. Beneficial effects of statins can be attributed to their lipid-lowering ability as well as to additional benefits. The so-called pleiotropic effects on low grade inflammation status have been described in subsets of subjects with different cardiovascular profiles. The most common inflammatory marker used in clinical practice is the high-sensitivity C-reactive protein (CRP) level, but a number of others has also been investigated.

Disturbances of glucose metabolism accompanied by insulin resistance are pro-inflammatory conditions which may accelerate atherosclerosis. Diabetic populations are at high cardiovascular risk and strict control of lipoprotein concentrations is recommended. Several recent studies showed the efficacy of statins on primary and secondary prevention of cardiovascular events in diabetic populations. The goal of 100 mg/dL for LDL-cholesterol may be too elevated for subjects at very high risk for whom a target of 70 mg/dl has been suggested. High statin doses may be necessary, which increases its adverse effects. Given that statin monotherapy may be insufficient for the desirable reduction in LDL levels, a combination of lipid-lowering agents has become frequent in clinical practice. In particular, statin and ezetimibe combination has been shown to be very effective in reducing total and LDL cholesterol levels.

Ezetimibe is a specific cholesterol absorption inhibitor that acts at the brush border of the small intestine, blocking the absorption of dietary and biliary cholesterol and plant sterols, resulting in intracellular cholesterol depletion via the Niemann-Pick C1-like transporter. Adding ezetimibe to statin therapy induces a 15% reduction in LDL levels compared with only 6% achieved by doubling the dose of statins. Data concerning the pleiotropic effects of this combination are controversial. One study, in which CRP level was used as the inflammatory marker, found that a combination of simvastatin and ezetimibe produced an incremental effect in lowering CRP, independently of the improvement in lipoprotein concentrations. Although few studies have confirmed this finding, as far as we know, data regarding simvastatin-ezetimibe combination induced-changes in serum interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a) levels are lacking. We tested the hypothesis that this combination would induce improvement in inflammatory status, as reflected by leukocyte count and CRP, IL-6 and TNF-α levels.

Therefore, this study evaluates whether the combination of lipid-lowering effects of low-to-moderate dose of simvastatin and ezetimibe also results in a synergistic effect that reduces the pro-inflammatory status of pre-diabetic subjects with mild-to-moderate hypercholesterolemia.

Subjects and Methods: