In addition, the vast majority of animal studies have shown that oral administration of PS reduces the progression atherosclerosis. However, it has been recently suggested that an increase in PS plasma concentrations may increase CV risk. Evidence to support this hypothesis come mainly from observations in sitosterolemic patients who hyperabsorb PS and cholesterol and display very high levels of PS, which may be associated with a premature atherosclerosis. Some epidemiological studies in non-sitosterolemic subjects have shown a positive correlation between PS plasma levels and coronary heart disease. However, these are observational studies and some of them present major methodological bias. In addition, recent studies with a larger number of subjects have indicated, either an absence or a negative relationship between PS and the incidence of CV disease.