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.

Objectives:

• 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.

Indications

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]

• 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 patients tolerate it at full doses.
• Some bile acid sequestrants are also FDA approved for adolescents (10 to 17 years of age).[2] Therefore, bile acid sequestrants are one of the few drugs safe for children with heterozygous familial hypercholesterolemia. 

Cholestyramine: It is used as adjunctive therapy to diet to reduce elevated serum cholesterol in patients with primary hypercholesterolemia (elevated LDL) who do not respond adequately to diet and to treat pruritus associated with partial biliary obstruction. The National Heart Lung and Blood Institute (NHLBI) studied the effects of cholestyramine on coronary atherosclerosis. The study looked at 116 people with 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 reducing LDL-C.[3][4] These results illustrate that bile acid sequestrants can effectively reduce cardiovascular disease and LDL-C compared to lifestyle changes alone.

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.[5]

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.[6][7]

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.[8] 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 combined with HMG-CoA reductase inhibitors (statins) or as monotherapy.

Colesevelam: Three double-blind, placebo-controlled trials with the use of colesevelam HCL (COL) in patients with diabetes mellitus type 2 (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.[2] 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.

Colestipol: 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 decreased LDL-C from 331.1 +/- 22.8 to 188.1 +/- 13.8 mg/dL. Diet plus placebo group showed no improvement.[5]

Mechanism of Action

The mechanism by which bile acid sequestrants reduce LDL-C involves malabsorption of bile acids in the intestine. 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 reduces 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]

Administration

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.

Cholestyramine

• It is available as a powder for oral suspension packets ( each containing 4 gm cholestyramine ) and a multidose powder for suspension container with scoop measurements for accurate dosing. The powder should be mixed with water or juice to avoid difficulty swallowing and avoid esophageal distress.
• The usual dose is 4 gm taken 1 to 2 times per day to lower LDL-C. Twice daily dosing is the recommendation, but it can be used up to 6 times daily. The dose can be increased slowly every one to two months. The usual maintenance dose is 8 to 16 gm daily. Maximum doses are 24 gm daily for treatment of primary hypercholesterolemia. 
• In children, it can be administered as 240 mg/kg daily of anhydrous cholestyramine resin in two to three divided doses, usually not to exceed 8 gm per day. 

Colestipol

• Colestipol is available as powder packet ( 5 gm ), granules packet ( 5 gm ), and oral tablets ( 1 gm ) of colestipol hydrochloride.
• It is administered as 2 g tablets once, or twice daily, and the dose can be increased by one tablet once or twice daily at 1 to 2-month intervals. The maximum dose is 20 gm daily. 
• The recommended daily adult dose for colestipol is one to six packets or scoopfuls administered preferably in divided doses. Starting dose is one packet once or twice daily and should be increased by one dose per day every one to two months. Colestipol powders are mixed with water or juice to avoid esophageal distress and accidental inhalation. 
• Safety and effectiveness in the pediatric population have not been established.

Colesevelam

• It is available as 625 mg tablets or granules for oral suspension packets containing 3.75 gm colesevelam. 
• The usual adult 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. Maximum doses are 3.75 gm daily.
• Colesevelam use is safe and effective as monotherapy or with a statin were studied in children, 10 to 17 years of age with heterozygous familial hypercholesterolemia (HeFH). Due to the tablet size, colesevelam for oral suspension is preferred in this population. Dose adjustments are not needed when colesevelam is given to children 10 to 17 years old. Colesevelam use is not studied in children younger than ten years of age or premenarchal girls.

Notes: To minimize side effects, all bile acid-binding sequestering agents 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]

Specific Patient Population

Pregnant Women: Bile acid sequestrants are pregnancy category C.  Limited data is available on its use in pregnant women and is insufficient to determine its safety in pregnant patients with hypercholesterolemia. Use if only potential benefits outweigh potential risks. Also, regular prenatal vitamins might not be sufficient while on bile acid-binding sequestering agents as their use interferes with the absorption of fat-soluble vitamins.

Breastfeeding Patients: As bile acid sequestrants are not absorbed systemically following oral administration, breastfed babies are not exposed to them with maternal use of these agents.

