Antilipemic Agent Bile Acid Sequestrants

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Continuing Education Activity

Bile acid sequestrants are FDA-approved to manage hypercholesterolemia. They can be used in combination with HMG-CoA reductase inhibitors (statins) or used as monotherapy. Often bile acid sequestrants are used as adjuvant therapy to complement exercise and dietary modifications. This activity discusses their indications, mechanism of action, adverse effects, contraindications, and administration to lower LDL- cholesterol.


  • Identify the mechanism of action of bile acid sequestrants.
  • Describe the adverse effects of bile acid sequestrants.
  • Review the appropriate monitoring and contraindications of bile acid sequestrants.
  • Summarize interprofessional team strategies for improving care coordination and communication to improve outcomes when using bile acid sequestrants.


Bile acid sequestrants, including colesevelam, colestipol, and cholestyramine, are approved by the Food and Drug Administration (FDA) in combination with restriction of dietary saturated and trans-fatty acids to manage hypercholesterolemia. They are indicated for patients with hypercholesterolemia without hypertriglyceridemia.[1] As monotherapy in the Lipid Research Clinics-Coronary Primary Prevention Trial (LRC-CPPT), they reduced low-density lipoprotein cholesterol (LDL-C)  by 20 % and cardiovascular events[2] In this trial, cholestyramine (24g/d) versus placebo reduced the primary outcome of combined coronary heart disease and non-fatal myocardial infarction by 19% in patients with primary hypercholesterolemia. They can be used in combination with HMG-CoA reductase inhibitors (statins) or as monotherapy.

Three double-blind, placebo-controlled trials with the use of colesevelam HCL (COL) in patients with Type II diabetes mellitus (T2D) patients showed reductions in LDL-C and hemoglobin (Hb)A1c. These results led to the FDA approval of COL as an adjuvant to exercise and dietary restriction for improving glycemic control in patients with T2D. Therefore, COL therapy is effective for patients with diabetes who have not met their HbA1c goal of below 7% or LDL-C goal of under 100 mg/dL or 30 to 49 %  or over 50 % reduction in LDL-C.[3] The main advantage of using bile acid sequestrants is that they are safe for administration combined with other anti-diabetic medications and statins. They are the safest LDL-C lowering therapy to date.

In an early study assessing bile acid sequestrants' use in Type IIA hyperproteinemia, subjects were randomized to a low cholesterol diet with either placebo or colestipol (30 mg) over seven years. The colestipol group had a decrease of LDL-C from 331.1 +/- 22.8 to 188.1 +/- 13.8 mg/dL.  Diet plus placebo group showed no improvement.[4] The National Heart Lung and Blood Institute (NHLBI) studied the effects of cholestyramine on coronary atherosclerosis. The study looked at 116 people who had type II hyperlipoproteinemia and coronary artery disease. Patients were all on a low-fat, low-cholesterol diet and assigned either placebo or 6 g of cholestyramine four times daily. Cholestyramine decreased LDL-C by 26% after randomization. Coronary artery disease progressed in 32% vs. 49% of patients in cholestyramine vs. placebo, respectively. The cardioprotective effects of cholestyramine appear to be largely due to a reduction of LDL-C.[5][6] These results illustrate that bile acid sequestrants can effectively reduce cardiovascular disease and reduce LDL-C compared to lifestyle changes alone.

Bile acid sequestrants are beneficial therapy in statin-intolerant patients (myalgia and myopathy). They can be used in combination with niacin and the cholesterol absorption inhibitor, ezetimibe, to achieve target goals in patients in both primary and secondary prevention. They can lower LDL-C between 15 to 30% if tolerated at full doses by patients.

