What are bile acid sequestrants?

What Are Bile Acid Sequestrants

Bile acid sequestrants are a class of non-absorbable resin medications that bind bile acids in the intestinal lumen, preventing their reabsorption and forcing the liver to synthesize new bile acids from cholesterol, thereby lowering LDL cholesterol levels. 1

Mechanism of Action

Bile acid sequestrants work through a well-defined physiological pathway:

• They bind bile salts within the intestinal lumen and prevent their enterohepatic reuptake in the terminal ileum, which results in depletion of the hepatic bile acid pool 1
• This depletion signals increased bile acid production in the liver, and because bile acids are synthesized from intracellular cholesterol, the intracellular cholesterol pool becomes depleted 1
• The cholesterol depletion upregulates 7-alpha-hydroxylase activity and increases LDL receptor expression, which pulls more LDL cholesterol from the bloodstream into liver cells 2
• This mechanism reduces circulating LDL cholesterol by approximately 18-25% at standard doses 2

Available Agents

There are currently three bile acid sequestrants used in clinical practice in the United States:

• First-generation agents: cholestyramine and colestipol - these are conventional sequestrants that have been used for over 50 years 3, 4
• Second-generation agent: colesevelam hydrochloride - this has enhanced specificity, greater affinity, and higher capacity for binding bile acids due to its engineered polymer structure 3

Clinical Applications

Primary Use: Hypercholesterolemia

• Bile acid sequestrants effectively lower LDL cholesterol by 15-26% when used as monotherapy 3
• They can be combined with statins for additive LDL-lowering effects in patients who fail to meet target levels with either medication alone 1
• Low-dose statin plus bile acid sequestrant combinations lead to greater or similar LDL-C reductions compared with high-dose statin monotherapy and may have a better safety profile 3
• They have been shown to lower the incidence of new coronary events and retard the progression of coronary atherosclerosis 5

Additional Therapeutic Uses

• Bile acid sequestrants are first-line therapy for bile acid diarrhea, with approximately 70% success rate in documented cases 2
• They may improve glycemic control in patients with type 2 diabetes mellitus 3, 4, 6
• Cholestyramine should be considered during pregnancy in women with familial hypercholesterolemia, ideally starting 3 months before planned conception 1

Safety Profile and Tolerability

Bile acid sequestrants are among the safest cholesterol-lowering drugs because they are not absorbed systemically and have no systemic drug-drug interactions 5, 3:

• They have been used clinically for more than 50 years with strong safety profiles 4
• Side effects are generally not serious but may be bothersome, including gastrointestinal symptoms such as bloating, constipation, and abdominal pain 2
• Approximately 11% of patients find cholestyramine intolerable due to unpalatability or side effects 2
• Modest lowering of dosage may preserve considerable LDL cholesterol lowering and virtually eliminate side effects 5

Critical Drug Interactions and Precautions

Timing of Other Medications

All other medications must be taken at least 1 hour before or 4-6 hours after bile acid sequestrants to avoid impaired absorption 2:

• They can significantly reduce absorption of warfarin and fat-soluble vitamins 2
• In liver transplant patients, bile acid sequestrants can decrease plasma mycophenolate levels by 35% and should generally be avoided 1, 2
• They should not be given to patients taking mycophenolate mofetil (MMF) or mycophenolic acid (MPA) 1
• When used with calcineurin inhibitors, bile acid sequestrants should be given greater than 2 hours before or after CNI dosing 1

Vitamin Supplementation Requirements

• Long-term use requires supplementation with water-miscible or parenteral forms of fat-soluble vitamins (A, D, E, K) to prevent deficiency 2
• Periodic assessment of vitamin K status via INR/prothrombin time may be prudent during long-term treatment 2
• Routine monitoring for malabsorption of fat-soluble vitamins (particularly vitamin K) and folate should be considered, especially during pregnancy 1

Specific Contraindications

• Avoid cholestyramine in Crohn's disease patients with extensive ileal resection (>100 cm) as it may worsen steatorrhea and increase caloric loss 2
• Bile acid sequestrants may modestly increase triglyceride levels, which is a consideration in patients with hypertriglyceridemia 1

Dosing Considerations

• Starting dose should be 2-4 g daily with gradual titration to minimize gastrointestinal side effects 2
• Maximum doses can reach up to 24 g daily 2
• For pediatric patients aged 10 years or older with LDL cholesterol 130-190 mg/dL, bile acid sequestrants may be considered as part of lipid-lowering therapy 1