Role of Colesevelam in Combination Lipid-Lowering Therapy

Abstract

Hyperlipidemia is associated with an increased risk of cardiovascular events; reducing low-density lipoprotein cholesterol (LDL-C), the primary target for cholesterol-lowering therapy, lowers the risk for such events. Although bile acid sequestrants were the first class of drugs to show a mortality benefit related to LDL-C lowering, statins are now considered first-line pharmacological therapy for reducing LDL-C levels because of their potency and their remarkable record of successful outcomes studies. Nevertheless, a substantial proportion of patients do not achieve LDL-C goals with statin monotherapy. In addition, because of adverse effects (primarily myopathy), some patients may be unwilling to use or unable to tolerate statin therapy at all or may not tolerate a full therapeutic statin dose. Also, statins may increase risk of new-onset diabetes in patients at high risk for diabetes. Thus, there remains a need for other lipid-lowering drugs to be used in combination with or in place of statins. The purpose of this article is to review available data from the literature on the use of colesevelam, a second-generation bile acid sequestrant, in combination with other lipid-lowering agents. Colesevelam has been studied in combination with statins, niacin, fibrates, and ezetimibe (including some three-drug combinations). An additive reduction in LDL-C was seen with all combinations. Other observed effects of colesevelam in combination with other lipid-lowering drugs include reductions in apolipoprotein (apo) B (with statins, fibrates, ezetimibe, statin plus niacin, or statin plus ezetimibe) and high-sensitivity C-reactive protein (with statins), and increases in apo A-I (with statins, ezetimibe, or statins plus niacin). Triglyceride levels remained relatively unchanged when colesevelam was combined with statins, fibrates, ezetimibe, or statin plus ezetimibe, and decreased with the triple combination of colesevelam, statin, and niacin. Colesevelam offset the negative glycemic effects of statins and niacin in subjects with insulin resistance or impaired glucose tolerance. Colesevelam was generally well tolerated when added to other lipid-lowering therapies in clinical trials, with gastrointestinal effects such as constipation being the predominant adverse events. Since colesevelam is not absorbed and works primarily in the intestine, it has a low potential for systemic metabolic drug–drug interactions with other drugs. Colesevelam has been shown to not interact with the lipid-lowering drugs lovastatin and fenofibrate; where interaction may be anticipated, separating dosing times by 4 h reduces the impact of any interaction. Available data confirms that colesevelam has additive cholesterol-lowering effects when used in combination with other lipid-lowering therapies. Furthermore, in some patient populations, the additional glucose-lowering effect of colesevelam may be beneficial in offsetting hyperglycemic effects of other lipid-lowering drugs.

Novel bile acid sequestrant: A biodegradable hydrogel based on amphiphilic allylamine copolymer

“…[1][2][3] Thus, various clinical therapies have been developed. For example, the medications containing statins, nicotinic acid, and bile acid sequestrant (BAS) can control human CVD by reducing the elevated total cholesterol level and lower the density lipoprotein cholesterol level.…”

Strategies for the use of nonstatin therapies

“…This effect translates into a reduction of CV events which is proportional to the degree of LDL-C lowering achieved [27,28]. Bile acid sequestrants may be used also in patients intolerant to statins as well as in those who do not tolerate increasing dose of statins, and may be combined with other lipidlowering drugs such as ezetimibe, resulting in a greater reduction of LDL-C levels compared with ezetimibe alone [29].…”

Statin myopathy: the fly in the ointment for the prevention of cardiovascular disease in the 21st century?

“…Ezetimibe, bile acid sequestrates and niacin are less efficacious than statins in lowering low density lipoprotein (LDL)-C, and the last two have their own unacceptable side effects, specifically nausea, bloating, constipation with resins and flushing with niacin [52,53]. Additionally, red rice yeast is biologically similar to lovastatin, but has not been extensively studied in the form of 'red rice yeast' so its long-term safety is uncertain [54].…”