Hepatic Impairment: There is no information on their use in patients with hepatic impairment.

Renal Impairment: Since bile acid sequestrants are chloride forms of anions exchange resin, they may produce hyperchloremic acidosis when used for prolonged periods. It is especially true when relative doses are higher, i.e., in younger and smaller patients. Caution when used in patients with volume depletion, renal insufficiency, or in patients receiving concomitant spironolactone.

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. Constipation is experienced by 10% of patients 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. Using it chronically correlates with bleeding problems in high doses, which is preventable using oral vitamin K therapy.

Cholestyramine: Its use requires caution in renally impaired patients as it can cause hyperchloremia acidosis, especially at higher doses. Asthma-like symptoms were not observed with colestipol but can occur with cholestyramine. Constipation associated with the use of cholestyramine can aggravate hemorrhoids. Resin therapy has reportedly produced transient and modest increases in serum transaminases and alkaline phosphatase.[1]

Colestipol: 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 are reported in patients using colestipol. Less than 1 in 1000 patients on colestipol have hypersensitivity, including urticaria or dermatitis. 

Other non-gastrointestinal adverse reactions reported at equal frequency in patients receiving colestipol or placebo were chest pain, tachycardia, angina, musculoskeletal pain, joint pains, aches or pains in the extremities, arthritis, and backache. Anorexia, weakness, fatigue, and swelling of the hands or feet have been infrequently reported.

Colesevelam: It can increase triglyceride levels which can cause acute pancreatitis. In clinical trials, gastrointestinal obstruction and vitamin K or fat-soluble vitamin deficiencies are reported with colesevelam use. The use of colesevelam hydrochloride might decrease the efficacy of oral contraceptives, which contain ethinyl estradiol and norethindrone. Therefore, patients are advised to take oral contraceptives at least 4 hours before administering colesevelam. 

Drug Interactions

• 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.

• Bile acid sequestrants may also decrease the absorption of many drugs by binding and excretion in the feces when taken concomitantly. Therefore, to avoid interference with the other drugs, especially narrow therapeutic index drugs, commonly thyroxine, digoxin, warfarin, hydrochlorothiazide, etc., should be taken 1 hour before or 4 hours after the bile acid sequestrants.

Contraindications

Bile acid sequestrants should not be used in patients with hypersensitivity to active ingredients or any of its components. 

Cholestyramine use is contraindicated in patients with complete biliary obstruction where bile is not secreted into the intestine. Some formulation contains phenylalanine, so it should be used with caution in patients with phenylketonuria.

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.[13]

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 simultaneously as taking bile acid sequestrants.[14]

Colesevelam hydrochloride is contraindicated in patients with triglyceride levels of more than 500 mg/dL or patients with a history of hypertriglyceridemia-induced pancreatitis. It is also contraindicated for patients with gastroparesis, other gastrointestinal motility disorders, patients at risk for bowel obstruction, and patients with a history of major gastrointestinal tract surgery or bowel obstruction.

Monitoring

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.[13] A mild increase in triglycerides occurs with bile acid sequestrants therapy.

Monitoring constipation at least two times, usually 4 to 6 weeks apart, is recommended as cholestyramine resin might produce or worsen pre-existing constipation. 

Monitor International Normalized Ratio (INR) frequently during initiation and then periodically for patients on anticoagulant treatment (warfarin).

Concomitant use with colesevelam hydrochloride may increase the exposure of Metformin extended-release formulation, so monitor patients' blood glucose levels and HgA1C.

Toxicity

Overdosage of cholestyramine (150% of the maximum recommended daily dosage) has been reported in patients taking it for several weeks. No adverse effects were reported. Excessive doses of colesevelam hydrochloride might cause more severe local gastrointestinal effects (e.g., constipation). If overdosage occurs, the primary potential problem would be obstruction of the gastrointestinal tract. At this time, the degree of possible obstruction, the location of such obstruction,  and the absence or presence of normal gut motility would determine its treatment.

Enhancing Healthcare Team Outcomes

Primary care providers are often the first to identify hypercholesterolemia in their patients and typically recommend bile acid sequestrants for their patients. Still, therapy requires an interprofessional healthcare team for optimal results. 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]