In addition to their expected effects on
lipid profile,
lipid-lowering agents may reduce cardiovascular events because of effects on nonclassic risk factors such as
insulin resistance and
inflammation.
Ezetimibe specifically blocks the absorption of dietary and biliary
cholesterol as well as
plant sterols. Although it is known that an additional reduction of
low-density lipoprotein cholesterol (
LDL-C) levels can be induced by the combination of
ezetimibe with
statins, it is not known if this can enhance some pleiotropic effects, which may be useful in slowing the atherosclerotic process. This study assessed the effects of
simvastatin and
ezetimibe, in monotherapy or in combination, on markers of endothelial function and
insulin sensitivity. Fifty prediabetic subjects with normo- or mild-to-moderate
hypercholesterolemia were randomly allocated to 2 groups receiving either
ezetimibe (10 mg/d) or
simvastatin (20 mg/d) for 12 weeks, after which the drugs were combined for both groups for an additional 12-week period. Clinical and laboratory parameters were measured at baseline and after 12 and 24 weeks of
therapy. Homeostasis model assessment of
insulin resistance index and the area under the curve of
insulin were calculated. As expected, both groups receiving drugs in isolation significantly reduced total
cholesterol, LDL-C,
apolipoprotein B, and
triglyceride levels; and additional reductions were found after the combination period (P < .05). After 12 weeks of monotherapy,
plasminogen activator inhibitor-1 levels and urinary
albumin excretion were lower in the
simvastatin than in the
ezetimibe group. No change in homeostasis model assessment of
insulin resistance index, area under the curve of
insulin, and
adiponectin levels was observed after either the monotherapies or the combined
therapy. However,
simvastatin combined with
ezetimibe provoked significant reductions in
E-selectin and intravascular cellular adhesion molecule-1 levels that were independent of
LDL-C changes. Our findings support claims that
simvastatin may be beneficial in preserving endothelial function in prediabetic subjects with normo- or mild-to-moderate
hypercholesterolemia. Alternatively, a deleterious effect of
ezetimibe on the endothelial function is suggested, considering the increase in intravascular cellular adhesion molecule-1 and
E-selectin levels.
Simvastatin and
ezetimibe, in isolation or in combination, do not interfere with
insulin sensitivity.