Colesevelam hydrochloride: evidence for its use in the treatment of hypercholesterolemia and type 2 diabetes mellitus with insights into mechanism of action

Abstract

Colesevelam hydrochloride is a molecularly engineered, second-generation bile acid sequestrant demonstrating enhanced specificity for bile acids which has been approved for use as adjunctive therapy to diet and exercise as monotherapy or in combination with a β-hydroxymethylglutaryl-coenzyme A reductase inhibitor for the reduction of elevated low-density lipoprotein cholesterol in patients with primary hypercholesterolemia. It is also the only lipid-lowering agent currently available in the United States which has been approved for use as adjunctive therapy in patients with type 2 diabetes mellitus whose glycemia remains inadequately controlled on therapy with metformin, sulfonylurea, or insulin. With the recent emphasis upon drug safety by the Food and Drug Administration and various consumer agencies, it is fitting that the role of nonsystemic lipid-lowering therapies such as bile acid sequestrants - with nearly 90 years of in-class, clinically safe experience - should be reexamined. This paper presents information on the major pharmacologic effects of colesevelam, including a discussion of recent data derived from both in vitro and in vivo rodent and human studies, which shed light on the putative mechanisms involved.

Keywords: bile acid sequestrants; cholesterol; colesevelam; low-density lipoprotein.

Figure 1

Chemical structure of colesevelam hydrochloride.

Figure 2

Bile acids as hormones in the regulation of metabolic processes. Reproduced with permission from Reasner. Abbreviations: CYP7A1, cholesterol 7 α-hydroxylase; FGF15/19, fibroblast growth factor 15/19; FGFR4, fibroblast growth factor receptor-4; Foxo1, forkhead box protein O1; FXRα, farnesoid X receptor-α; GLP-1, glucagon-like peptide-1; GR, glucocorticoid receptor; HNF-4, hepatocyte nuclear factor-4; JNK, c-Jun N-terminal kinase; LRH-1, liver receptor homolog-1; PEPCK, phosphoenolpyruvate carboxykinase; PPARα, peroxisome proliferator-activated receptor-α; SHP, small heterodimer partner.