In this paper, a mathematical model is presented that simulates the reductions in LDL cholesterol after separate and combined intake of atorvastatin and phytosterols/-stanols in humans. We demonstrated that a daily intake of 2 g phytosterols/-stanols reduces LDL cholesterol level by about 8% to 9% on top of the reduction resulting from statin use. This level of reduction is consistent with the findings of randomised controlled trials [23–28]. The additional decrease in LDL cholesterol caused by phytosterol/-stanol use at the recommended level of 2 g/d appeared to be similar or even greater than the decrease achieved by doubling the statin dose, a finding that has been observed previously in human trials [23, 29]. The reduction in LDL cholesterol level due to phytosterol/-stanol use results from a decrease in the intestinal uptake of dietary cholesterol (additional effect) and a reduction in enterohepatic recycling (multiplicative effect). For daily statin doses of 20 mg or more, the contribution of the enterohepatic recycling reduction is 55% or more. When no statin is used, this contribution is 68%.
Mathematical models provide a valuable means of interpreting experimental data and improving the ability to predict the response to a given treatment. Other modelling studies have focused on cholesterol metabolism, but are merely aimed at answering questions on the cellular level or tend to focus on specific areas of cholesterol metabolism, such as the fluid dynamics of lipid accumulation on the arterial wall or the chemical kinetics of LDL oxidation [30–32].
In the present study, the separate and combined effects of the cholesterol-lowering drug atorvastatin and functional foods with phytosterols/-stanols in humans were modelled. Yet, this model can easily be applied to other statins and similar acting (functional) foods as well. Products with soluble dietary fibres, for example, are also known to lower total and LDL cholesterol by reducing the intestinal (re)absorption of cholesterol and bile acids, although they work by a different mechanism as phytosterols/-stanols [4, 33, 34]. Moreover, individuals' specific reductions in total and LDL cholesterol can be predicted, based on certain genetic variants. For example, the ratio of cholesterol synthesis to cholesterol absorption varies between individuals and is an important determinant for the cholesterol pool size . Also mutations in the LDL receptor gene causing familial hypercholesterolaemia can be modelled by varying the parameter V
There are a few possible directions for improving our model. First, the model could be extended by including the up- and down regulatory mechanisms involving the LDL receptors. Nonetheless, since we assumed that the clearing of (V)LDL cholesterol from the blood follows Michaelis-Menten kinetics, we implicitly included receptor-mediated uptake in the model. Also other regulatory control pathways were disregarded, such as the existence of a hepatic cholesteryl ester pool that might be involved in cholesterol homeostasis and the regulatory loop in the synthesis of LDL receptors . Another extension would include reverse cholesterol transport mediated by HDL . Moreover, the proposed model assumes that the reducing effects of statins and functional foods are independent of each other. Although this is likely the case for the combination of phytosterols/-stanols and statins,[22, 24, 36, 37] it is uncertain whether this applies for other food-drug combinations. It has, for example, been proposed that soluble dietary fibres reduce the intestinal uptake of statins [38, 39]. Our model should be extended to include such an interaction.
In conclusion, we proposed a simplified mathematical model to simulate the reduction in LDL cholesterol after separate and combined intake of statins and functional foods acting on intestinal (re)absorption of cholesterol or bile acids in humans. In future work, this model can be extended to include more complex (regulatory) mechanisms.