Bile acid sequestrants

Bile acid sequestrants (BAS), also known as bile acid-binding resins, are a class of non-absorbable anion-exchange resins primarily used to lower low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemia. Additionally, they have indications in bile acid–induced diarrhea and off-label use in glycemic control for type 2 diabetes mellitus. They exert their effects by binding bile acids in the intestinal lumen, interrupting their enterohepatic circulation, and enhancing bile acid excretion.

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1. Mechanism of Action

Bile acid sequestrants are large, positively charged polymeric resins that bind negatively charged bile acids in the small intestine. Once bound, the bile acids are excreted in the feces rather than being reabsorbed into the portal circulation.

Resulting pharmacologic effects:

• Reduction in enterohepatic bile acid recycling

• Upregulation of hepatic LDL receptors to compensate for bile acid loss

• Increased hepatic conversion of cholesterol to bile acids via activation of cholesterol 7α-hydroxylase (CYP7A1)

• Decrease in serum LDL-C levels by up to 20% (monotherapy)

• Possible increase in triglyceride synthesis due to compensatory hepatic lipogenesis

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2. Approved Agents

A. Cholestyramine

• Brand names: Questran®, Prevalite®, Locholest®

• Powder for oral suspension

• Strongest bile acid-binding capacity among BAS

• Also used in pruritus secondary to cholestasis

B. Colestipol

• Brand names: Colestid®

• Available as tablets and granules

• Slightly better tolerability than cholestyramine

C. Colesevelam

• Brand name: Welchol®

• Tablet and oral suspension

• Higher specificity and binding capacity

• FDA-approved for:

  • Hyperlipidemia

  • Type 2 diabetes mellitus (as adjunct to diet and antidiabetic medications)

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3. Clinical Indications

A. Hypercholesterolemia

• Primary indication

• Especially useful in:

  • Statin-intolerant patients

  • Pregnancy (non-systemic nature)

  • Pediatric familial hypercholesterolemia

• LDL-C reductions of 10–20%

• No effect or slight increase in HDL-C

• May raise triglycerides by 5–10%

B. Bile Acid Diarrhea / Bile Acid Malabsorption

• Effective in type 2 bile acid diarrhea (idiopathic)

• Also used in:

  • Crohn's disease with ileal resection

  • Post-cholecystectomy diarrhea

C. Type 2 Diabetes Mellitus

• Colesevelam only

• Reduces HbA1c by ~0.5%

• Mechanism likely involves reduced glucose absorption and GLP-1 modulation

D. Other Uses (Off-label or Rare):

• Digitalis toxicity (cholestyramine binds digoxin in the gut)

• Pruritus of cholestasis (e.g., primary biliary cholangitis)

• Adjunctive therapy in sitosterolemia

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4. Pharmacokinetics

• Absorption: Not absorbed systemically

• Distribution: Limited to GI tract

• Metabolism: None

• Excretion: Excreted in feces with bound bile acids

• Onset of action: Within 1–2 days for lipid-lowering

• Maximum effect: 2–4 weeks of regular dosing

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5. Dosage and Administration

Agent	Typical Adult Dose Range	Frequency
Cholestyramine	4–24 g/day (divided doses)	1–2 times daily
Colestipol	5–30 g/day (tablets or granules)	1–2 times daily
Colesevelam	3.75 g/day (6 x 625 mg tabs or 1.875 g BID)	Once or twice daily

Administration Notes:

• Take with meals

• Mix powders in water or juice

• Other medications should be taken at least 1 hour before or 4–6 hours after to avoid binding

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6. Adverse Effects

Gastrointestinal (most common):

• Constipation (up to 20%)

• Abdominal bloating

• Flatulence

• Nausea

• Dyspepsia

• Fecal impaction (elderly at greater risk)

Nutritional:

• Impaired absorption of fat-soluble vitamins (A, D, E, K)

• Reduced absorption of folic acid and iron (rarely clinically significant)

• Hyperchloremic metabolic acidosis (rare, especially in pediatric use)

Other:

• Increased triglyceride levels

• Esophageal irritation (improper administration of powders)

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7. Contraindications

• Complete biliary obstruction

• Triglycerides >500 mg/dL (risk of pancreatitis)

• History of hypertriglyceridemia-induced pancreatitis

• Hypersensitivity to resin components

• Dysphagia or GI motility disorders (risk of obstruction)

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8. Precautions

• Use with caution in:

  • Patients with baseline triglycerides >300 mg/dL

  • Children (risk of nutrient deficiencies)

  • Pregnancy and lactation: Cholestyramine and colesevelam are safe, but may impair vitamin absorption

• Long-term use requires monitoring of:

  • Lipid panels

  • Fat-soluble vitamin levels (especially vitamin K if bleeding risk is present)

  • Adherence due to palatability issues (especially cholestyramine)

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9. Drug Interactions

BAS may bind and reduce bioavailability of:

• Digoxin

• Warfarin

• Thiazide diuretics

• Thyroid hormones (levothyroxine)

• Statins (especially pravastatin and fluvastatin)

• Fat-soluble vitamins

• Oral contraceptives

• Immunosuppressants (e.g., mycophenolate mofetil)

Management:

• Space administration times

• Monitor drug efficacy

• Consider colesevelam (lower binding potential)

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10. Advantages and Limitations

Advantages	Limitations
Non-systemic (no systemic toxicity)	Poor palatability (cholestyramine, colestipol)
Safe in pregnancy	GI side effects common
No hepatic metabolism	Drug–drug interactions due to binding
Colesevelam effective in diabetes	Not effective in lowering triglycerides

11. Summary of Key Agents

Generic Name	Brand Name	Dosage Form	Primary Uses	Unique Notes
Cholestyramine	Questran	Oral powder	Hypercholesterolemia, pruritus	Strongest binder, high GI side effects
Colestipol	Colestid	Powder, tablets	Hypercholesterolemia	Milder GI profile, inconvenient dosing
Colesevelam	Welchol	Tablets, powder	Hypercholesterolemia, T2DM	Best tolerated, no systemic absorption

12. Clinical Guidelines and Therapeutic Role

A. ACC/AHA Guidelines for Dyslipidemia:

• BAS are second-line agents for LDL-C reduction

• Useful in statin-intolerant patients

• Should not be used in patients with high triglycerides

B. NICE and EASD Guidelines for Diabetes:

• Colesevelam may be considered as an adjunct to metformin

• Lower efficacy than SGLT2 inhibitors or GLP-1 agonists