The effects of colestipol on the metabolism of very-low-density lipoproteins in man

Abstract

Bile acid-binding resins, currently used for the treatment of Type II hyperlipoproteinemia, decrease LDL cholesterol by 25 to 35 per cent. Elevations of plasma triglycerides sometimes occur with resin therapy, suggesting that alterations in metabolism may not be confined solely to LDL. To characterize the effects of the resins on lipoproteins in greater detail, we carried out two studies using colestipol. In the acute study, seven Type IIA patients were studied on a metabolic ward before and for the first 7 to 10 days after initiation of therapy. Blood samples were drawn after 12 to 14 hour fasts every 1 to 3 days during hospitalization and at frequent intervals thereafter for the first 2 to 6 months of therapy. In the chronic study, 12 Type II patients were studied as outpatients at monthly intervals. Three fasting plasma samples were obtained before therapy and three additional samples were ovtained between 3 and 12 months after commencement of treatment. Lipoprotein quantification of individual plasma samples was performed by combined ultracentrifugal and MnCl2-heparin precipitation techniques. The size distribution of ultracentrifugally isolated VLDL was assessed by column chromatography in Sepharose 2B. In the acute study, LDL-Chol fell 24 to 28 hours after initiation of therapy in each subject. Concomitantly, VLDL-TG rose. By days 5 to 8, mean LDL-Chol of the group had fallen by 30 per cent and mean VLDL-TG had risen by 35 per cent. Although mean VLDL-Chol also rose (by about 14 per cent), since VLDL-TG rose more, VLDL became enriched with respect to TG. At peak triglyceridemia, LDL and HDL were also found to be relatively TG-enriched. Between 7 and 30 days after initiation of therapy, VLDL-TG levels returned to and below baseline as LDL-Chol continued to fall. LDL and HDL compositions also returned toward baseline. On gel filtration chromatography of VLDL, obtained during therapy, a peak, which was not present in baseline samples, appeared in the void volume of the column. The amounts of VLDL eluting in the usual positions were also increased. Thus, acute therapy was accompanied by (1) transient rises in levels of triglyceride-enriched VLDL of apparently larger size, (2) falls in LDL-Chol, and (3) changes in the composition of LDL and HDL. In the chronic study, mean total-Chol fell from 345 to 258 mg. per deciliter and mean LDL-Chol fell from 277 to 188 mg. per deciliter (p less than 0.001 for both comparisons). Total-TG and VLDL-TG were not significantly altered. The compositions of VLDL and HDL were unchanged from pretreatment values while LDL became relatively TG-enriched. These findings suggest that acutely colestipol produced alterations in the metabolism of all lipoproteins, but that with prolonged therapy, the levels of VLDL and HDL returned toward pretreatment levels.