What is Colesevelam?
Colesevelam is a non-absorbed, polymeric bile acid sequestrant that binds bile acids in the intestine to lower LDL cholesterol levels and, uniquely among bile acid sequestrants, also improves glycemic control in patients with type 2 diabetes. 1
Mechanism of Action
Colesevelam works by binding bile acids in the intestinal lumen with high affinity, preventing their reabsorption and interrupting the enterohepatic circulation 2. This process:
- Depletes hepatic bile acid pools, triggering upregulation of cholesterol 7-α-hydroxylase, which increases conversion of cholesterol to bile acids 2
- Reduces intrahepatic cholesterol stores, leading to increased LDL receptor expression on liver cells 2
- Enhances LDL particle clearance from blood, resulting in decreased serum LDL-C levels 2
The polymer structure is poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide, making it hydrophilic but insoluble in water 1.
Clinical Efficacy
LDL Cholesterol Reduction
As monotherapy, colesevelam 3.75 g daily reduces LDL-C by approximately 15-18% 2. When combined with low- to moderate-intensity statins, it provides an additional 10-16% LDL-C reduction beyond statin therapy alone 2.
Glycemic Benefits
Colesevelam is the only FDA-approved single agent that lowers both LDL-C and hemoglobin A1c in adults with type 2 diabetes 3. It modestly improves glycemic control in patients with type 2 diabetes, though the exact mechanism remains incompletely defined 2.
Cardiovascular Outcomes
Historical evidence from the LRC 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-C lowering 2.
FDA-Approved Indications
Colesevelam is approved for 1:
- Adults with primary hyperlipidemia - as adjunct to diet and exercise to reduce elevated LDL-C (monotherapy or combined with statins)
- Adults with type 2 diabetes - as adjunct to diet and exercise to improve glycemic control
- Pediatric patients (boys and postmenarchal girls aged 10-17 years) with heterozygous familial hypercholesterolemia - when unable to reach LDL-C targets after adequate diet and lifestyle modification trials
Dosing and Administration
The standard dose is 3.75 g daily, administered either as:
- Tablets: 6 tablets once daily OR 3 tablets twice daily with meals and liquid 2
- Oral suspension: One 3.75 g packet once daily OR one 1.875 g packet twice daily, mixed with 8 ounces of water, fruit juice, or diet soft drink, taken with meals 2
The oral suspension formulation contains citrus flavoring and is bioequivalent to the tablet form, offering improved convenience and compliance 3.
Contraindications
Colesevelam is contraindicated in patients with: 1
- Serum triglyceride levels >500 mg/dL
- History of hypertriglyceridemia-induced pancreatitis
- History of bowel obstruction
Warnings and Precautions
Hypertriglyceridemia Risk
Colesevelam can increase triglyceride levels, potentially causing acute pancreatitis 2, 1. Monitor lipid panels including triglycerides regularly, and instruct patients to discontinue therapy and seek immediate medical attention if symptoms of acute pancreatitis develop 1.
Gastrointestinal Obstruction
Cases of bowel obstruction have occurred 1. Avoid colesevelam in patients with gastroparesis, other GI motility disorders, or history of major GI tract surgery who may be at increased risk for bowel obstruction 2, 1.
Fat-Soluble Vitamin Deficiencies
Colesevelam may decrease absorption of fat-soluble vitamins (A, D, E, K) 1. Patients with susceptibility to vitamin K deficiency (e.g., those on warfarin or with malabsorption syndromes) are at increased risk 1. Patients requiring oral vitamin supplementation should take vitamins at least 4 hours before colesevelam 1.
Drug Interactions
Due to potential decreased absorption of other medications, administer other drugs at least 4 hours before colesevelam 2, 1. However, colesevelam has fewer drug interactions compared to older bile acid sequestrants like cholestyramine and colestipol 4.
Phenylketonuria Warning
Each 3.75 g dose of oral suspension contains 33.6 mg phenylalanine, which can be harmful to patients with phenylketonuria 1.
Tolerability Profile
Colesevelam has significantly better gastrointestinal tolerability compared to older bile acid sequestrants 5, 6. The most common adverse effects are:
- Constipation and dyspepsia (most frequent) 2, 6
- Gas, bloating, and abdominal cramps (less common than with cholestyramine/colestipol) 2
Colesevelam lacks the severe constipating effects typical of traditional bile acid sequestrants, which improves patient compliance 5, 4.
Clinical Positioning
Combination Therapy Advantages
Colesevelam provides a dose-sparing effect when combined with statins, potentially reducing statin-related side effects or drug interactions 4. This makes it particularly valuable when LDL-C remains ≥100 mg/dL despite maximal tolerated statin therapy 2.
Special Populations
Colesevelam may be particularly useful in patients who cannot tolerate first-line therapies, including organ transplant recipients, patients with cholestatic liver disease, and those with end-stage renal disease 4. In pediatric patients with heterozygous familial hypercholesterolemia, colesevelam 3.75 g daily is well-tolerated for up to 26 weeks 7.