Colesevelam hydrochloride, alone or combined with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (i.e., statin), is used as an adjunct to dietary therapy and exercise to decrease elevated serum low-density lipoprotein (LDL)-cholesterol concentrations in the management of primary hypercholesterolemia (Frederickson type IIa). The effect of colesevelam, alone or in combination with a statin, on cardiovascular morbidity and mortality has not been established.
The American College of Cardiology (ACC)/American Heart Association (AHA) guideline for management of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults states that nondrug therapies (i.e., lifestyle modifications), which include adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight, are the foundation of atherosclerotic cardiovascular disease (ASCVD) prevention. Drug therapy is not a substitute for but an adjunct to these nondrug therapies and measures, which should be continued when drug therapy is initiated. For additional details on lifestyle modifications, consult the most recent AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk (available at http://www.cardiosource.org or http://my.americanheart.org).
The ACC/AHA cholesterol management guideline states that nonstatin therapies (e.g., bile acid sequestrants) do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. However, nonstatin drugs may be useful as adjuncts to statin therapy in certain high-risk patients (e.g., patients with ASCVD, patients with LDL-cholesterol concentrations of 190 mg/dL or higher, patients with diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate even a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy. When a nonstatin drug is required, selection of the nonstatin drug should be based on a favorable benefit-risk ratio (i.e., demonstrated benefit of ASCVD risk reduction outweighs risks of adverse effects and drug interactions) and patient preferences. For additional details on prevention of ASCVD, and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).
The safety and efficacy of colesevelam for the management of Fredrickson type I, III, IV, or V dyslipidemia have not been established.
Reductions in total cholesterol and LDL-cholesterol concentrations achieved with usual dosages of colesevelam hydrochloride substantially exceed those of placebo. Mean reductions of 7-10% in total cholesterol, 15-19% in LDL-cholesterol, and 12% in apolipoprotein B (apo B) concentrations, and mean increases of 3-8% in high-density lipoprotein (HDL)-cholesterol concentrations have been reported in controlled and uncontrolled studies of patients with primary hypercholesterolemia who received recommended daily dosages of colesevelam hydrochloride (3.75-4.5 g) for at least 6 weeks. Like other bile acid sequestrants, therapy with colesevelam has been associated with slight increases (5-10%) in triglyceride concentrations.
Colesevelam appears to be equally effective in reducing LDL-cholesterol concentrations whether the daily dosage is given as 1 or 2 divided doses. In patients who received 3.75 g of colesevelam hydrochloride as a single dose with breakfast, a single dose with dinner, or as divided doses with breakfast and dinner, mean reductions in LDL-cholesterol concentrations of 18, 15, and 18% respectively, were observed.
Data from several randomized, placebo-controlled studies indicate that combination therapy with colesevelam and other antilipemic agents (e.g., statins, fenofibrate) may produce additive antilipemic effects. The addition of colesevelam hydrochloride (2.3-3.75 g daily) to usual dosages of various statins (i.e., atorvastatin, lovastatin, simvastatin) further reduced total cholesterol and LDL-cholesterol concentrations by 4-9 and 8-16%, respectively. Reductions in LDL-cholesterol concentrations produced by concomitant low-dose atorvastatin (10 mg daily) and colesevelam hydrochloride (3.75 g daily) were not substantially different from those achieved with high-dose atorvastatin (80 mg daily) therapy. The addition of colesevelam hydrochloride (3.8 g daily) to current fenofibrate therapy (160 mg daily) in patients with mixed dyslipidemia reduced total and LDL-cholesterol concentrations by 6 and 10%, respectively, but increased triglyceride concentrations by 6%.
For additional information on the use of colesevelam or other antilipemic agents in the treatment of lipoprotein disorders, prevention of cardiovascular events, and other conditions, see General Principles of Antilipemic Therapy in the HMG-CoA Reductase Inhibitors General Statement 24:06.08.
Colesevelam hydrochloride is used in combination with metformin, sulfonylurea, or insulin monotherapy or in combinations of these and other oral antidiabetic agents as an adjunct to diet and exercise for the management of type 2 (noninsulin-dependent) diabetes mellitus. Safety and efficacy of colesevelam as monotherapy or in combination with a dipeptidyl peptidase-4 (DPP-4) inhibitor have not been established in the management of type 2 diabetes mellitus, and colesevelam has not been studied extensively in combination with thiazolidinediones. In addition to adequate glycemic control, intensive control of dyslipidemia is warranted in patients with diabetes mellitus.
Data from several randomized, placebo-controlled studies of 16-26 weeks' duration in patients with type 2 diabetes mellitus inadequately controlled with metformin, sulfonylurea, or insulin monotherapy or combinations of these agents with other oral antidiabetic agents indicate that add-on therapy with colesevelam hydrochloride (3.75 g daily) produced an average reduction in hemoglobin A1c (HbA1c) of 0.5% from baseline compared with that observed with placebo. Fasting plasma glucose concentrations were reduced by an average of 14 mg/dL from baseline following the addition of colesevelam to metformin- or sulfonylurea-based therapy; such reduction in glucose concentrations was not observed following the addition of colesevelam to insulin-based therapy. Add-on colesevelam therapy in diabetic patients receiving metformin, sulfonylurea, or insulin therapy reduced serum LDL-cholesterol concentrations by 12-16%, a reduction of similar magnitude to that observed in patients receiving colesevelam for primary hypercholesterolemia.
The addition of colesevelam to insulin- or sulfonylurea-based therapy increased serum triglyceride concentrations by a median of 20-25% from baseline; no appreciable increase in serum triglyceride concentrations occurred with addition of colesevelam to metformin-based therapy.
(See Contraindications under Cautions.)
Colesevelam is not effective as sole therapy for type 1 diabetes mellitus or diabetic ketoacidosis.