colesevelam

Colesevelam is a second-generation, non-absorbed bile acid sequestrant (similar class to cholestyramine and colestipol, but better tolerated). Mechanism: it binds bile acids in the gut lumen, interrupting enterohepatic circulation, forcing the liver to use hepatic cholesterol to synthesize new bile acids. This upregulates hepatic LDL receptors, increasing LDL clearance from the blood, thus lowering LDL-C by roughly 15-20%. It may cause a modest increase in triglycerides, making it less ideal in patients with hypertriglyceridemia. Additionally, colesevelam has an FDA-approved indication for improving glycemic control in type 2 diabetes mellitus, though the exact mechanism for glucose lowering is not fully understood—proposed mechanisms include effects on FXR (farnesoid X receptor) signaling and GLP-1 secretion. Clinical use: often used as adjunct therapy in patients with hyperlipidemia who cannot tolerate statins or need additional LDL lowering, and it is considered safe in pregnancy due to lack of systemic absorption. Adverse effects mainly include GI symptoms (constipation, bloating, dyspepsia) due to its non-absorbable resin nature. Important drug interactions: it can bind and reduce the absorption of other drugs (e.g., oral contraceptives, warfarin, thyroid hormones, other lipid-soluble vitamins), so other medications should be taken 1 hour before or 4 hours after colesevelam. Contraindications include bowel obstruction and triglycerides >500 mg/dL (risk of pancreatitis due to TG elevation). Unlike cholestyramine, colesevelam has fewer GI side effects and drug interactions, making it more tolerable for long-term use.