What are bile acid sequestrants?

What Are Bile Acid Sequestrants

Bile acid sequestrants are medications that bind bile acids in the intestinal lumen, preventing their reabsorption in the terminal ileum, which depletes hepatic bile acids and triggers upregulation of LDL receptors, thereby lowering LDL cholesterol by 18-25% at standard doses. 1, 2

Mechanism of Action

Bile acid sequestrants work through a specific biochemical pathway:

• They bind bile salts within the intestinal lumen and prevent their enterohepatic reuptake, disrupting the normal recycling of bile acids back to the liver 1
• This depletion signals increased bile acid synthesis from intracellular cholesterol, consuming the hepatic cholesterol pool 1
• The depleted intracellular cholesterol triggers upregulation of LDL receptors on hepatocytes, increasing hepatic uptake of LDL from circulation and lowering serum LDL cholesterol levels 3
• These agents are not absorbed systemically - they are high molecular weight polymers that remain in the gastrointestinal tract and are excreted in feces (less than 0.17% urinary excretion) 3

Available Agents

Three bile acid sequestrants are currently used in the United States:

First-Generation Agents

• Cholestyramine: dosed up to 24 g daily, reduces LDL cholesterol by 18-25% 2, 4
• Colestipol: requires doses up to 20 g daily for comparable LDL reduction 2, 3

Second-Generation Agent

• Colesevelam: dosed at 3.75 g daily, has enhanced specificity and fewer drug interactions compared to first-generation agents 5, 6

Clinical Indications

Primary use is as adjunct to diet and exercise for lowering elevated LDL cholesterol in adults with primary hyperlipidemia 5

• Approved for boys and postmenarchal girls aged 10-17 years with heterozygous familial hypercholesterolemia who cannot reach LDL targets despite diet and lifestyle modification 5
• Can be combined with statins for additive LDL-lowering effect when either medication alone fails to achieve target levels - one pediatric study found no increase in adverse effects with combination therapy (grade B evidence) 1
• Cholestyramine is first-line therapy for bile acid diarrhea, with approximately 70% success rate 4

Important Drug Interactions and Timing

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

Critical interactions include:

• Significantly reduces absorption of warfarin, thyroid preparations, digoxin, and fat-soluble vitamins 2, 4
• Decreases mycophenolate levels by 35% - should generally be avoided in liver transplant patients 2, 4
• Colesevelam reduces absorption of glyburide, levothyroxine, and oral contraceptives despite having fewer interactions than first-generation agents 2

Adverse Effects and Monitoring

Common tolerability issues:

• Gastrointestinal distress is the primary limitation - approximately 11% of patients find cholestyramine intolerable due to bloating, constipation, abdominal pain, and unpalatability 4, 7
• Can increase triglyceride levels - contraindicated in patients with triglycerides >500 mg/dL or history of hypertriglyceridemia-induced pancreatitis 1, 5
• Cases of bowel obstruction have occurred - not recommended in patients with gastroparesis, gastrointestinal motility disorders, or those who have had major GI surgery 5

Vitamin Supplementation Requirements

Fat-soluble vitamins (A, D, E, K) may require supplementation during long-term use 2, 4

• Patients on warfarin or with malabsorption syndromes are at increased risk for vitamin K deficiency 5
• Periodic assessment of vitamin K status via INR/prothrombin time is prudent during long-term treatment 2, 4
• Patients on oral vitamin supplementation should take vitamins at least 4 hours prior to bile acid sequestrants 5

Cardiovascular Outcomes

The LRC-CPPT trial demonstrated that cholestyramine reduced the combined rate of coronary heart disease death plus non-fatal myocardial infarction by 19% over seven years in middle-aged men with elevated cholesterol 3

• Intensive lipid-lowering with bile acid sequestrants plus nicotinic acid or lovastatin significantly reduced progression and increased regression of coronary atherosclerotic lesions in randomized controlled trials 3
• Treatment results in significant increases in lipoprotein LpAI, which promotes cholesterol efflux from cells and may have antiatherogenic effects 3

Special Populations and Contraindications

Avoid in Crohn's disease patients with extensive ileal resection (>100 cm) as it may worsen steatorrhea and increase caloric loss 4

Do not use for type 1 diabetes or diabetic ketoacidosis 5

Not studied in Fredrickson Type I, III, IV, and V dyslipidemias 5