Some bile acid sequestrants are also FDA approved for adolescent patients (10 to 17 years of age).[3] Therefore, bile acid sequestrants are one of the few drugs safe for children with heterozygous familial hypercholesterolemia. Studies have assessed the use of cholestyramine in children with type II hyperlipoproteinemia (12 g/day), and while most patients had normal cholesterol blood concentrations after six months, adherence was often poor. Only 55% of children were still on treatment at six years, and 48% after eight years. Adherence plays a critical role in this population since this group will likely require lifelong lipid-lowering therapies.[4]

Bile acid sequestrants are also safe to use in pregnant patients with hypercholesterolemia. As an off-label use, cholestyramine can treat chronic diarrhea due to bile acid malabsorption. They can also help treat pruritus resulting from elevated concentrations of bile acids and as adjunctive therapy to Graves disease hyperthyroid patients.[7][8]

Mechanism of Action

The mechanism by which bile acid sequestrants reduce LDL-C involves malabsorption of bile acids in the intestine, where it forms an insoluble complex that gets excreted in the feces, causing the depletion of bile acids from the enterohepatic circulation. Since it is not intestinally digestible, it is biochemically unchanged when passing through the intestines. As bile acid concentrations decrease, more hepatic cholesterol converts to bile acids due to disinhibition of cholesterol 7-alpha hydroxylase, the rate-limiting step in bile acid production; this decreases hepatic cholesterol and upregulation of hepatic  LDL receptors, and consequentially there is a decrease in LDL-C blood concentrations. Some evidence suggests that bile acid sequestrants also cause an increase in 3-hydroxy-3-methyl glutaryl-coenzyme A, the rate-limited step in hepatic cholesterol synthesis.[9]

Although cholesterol synthesis increases with the use of bile acid sequestrants, the plasma cholesterol does not rise due to the shunting of newly formed cholesterol to bile acid synthesis pathways. Bile acid sequestrants may also have a role in reducing inflammation. One double-blind, placebo-controlled study found that colesevelam HCL monotherapy (3.75 g/day for six weeks) lowered high sensitivity-C reactive protein by 15.9%.[10]


Bile acid sequestrants are administered orally as a prepared suspension or tablets, preferably at mealtime. It is recommended to be taken at various times during the day, depending on the resin and dosage form. The three that are available are cholestyramine, colestipol, and colesevelam; maximum doses are 24, 20, and 3.75g, respectively. For cholestyramine, 4 g 1 to 2 times/day is desirable to lower LDL-C. Twice daily dosing is the recommendation, but it can be used up to 6 times daily. Colestipol can be used as 2 g tablets once or twice daily and can be increased by 2 g once or twice daily at 1 to 2-month intervals. Both cholestyramine and colestipol are powders mixed with water or juice. Colesevelam oral dosing is 3.75 g/day in 1 or 2 divided doses for diarrhea associated with bile acid malabsorption, hyperlipidemia, and/or T2DM. The FDA recently approved a form of colesevelam as a chewable bar intended for administration with meals. To minimize side effects, they should be started at the lowest dose and titrated up gradually. Also, increasing fiber in the diet, such as bran and psyllium husk, can help with adherence. However, there tends to be poor adherence with large doses of bile acid sequestrants making bile acid sequestrants greater than 15 g two times daily ineffective.[11] If resin treatment gets discontinued, cholesterol blood concentrations return to pretreatment blood concentrations in approximately one month.[12]

Adverse Effects

Since bile acid sequestrants are not absorbed in the gastrointestinal tract, they have limited systemic side effects. Some of the most common adverse effects are gastrointestinal, including constipation, stomach pain, bloating, vomiting, heartburn, loss of appetite, indigestion, and upset stomach. One of the most common side effects is constipation (10% in those taking colestipol and 28% in those taking cholestyramine). These side effects occur more commonly with larger doses and older patients (older than 65 years). They can exacerbate peptic ulcer disease and hemorrhoids.

