Modelling approach to simulate reductions in LDL cholesterol levels after combined intake of statins and phytosterols/-stanols in humans

Abstract

Background: To examine the effects on LDL cholesterol of the combined use of statins and phytosterols/-stanols, in vivo studies and clinical trials are necessary. However, for a better interpretation of the experimental data as well as to possibly predict cholesterol levels given a certain dosing regimen of statins and phytosterols/-stanols a more theoretically based approach is helpful. This study aims to construct a mathematical model to simulate reductions in low-density lipoprotein (LDL) cholesterol in persons who combine the use of statins with a high intake of phytosterols/-stanols, e.g. by the use of functional foods.

Methods and results: The proposed model includes the cholesterol pool size in the liver and serum levels of very low-density lipoprotein (VLDL) cholesterol. Both an additional and a multiplicative effect of phytosterol/-stanol intake on LDL cholesterol reduction were predicted from the model. The additional effect relates to the decrease of dietary cholesterol uptake reduction, the multiplicative effect relates to the decrease in enterohepatic recycling efficiency, causing increased cholesterol elimination through bile. From the model, it was 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. 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.

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.

Figure 1

Simplified scheme of LDL cholesterol metabolism in humans. For detailed description of the model see text. The definition of the model variables are summarised in Table 1.

Figure 2

Simulated dose-response relation between in vitro plasma atorvastatin concentration (ng/ml) and hydroxymethylglutaryl-coenzyme A (HMG-CoA) inhibition (%) in humans. Maximum inhibition is 97.8% and the concentration at half maximum inhibition is 1.64 (ng/ml). Solid symbols present data by Shum et al. [7]

Figure 3

Simulated reduction (%) in LDL cholesterol after treatment with different doses of atorvastatin. The solid line shows the fit to the model and symbols represent experimental data from Berry et al. [21] Values for the Michaelis-Menten parameters are: effective maximum LDL cholesterol reduction (R_{P, max}) = 0.544 and half maximum reduction statin dose (S_{P, 1/2}) = 6.7 mg/d. The dashed lines show the 5% and 95% uncertainty range in reduction obtained by correlated sampling (correlation coefficient ρ = 0.88) of R_{P, max} and S_{P, 1/2} from their covariance matrix.

Figure 4

Simulated reduction (%) in LDL cholesterol after treatment with different doses of phytosterols/-stanols. The solid line shows the fit to the model and symbols represent experimental data from Demonty et al. [22] Values for the Michaelis-Menten parameters are: effective maximum LDL cholesterol reduction (R_{U, max}) = 0.221 and half maximum reduction phytosterol/-stanol dose (PS_{U, 1/2}) = 1.78 mg/d. The dashed lines show the 5% and 95% uncertainty range in reduction obtained by correlated sampling (correlation coefficient ρ = 0.98) of R_{U, max} and PS_{U, 1/2} from their covariance matrix.

Figure 5

Simulated reduction (%) in LDL cholesterol after combined treatment with different doses of free phytosterols/-stanols and atorvastatin in humans. The lines from upper to lower show LDL cholesterol reduction for subjects that are exposed to no atorvastatin, or daily doses of 20, 40 or 80 mg atorvastatin, respectively.