Avasimibe is a novel orally bioavailable ACAT inhibitor, currently under clinical development (phase III trials). It was safe when administered to rats, dogs, and humans. In vitro studies in human macrophages demonstrated that
avasimibe reduces foam cell formation not only by enhancing free
cholesterol efflux, but also by inhibiting the uptake of modified
LDL. The concentration-dependent reduction in cellular
cholesteryl ester content in these cells was not accompanied by an increase in intracellular free
cholesterol, which is in agreement with a good safety profile for
avasimibe. In the liver,
avasimibe caused a significant reduction in the secretion of
apo B and
apo B-containing
lipoproteins into plasma.
Avasimibe induced
cholesterol 7alpha-hydroxylase and increased
bile acid synthesis in cultured rat hepatocytes, and its administration to rats did not produce an increase in lithogenicity index of the bile. The hypolipidemic efficacy of the compound was demonstrated in
cholesterol-fed as well as in non-
cholesterol-fed animals. In these models, plasma
cholesterol levels were reduced, mainly due to the decrease in the non-
HDL cholesterol fraction. Clinical data are scarce, but in a study performed in 130 men and women with combined
hyperlipidemia and
hypoalphalipoproteinemia,
avasimibe, 50-500 mg/day, significantly reduced plasma total
triglyceride and
VLDL-cholesterol. Although total
cholesterol, LDL-
cholesterol, and
HDL-cholesterol were unchanged, it must be stressed that animal data suggest that
avasimibe may have direct antiatherosclerotic activity in addition to its
cholesterol-lowering effect.
Avasimibe treatment can also contribute to increase plaque stability, as it reduces the accumulation of
lipids in the arterial wall, inhibits macrophage infiltration into the media and reduces
matrix metalloproteinase expression and activity. Moreover,
avasimibe and
statins have been shown to have synergistic effects, and the combination
therapy may not only inhibit atherosclerotic lesion progression but also induce lesion regression, independently of changes in plasma
cholesterol.