Cholestyramine use requires caution in renally impaired patients as it can cause hyperchloremia acidosis, especially at higher doses. Some report a wide array of adverse effects, including edema, syncope, dizziness, drowsiness, headaches, neuralgia, paresthesia, skin rashes, irritation, weight gain or loss, abdominal pain, biliary colic, constipation, dental discoloration, diarrhea, steatorrhea, abnormal hepatic function test, anemia, adenopathy, dyspnea,  or wheezing, less than 1 in 1000 patients on colestipol have hypersensitivity including urticaria or dermatitis. Asthma-like symptoms were not observed with colestipol but can occur with cholestyramine. Resin therapy has reportedly produced transient and modest increases in serum transaminases and alkaline phosphatase.[1]


Indications for bile acid sequestrants do not include patients with complete biliary obstruction. If used chronically, it shows a correlation with bleeding problems in high doses, which is preventable by using oral vitamin K therapy. Bile acid sequestrants may also decrease the absorption of many drugs by binding and excretion in the feces when taken concomitantly. To avoid interference with the other drugs commonly, thyroxine, digoxin, and warfarin, hydrochlorothiazide, they should be taken 1 hour before or 4 hours after the bile acid sequestrants. It can also induce malabsorption of fat-soluble vitamins, and therefore patients with fat-soluble vitamin deficiencies should avoid bile acid sequestrants use. If using bile acid sequestrants with fat-soluble vitamins (vitamins A, D, E, and K ) and folic acid, the patient should take the vitamins over 4 hours before. Some studies have shown that colestipol can bind T4 in the gut in vitro. Theoretically, this binding can disrupt normal T4 reabsorption causing hypothyroidism. However, further investigation found that euthyroid patients had normal thyroid concentrations throughout resin treatment. As a precaution, patients taking supplemental thyroid should not take their thyroid medications at the same time as taking bile acid sequestrants.[13]

Bile acid sequestrants are inappropriate for use in patients with serum triglycerides greater than 300 mg/dl or in those who have type III hyperlipoproteinemia since they can exacerbate hypertriglyceridemia and put the patient at risk for pancreatitis. Bile acid sequestrants are used with caution in patients with triglyceride concentrations of 250 to 299 mg/dL with regular monitoring every 4 to 6 weeks after administration, with discontinuation of therapy if triglycerides exceed 400 mg/dL.[14]


The monitoring of bile acid sequestrants therapy is via a reduction in LDL-C concentrations. Bile acid sequestrants lead to lipid reduction after approximately two weeks. The lipid profile requires measurement before initiating treatment, and the fasting lipid profile should be checked 4 to 12 weeks after starting therapy and every 3 to 12 months after that.[14] A mild increase in triglycerides occurs with bile acid sequestrants therapy.

Enhancing Healthcare Team Outcomes

Primary care physicians are often the first to identify hypercholesterolemia in their patients and are typically the providers who recommend bile acid sequestrants for their patients. Still, therapy requires an interprofessional healthcare team for optimal results. Managing patients with bile acid sequestrants requires an interprofessional approach to management. Nurse practitioners and physician assistants can be critical to ensuring proper patient follow-ups and monitoring the efficacy of treatments. Nutritionists and diabetes educators can also consult on the case to help educate patients on appropriate lifestyle modifications to support patients who need to make these changes while on bile acid sequestrants. Endocrinologists or cardiologists may offer consult when patients have a complex presentation, are unresponsive to bile acid sequestrants, or have severe complications from bile acid sequestrants. Nursing will be on hand to counsel patients, provide administration instruction, and monitor adherence and treatment results on subsequent visits. Importantly, pharmacists play a critical role in evaluating proper bile acid sequestrants administration and preventing polypharmacy in patients who are often taking multiple medications, checking for drug interactions, verifying dosing, reporting all findings to the rest of the team.

An interprofessional team approach, including physicians, specialists, specialty trained nurses and educators, and pharmacists who are conversing across disciplines to optimize patient-specific management, is critical in utilizing bile acid sequestrants. [Level 5]

Article Details

Article Author

Daniella Lent-Schochet

Article Editor:

Ishwarlal Jialal


9/28/2021 1:01:07 PM



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