The Effect of Colesevelam Treatment on Bile Acid and Lipid Metabolism and Glycemic Control in Healthy Men

Abstract

The treatment of hypercholesterolemia with bile acid (BA) sequestrants results in upregulation of BA synthesis through the classical pathway initiated by cholesterol 7α-hydroxylase (CYP7A1). To characterize the detailed dynamics of serum lipid and BA concentrations and the BA synthesis rate in response to treatment with BA sequestrants and to determine whether the -203A/C promoter polymorphism of the CYP7A1 encoding gene (CYP7A1) affects such a response, this pilot study was carried out in healthy men (8 homozygous for the -203A allele and 8 homozygous for the -203C allele of CYP7A1). The subjects were treated for 28 days with colesevelam and blood was drawn for analysis before and on days 1, 3, 7, 14 and 28 of treatment. The response of lipids, BA, fibroblast growth factor-19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4) to colesevelam did not differ between carriers of -203A and -203C alleles; their data were then aggregated for further analysis. Colesevelam treatment caused immediate suppression of FGF19 concentration and a fivefold increase in CYP7A1 activity, as assessed from C4 concentration, followed by a 17 % decrease in LDL-cholesterol. Although total plasma BA concentrations were not affected, the ratio of cholic acid/total BA rose from 0.25±0.10 to 0.44±0.16 during treatment at the expense of decreases in chenodeoxycholic and deoxycholic acid.

Bile acids in glucose metabolism in health and disease

“…Hence, one BA sequestrant, colesevelam, is a US Food and Drug Administration–approved drug used to treat diabetes. T2DM patients treated for 12 weeks with colesevelam showed a significant reduction in HbA1c and postprandial glucose levels ( Zieve et al, 2007 ), even when colesevelam was given in combination with other antidiabetic drugs ( Fonseca et al, 2010 ), whereas healthy insulin-sensitive subjects remained unaffected by colesevelam treatment ( Blahová et al, 2016 ). Some T2DM patients treated with colesevelam exhibited an increase in plasma triglyceride levels, which precludes colesevelam treatment in T2DM subjects with hyperglyceridemia ( Fonseca et al, 2010 ).…”

Fibroblast Growth Factor 15/19: From Basic Functions to Therapeutic Perspectives

“…Conversely, administration of UDCA to obese patients for three weeks reduces their circulating FGF19 levels (111). Basal circulating FGF19 levels are also reduced following treatment with BA sequestrants in patients (109,(112)(113)(114). After cessation of treatment, FGF19 displays rebound increases above baseline levels (114).…”

Modulation of Bile Acid Metabolism to Improve Plasma Lipid and Lipoprotein Profiles

“…We have summarized the results of the main recent human studies in Table 1 to get a better grasp on the effects of BAS treatment on plasma lipids in different patient groups. [ 57,58]. Notably, cholestyramine was the first drug to demonstrate LDL-C lowering and protection against coronary heart disease in a randomized clinical trial that included 3806 asymptomatic middle-aged men with primary hypercholesterolemia [4,5].…”

“…We have summarized the re human studies in Table 1 to get a better grasp on the effects of BA lipids in different patient groups. bile acids translates into effects on hepatic cholesterol and lipoprotein metabolism, including stimulation of LDLR-mediated hepatic LDL-C uptake from the blood circulation [57,58]. Notably, cholestyramine was the first drug to demonstrate LDL-C lowering and protection against coronary heart disease in a randomized clinical trial that included 3806 asymptomatic middle-aged men with primary hypercholesterolemia [4,5].…”