Therapeutic Class Overview Bile Acid Sequestrants Therapeutic Class • Overview/Summary: The major action of the bile acid sequestrants in modifying lipids is through binding to bile acids in the intestine causing an interruption of their reabsorption. This reduction leads to feedback regulation to increase the conversion of cholesterol to bile acids. The major action of these agents is to reduce low density lipoprotein cholesterol (LDL-C) specifically; therefore, use of a bile acid sequestrant is effective in patients with mild to moderate elevations of LDL-C.1,2 When administered as monotherapy these agents have the potential to reduce LDL-C by 10 to 24%.2 Bile acid sequestrants are also effective as add on therapy in patients with markedly elevated LDL-C who are already receiving a hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) or niacin.1,2 According to treatment guidelines, in patients who require LDL-C lowering and who do not achieve lipid goals with the use of a statin alone, consideration should be given to either increasing the dose of the statin or to adding a bile acid sequestrant or niacin to treatment.1 Bile acid sequestrants can also be added to statins for the treatment of heterozygous familial hypercholesterolemia, and they are recognized as the therapy of choice for the management of pruritus associated with primary biliary cirrhosis.3,4 There are three bile acid sequestrants available including cholestyramine (Prevalite®, Questran®, Questran Light®), colesevelam (Welchol®) and colestipol (Colestid®, Flavored Colestid®). All of the agents are Food and Drug Administration (FDA)-approved for adjunct treatment in patients with hypercholesterolemia.5-9 Cholestyramine is also FDA-approved for relief of pruritus associated with partial biliary obstruction.5,6 Colesevelam is also FDA-approved for use as monotherapy in children 10 to 17 years of age for the treatment of heterozygous familial hypercholesterolemia and as adjunct therapy to diet and exercise to improve glycemic control in adults with type 2 diabetes.9 Cholestyramine and colestipol are both available as powders (colestipol is available in two flavors) to be mixed with water or juice, and are typically administered once or twice daily with meals.5-8 Colestipol is also available as a tablet (Colestid®).7,8 Colesevelam is also available as a powder and as a tablet, and is typically administered once or twice daily.9 Colesevelam is more potent compared to either cholestyramine or colestipol.1 In addition, colesevelam may be more easily administered and better tolerated compared to the other agents.1,2 All bile acid sequestrants are available generically, with the exception of colesevelam (Welchol®). Table 1. Current Medications Available in the Therapeutic Class5-9 Generic Food and Drug Administration-Approved Dosage Form/ Generic (Trade Name) Indications Strength Availability Cholestyramine Adjunctive therapy to diet for the reduction of Powder: (Prevalite®*, elevated serum cholesterol in patients with 4 g ® Questran *, primary hypercholesterolemia who do not respond Questran adequately to diet†, relief of pruritus associated Light®*) with partial biliary obstruction‡ Colesevelam Adjunct to diet and exercise to improve glycemic Powder: (Welchol®) control in adults with type 2 diabetes, adjunct to 3.75 g diet and exercise to reduce elevated low density lipoprotein cholesterol levels in adults with primary Tablet: hyperlipidemia as monotherapy or in combination 625 mg - with a statin, monotherapy or in combination with a statin to reduce low density lipoprotein cholesterol levels in boys and postmenarchal girls 10 to 17 years of age with heterozygous familial hypercholesterolemia§ Colestipol Adjunctive therapy to diet for the reduction of Granules: (Colestid®*, elevated serum cholesterol and low density 5 g Flavored lipoprotein cholesterol in patients with primary Colestid®*) hypercholesterolemia who do not respond Powder: Page 1 of 4 Copyright 2013 • Review Completed on 07/22/2013 Therapeutic Class Overview: bile acid sequestrants Generic Food and Drug Administration-Approved Dosage Form/ Generic (Trade Name) Indications Strength Availability adequately to diet* 5 g Tablet: 1 g *Generic available in at least one dosage form and/or strength. †May be useful to lower low density lipoprotein cholesterol (LDL-C) levels in patients who also have hypertriglyceridemia, but it is not indicated where hypertriglyceridemia is the abnormality of most concern. ‡Has been shown to have a variable effect on serum cholesterol in these patients. Patients with primary biliary cirrhosis may exhibit elevated cholesterol as part of their disease. §If after an adequate trial of diet therapy the following findings are present: