Colesevelam

Summary Abstract Colesevelam hydrochloride (Cholestagel®, WelChol®) is an orally administered, non-absorbable, polymeric, bile-acid-binding agent with a higher affinity for glycocholic acid in vitro and greater capacity for binding bile acids in vivo than other bile-acid-binding agents. In randomized controlled trials in patients with primary hypercholesterolemia, colesevelam monotherapy reduced mean serum low-density lipoprotein-cholesterol (LDL-C) levels by 9–19%. In combination with an HMG-CoA reductase inhibitor (statin) or fenofibrate, colesevelam induced additive reductions in LDL-C 10–16% greater than those achieved by monotherapy with a statin (in patients with primary hypercholesterolemia) or fenofibrate (in patients with mixed hyperlipidemia). Colesevelam was generally well tolerated, with a relatively low incidence of gastrointestinal adverse events and a high compliance rate. Thus, colesevelam provides a useful addition to primary therapy with statins in the treatment of primary hypercholesterolemia, or fenofibrate in the treatment of mixed hyperlipidemia. Pharmacologic Properties Colesevelam, like other bile-acid-binding agents, retains bile acids within the intestinal tract, preventing enterohepatic circulation, depleting hepatic bile acids, and increasing the hepatic conversion of cholesterol to bile acids. Colesevelam is a hydrophilic, insoluble polymer that has negligible absorption and systemic distribution. It has a higher affinity in vitro for glycocholic acid than other bile-acid-binding agents, such as cholestyramine or colestipol, and a greater in vivo capacity for bile-acid excretion. In healthy volunteers with mild to moderate hypercholesterolemia, administration of colesevelam 2.3 or 3.8 g/day for 28 days increased the excretion of bile acids ≈3-fold and reduced LDL-C levels by 10% or 13%. While other bile-acid-binding agents slow the absorption of some concomitantly administered drugs, no clinically important pharmacokinetic interactions occur between colesevelam and digoxin, fenofibrate, lovastatin, metoprolol, quinidine, valproic acid, sustained-release verapamil, or warfarin. Therapeutic Efficacy In patients with primary hypercholesterolemia, monotherapy with colesevelam 2.3–4.5 g/day reduced serum LDL-C levels (9–19%) in a dose-related manner during a 6- or 24-week period of treatment. Colesevelam administered in combination with atorvastatin, lovastatin, pravastatin, or simvastatin resulted in additive reductions in mean serum LDL-C levels 10–16% greater than those induced by statin monotherapy. In patients with mixed hyperlipidemia, colesevelam 3.75 g/day for 6 weeks reduced mean serum LDL-C levels by an additional 10% when added to ongoing fenofibrate 160 mg/day therapy. In general, colesevelam monotherapy or combination therapy was also associated with favorable changes in other serum lipid levels, reducing total cholesterol levels and inducing small but significant increases in highdensity lipoprotein-cholesterol levels. Serum triglyceride levels increased with respect to baseline levels in several trials, but these changes did not differ significantly from those with placebo, except for a decline in one trial when used in combination with simvastatin in previously untreated patients, and an increase in another when added to existing stable simvastatin therapy. Tolerability Overall, the adverse event profile of colesevelam as monotherapy, or in combination with statins or fenofibrate, was favorable compared with that of placebo, or monotherapy with other lipid-modifying agents, although the incidences of gastrointestinal adverse events (constipation and dyspepsia) were numerically higher in colesevelam monotherapy than placebo recipients, and the incidences of constipation and myalgia were numerically higher in recipients of colesevelam plus statin combination therapy than monotherapy. However, overall colesevelam treatment compliance was high, with only 8% of colesevelam recipients in a 24-week trial withdrawing because of treatment-related adverse events.