Atherosclerosis is a chronic inflammatory process, and some of the benefits of statins are thought to be related to their ability to reduce inflammation. A study by James K. Liao and colleagues published online December 15 in Circulation raises questions as to whether ezetimibe lacks these antiinflammatory effects. Statins reduce production of cholesterol in the liver by inhibiting an enzyme called HMG-CoA reductase (see figure 1 in this paper), and inhibiting this enzyme also reduces production of rho kinase, a substance that increases vascular inflammation. By contrast, ezetimibe works by reducing cholesterol absorption in the intestines. Although ezetimibe lowers LDL ("bad") cholesterol, it does not reduce production of rho kinase (and in fact may increase it).

One way of measuring inflammation is by testing the brachial (upper arm) artery's ability to relax in response to increased blood flow through a test called flow mediated dilation (FMD). Low FMD is a marker for increased cardiovascular risk and an early sign of atherosclerosis.

The study compared the effects of a moderate dose of a statin (40 mg. simvastatin) with a lower dose of the statin combined with ezetimibe (10 mg simvastatin/10 mg ezetimibe) on FMD and rho kinase in patients with high cholesterol. Another group of patients received a placebo. The higher dose of simvastatin and the combination of simvastatin and ezetimibe lowered LDL to a similar extent. No change in rho kinase activity or FMD was found in the placebo group or the simvastatin/ezetimibe group, but in the group that received simvastatin alone rho kinase activity was reduced and FMD increased, indicating decreased inflammation. In addition, a strong statistical association was found between changes in FMD and changes in rho kinase activity. The inhibition of rho kinase activity was statistically significant even after controlling for changes in LDL, supporting the idea that inhibition of rho kinase by statins is independent of cholesterol lowering.

The authors conclude that the findings of their study may help explain the disappointing results of the ENHANCE study, in which ezetimibe did not alter the progression of atherosclerosis when added to a statin.

-- Marilyn Mann