What is a bile acid sequestrant?

What is a Bile Acid Sequestrant

Bile acid sequestrants are non-absorbable resins that bind bile acids in the intestinal lumen, preventing their reabsorption and forcing the liver to convert more cholesterol into bile acids, thereby lowering LDL cholesterol levels by 18-25%. 1

Mechanism of Action

Bile acid sequestrants work by disrupting the enterohepatic circulation of bile acids. 1 The mechanism proceeds through the following steps:

• The resin binds bile acids in the intestine, forming an insoluble complex that is excreted in feces rather than being reabsorbed. 1, 2
• This depletes the hepatic bile acid pool by approximately 40%, triggering upregulation of the enzyme cholesterol 7-alpha-hydroxylase, which converts cholesterol to bile acids. 1, 2
• The depletion of intracellular cholesterol signals increased production and activity of LDL receptors on liver cells. 1
• These compensatory effects result in increased clearance of LDL cholesterol from the blood, decreasing serum LDL-C levels by 18-25%. 1

Available Agents

Three bile acid sequestrants are FDA-approved in the United States:

• First-generation agents: Cholestyramine (24g daily) and colestipol (20g daily) are older, less well-tolerated resins. 1
• Second-generation agent: Colesevelam (4.5g daily) has enhanced specificity, greater affinity, and higher capacity for binding bile acids due to its engineered polymer structure. 1, 3

Clinical Indications

Bile acid sequestrants are FDA-approved as adjunct to diet and exercise for reducing elevated LDL cholesterol in adults with primary hyperlipidemia. 3

• Colesevelam is also approved for boys and postmenarchal girls aged 10-17 years with heterozygous familial hypercholesterolemia who fail to reach LDL-C targets despite diet and lifestyle modification. 1, 3
• Colesevelam additionally has FDA approval for improving glycemic control in adults with type 2 diabetes mellitus. 1, 3

Cardiovascular Outcomes

The Lipid Research Clinics Coronary Primary Prevention Trial demonstrated that bile acid sequestrants reduce coronary heart disease events in hypercholesterolemic patients, with benefit proportional to the degree of LDL cholesterol lowering. 1

• For every 1% reduction in LDL-C levels, relative risk for major coronary heart disease events is reduced by approximately 1%. 4

Combination Therapy

Bile acid sequestrants augment the LDL-lowering effects of statins through complementary mechanisms, with additive efficacy. 1

• The American College of Cardiology recommends bile acid sequestrants as second-line non-statin therapy if patients have inadequate response to ezetimibe or are ezetimibe-intolerant. 4
• In pediatric patients, bile acid sequestrants may be combined with statins for those who fail to meet LDL cholesterol targets with either medication alone, with no increase in adverse effects. 1

Important Contraindications and Precautions

Bile acid sequestrants are contraindicated in patients with serum triglyceride levels greater than 500 mg/dL, history of hypertriglyceridemia-induced pancreatitis, or history of bowel obstruction. 3

• These agents can increase triglyceride levels and should not be used in patients with baseline hypertriglyceridemia (>300 mg/dL). 1, 4
• Bile acid sequestrants are not absorbed systemically and have no systemic drug-drug interactions, but may interfere with absorption of other medications. 2, 3
• Other medications should be administered at least 4 hours before bile acid sequestrants to avoid binding interactions. 1, 3
• These agents may decrease absorption of fat-soluble vitamins (A, D, E, K); patients on oral vitamin supplementation should take vitamins at least 4 hours prior to the sequestrant. 3

Common Adverse Effects

Gastrointestinal side effects (constipation, bloating, nausea) are the primary limitation of bile acid sequestrants, particularly with first-generation agents. 1

• Colesevelam has somewhat lower gastrointestinal side effects compared to cholestyramine and colestipol. 1