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.

Fig. 1

Percent reductions from baseline in low-density lipoprotein cholesterol (LDL-C) in studies evaluating colesevelam (COL) administered in combination with a statin: a COL and atorvastatin (ATO) alone and in combination [41], b COL and lovastatin (LOV) alone and in combination [40], and c COL and simvastatin (SIM) alone and in combination [42]. ^a p < 0.01 for all between-group comparisons. ^b p < 0.01 for all between-group comparisons except COL + ATO 10 mg/day vs. ATO 80 mg/day (p = 0.07). ^c p < 0.05 vs. placebo. ^d p < 0.05 vs. each monotherapy. ^e p < 0.0001 vs. placebo. ^f p ≤ 0.001 vs. each monotherapy. ^gCOL and LOV given together at dinner. ^hCOL given at dinner and LOV administered at bedtime. ATO panel adapted from Hunninghake et al. [41], with permission from Elsevier. LOV panel reproduced from Davidson et al. [40], Copyright © 2001 Wiley Periodicals, Inc., with permission from John Wiley & Sons, Inc. SIM panel adapted from Knapp et al. [42], with permission from Elsevier