Responders and Non-responders to the therapy of Hypercholesterolemia

Abstract

Plant stanol margarines are recommended as a lipid-lowering dietary supplement in the treatment of hypercholesterolemia. Parameters predicting the individual cholesterol-lowering effect have not been elucidated so far. Therefore, the responsiveness to sitostanol-supplemented margarine in a specially selected population was investigated. Eight subjects with the lowest and eight subjects with the highest ratios of lathosterol to campesterol in serum were included in the study from a total number of 137 male subjects with hypercholesterolemia. They received 1 g sitostanol-supplemented margarine b.i.d. for four weeks. Serum lipoproteins, the cholesterol precursor lathosterol, the plant sterols campesterol and sitosterol were measured. Subjects with a low ratio of lathosterol to campesterol had a significant decrease of serum total cholesterol (-14.2%; p < 0.01) and LDL cholesterol (-13.8%; p < 0.01; responder). In subjects with a high ratio there was no significant change in total cholesterol and LDL cholesterol (2.2 and 4.3%; non-responder). The ratio of serum lathosterol to campesterol predicts the reduction of total cholesterol and LDL cholesterol during administration of sitostanol-supplemented margarine in patients with mild hypercholesterolemia.<br /> Ezetimibe is an cholesterol absorption inhibitor recommended for the treatment of hypercholesterolemia. In order to elucidate the parameters predicting the inter-individual cholesterol lowering effect, the responsiveness of LDL cholesterol lowering of ezetimibe in healthy volunteers was investigated and potential genetic associations between the serum surrogate markers and common polymorphisms of the ABCG5/ABCG8 genes was assessed. One hundred twenty one male subjects were screened for their ratio of lathosterol to campesterol in serum. Eight subjects with the lowest and 7 subjects with the highest ratio participated in the study. They received ezetimibe 10 mg/day for 4 weeks. Serum lipoproteins, the cholesterol precursor lathosterol as well as the plant sterols campesterol and sitosterol were measured. Subjects with a low ratio of lathosterol to campesterol showed a good response to treatment with a significant decrease of serum total (-25 %; p< 0.0001) and LDL cholesterol (-33 %; p< 0.0001). In contrast, subjects with a high ratio did not display a significant change in serum total or LDL cholesterol (-9%). The Q604E polymorphism of the ABCG5 gene was unevenly distributed in responders and non-responders. The responders were homozygous or heterozygous carries of the wild-type Q604 allele, whereas non-responders carried predominantly the minor allele Q604E. The response to ezetimibe in reduction of total and LDL cholesterol is predicted by the ratio of lathosterol to campesterol in serum and non-response might be due to the predominance of minor allele Q604E polymorphism in ABCG5 gene. <br /> In both the studies the ratio of serum lathosterol to campesterol served as good predictor for responsiveness to sitostanol ester margarine (Responder Study 1) and ezetimibe (Responder Study 2) in lowering cholesterol.