LDL-C remains ≥190 mg/dL or LDL-C remains ≥160 mg/dL and there is a positive family history of premature cardiovascular disease or two or more other cardiovascular disease risk factors are present in the pediatric patient. Evidence-based Medicine • Clinical trials have consistently demonstrated the “superiority” of bile acid sequestrants over placebo in the management of hyperlidpidemia.10-19 In line with current clinical guidelines, results demonstrated that the addition of a bile acid sequestrant to another lipid lowering agent has the potential to produce further reductions in low density lipoprotein cholesterol levels compared to monotherapy with either of the agents.17-21 • The Lipid Research Clinical Coronary Primary Prevention trial demonstrated that compared to placebo, treatment with cholestyramine reduced the risk of coronary heart disease death and/or nonfatal myocardial infarction in asymptomatic males with primary hypercholesterolemia (P<0.05).22,23 • Several placebo-controlled trials have demonstrated the safety and efficacy of colesevelam as adjunct therapy in adults with type 2 diabetes. Significant reductions in glycosylated hemoglobin (HbA1c) levels were observed when colesevelam was added to stable oral antidiabetic treatment regimens. A small (N=169), 16-week trial demonstrated that least squares mean reductions in HbA1c levels with colesevelam were comparable to either thiazolidinediones or dipeptidyl peptidase 4 inhibitors when added to background metformin therapy.24-31 • In a Cochrane Review of six randomized controlled trials, the addition of colesevelam to other hypoglycemic agents significantly reduced HbA1c compared to placebo (mean difference, -0.5%; P<0.00001). In addition, colesevelam with add-on hypoglycemic agents demonstrated a significant reduction in fasting plasma glucose compared to placebo (mean difference, -15 mg/dL; P<0.0001).32 Key Points within the Medication Class • According to Current Clinical Guidelines: o Therapeutic lifestyle changes remain an essential modality in the management of patients with hypercholesterolemia.1,3,33 o In general, hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are considered first-line therapy for decreasing low density lipoprotein cholesterol (LDL-C) levels. If after six weeks, lipid goals are not achieved with statin monotherapy, a dosage increase or the addition of a bile acid sequestrant or niacin should be considered.1 o Statins are also considered first-line in the treatment of heterozygous familial hypercholesterolemia, but if required a bile acid sequestrant can be added to therapy.3 o Bile acid sequestrants are recognized as the therapy of choice for the management of pruritus associated with primary biliary cirrhosis.4 o In the management of patients with diabetes, the American Association of Clinical Endocrinologists note that colesevelam may provide a possible benefit or few adverse events when given as part of dual or triple therapy in addition to metformin in patients with a glycosylated hemoglobin of ≥7.5%.34 o In general, the American Diabetes Association recommends that a statin be added to lifestyle therapy, regardless of baseline lipid levels, in patients with diabetes. If maximally tolerated doses of statins fail to significantly lower LDL-C (<30% reduction from baseline), no strong evidence exists that combination therapy should be used. Niacin, fenofibrate, ezetimibe, and bile acid sequestrants offer additional LDL-C lowering compared to statins alone; however, Page 2 of 4 Copyright 2013 • Review Completed on 07/22/2013 Therapeutic Class Overview: bile acid sequestrants there is no evidence that combination therapy provides a significant cardiovascular disease risk reduction over statin therapy alone.35 • Other Key Facts: o All of the bile acid sequestrants are available as a powder, while colesevelam and colestipol are also available as a tablet. o All bile acid sequestrants are administered once or twice daily. o Cholestyramine and colesevelam have additional Food and Drug Administration-approved indications other than management of hypercholesterolemia. o Colesevelam is the most potent bile acid sequestrant and may be more easily administered and better tolerated compared to the other agents.1,2 o Cholestyramine and colestipol are available generically. References 1. National Cholesterol Education Program (NCEP). Detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report, 2002 [guideline on the internet]. NCEP. 2002 [cited 2013 Jul 22]. Available from: http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm. 2. Rosenson RS. Lipid lowering with drugs other than statins and fibrates. In: Basow DS (Ed). UpToDate [database on the internet]. Waltham (MA): UpToDate; 2013 [cited