Cholestyramine for High Cholesterol
Cholestyramine is an effective second-line agent for lowering LDL cholesterol by 15-30%, primarily indicated as adjunctive therapy to diet in patients with primary hypercholesterolemia who do not respond adequately to diet alone, though statins have largely replaced it as first-line therapy due to superior efficacy and tolerability. 1, 2
Mechanism and Efficacy
Cholestyramine binds bile acids in the intestinal lumen, preventing their enterohepatic reabsorption, which depletes the hepatic cholesterol pool and upregulates LDL receptor expression, resulting in increased LDL clearance from circulation. 1, 2
At standard doses of 8-16 g/day, cholestyramine reduces LDL cholesterol by 18-25%, with the 8 g dose producing approximately 17-27% reduction and 16 g producing 26-31% reduction. 1, 3
The lipid-lowering effect occurs rapidly, with the majority of LDL reduction seen within the first 14 days to 1 month of therapy. 2, 4
Cardiovascular Outcomes Evidence
The landmark LRC-CPPT trial demonstrated that cholestyramine reduced the combined rate of coronary heart disease death plus non-fatal myocardial infarction by 19% over 7.4 years in asymptomatic middle-aged men with primary hypercholesterolemia. 5, 2
Coronary arteriography studies (NHLBI Type II Coronary Intervention Trial and STARS) showed that cholestyramine monotherapy slows progression and promotes regression of coronary atherosclerotic lesions. 2
Current Role in Treatment Algorithm
Cholestyramine is now primarily used as add-on therapy when statin monotherapy fails to achieve LDL cholesterol goals, rather than as first-line monotherapy. 1, 5
The American College of Cardiology recommends considering bile acid sequestrants (with colesevelam preferred over cholestyramine due to better tolerability) when additional LDL lowering is needed beyond statin therapy. 1
Combination therapy with cholestyramine plus statins produces additive LDL-lowering effects, with an additional 10-16% reduction when added to low- to moderate-intensity statin therapy. 1
Dosing and Administration
Start with 4-8 g/day (1-2 packets or scoopfuls) divided into two doses, titrating gradually to a maintenance dose of 8-16 g/day based on lipid response assessed at 4-week intervals. 2
Maximum recommended dose is 24 g/day (6 packets), though most benefit is achieved at lower doses. 2
Must be mixed with at least 2-3 ounces of water or non-carbonated beverage; never take in dry powder form due to risk of esophageal obstruction. 2
Administer at mealtime, though timing may be modified to avoid drug interactions. 2
Critical Drug Interactions and Monitoring
All other medications must be taken at least 1 hour before or 4 hours after cholestyramine to avoid impaired absorption. 5
Particularly critical interactions include thyroid hormone replacement, warfarin, oral contraceptives, cyclosporine, phenytoin, and sulfonylureas. 5
Monitor for fat-soluble vitamin deficiencies (especially vitamins D and K) and folate; supplementation should be given at least 4 hours before cholestyramine. 6, 5
Monitor triglyceride levels closely, as cholestyramine may increase triglycerides by 25-85%, particularly problematic in patients with familial combined hyperlipidemia or baseline hypertriglyceridemia. 1, 7, 4
Cholestyramine is contraindicated when triglycerides exceed 500 mg/dL due to risk of hypertriglyceridemia-induced pancreatitis. 1
Adverse Effects and Tolerability Issues
Gastrointestinal side effects (bloating, constipation, nausea, abdominal discomfort) occur in approximately 31% of patients and represent the primary limitation to long-term use. 6, 7
These side effects significantly limit patient adherence compared to statins and newer agents. 1
Additional contraindications include bowel obstruction, complete biliary obstruction, and history of serious hypersensitivity. 1
Special Populations
Children and Adolescents
In children aged 10-17 years with heterozygous familial hypercholesterolemia, cholestyramine is indicated after dietary therapy fails, defined as LDL-C ≥190 mg/dL regardless of family history, or LDL-C ≥160 mg/dL with positive family history of premature CVD. 6, 5
Start at 4-5 g/day and titrate up to 8-16 g/day as tolerated, producing 13-20% LDL reduction in pediatric studies. 1, 6
Colesevelam is FDA-approved for boys and post-menarchal girls aged 10-17 years with heterozygous familial hypercholesterolemia and may be better tolerated than cholestyramine. 1, 6
Regular monitoring of vitamin D and folate levels is essential in growing children. 6
Patients with Diabetes
- Cholestyramine may improve glycemic control modestly in patients with type 2 diabetes, though colesevelam has the only FDA-approved indication for this purpose. 1, 5
Clinical Pearls
The newer bile acid sequestrant colesevelam (4.5 g/day) produces similar LDL lowering (15-18%) with fewer gastrointestinal side effects and once-daily dosing, making it preferable when a bile acid sequestrant is indicated. 1
HDL cholesterol may increase modestly (3-8%) with cholestyramine therapy, likely due to reduced cholesteryl ester transfer protein (CETP) activity. 1, 8
Exclude secondary causes of hypercholesterolemia (poorly controlled diabetes, hypothyroidism, nephrotic syndrome, obstructive liver disease) before initiating therapy. 2
A favorable cholesterol reduction trend should occur within the first month; if not achieved, consider increasing the dose or adding combination therapy. 2