Cholesterol absorption inhibitors

Overview
Cholesterol absorption inhibitors are lipid-lowering agents that reduce the intestinal uptake of dietary and biliary cholesterol. They are most commonly used to treat hypercholesterolemia, either as monotherapy in statin-intolerant patients or in combination with statins to achieve greater low-density lipoprotein cholesterol (LDL-C) reduction. By limiting cholesterol absorption from the gut, these agents decrease hepatic cholesterol stores, which upregulates LDL receptors and enhances clearance of LDL-C from the blood.

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Mechanism of Action

• The primary drug in this class, ezetimibe, selectively inhibits the Niemann–Pick C1-like 1 (NPC1L1) transporter in the small intestinal brush border.

• This transporter mediates the uptake of cholesterol and plant sterols from the intestinal lumen into enterocytes.

• Blocking NPC1L1 reduces cholesterol delivery to the liver via chylomicron remnants.

• The liver compensates by increasing LDL receptor expression, thereby removing more LDL-C from the circulation.

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Available Agents

• Ezetimibe – the only widely used cholesterol absorption inhibitor in clinical practice.

• Ezetimibe + Statin combinations:

  • Ezetimibe/simvastatin (Vytorin)

  • Ezetimibe/atorvastatin (Liptruzet – some markets)

  • Ezetimibe/rosuvastatin (various brands)

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Therapeutic Uses

• Primary hypercholesterolemia – monotherapy or adjunct to statin therapy.

• Homozygous familial hypercholesterolemia (HoFH) – in combination with statins ± other agents.

• Homozygous sitosterolemia – reduces plant sterol absorption.

• May be used in combination regimens for patients not achieving LDL-C goals with statins alone or who are statin-intolerant.

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Dosage and Administration

• Ezetimibe: 10 mg orally once daily, with or without food.

• Fixed-dose combinations with statins follow the same 10 mg ezetimibe content plus the statin dose appropriate for the patient.

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Contraindications

• Active liver disease or unexplained persistent elevations of hepatic transaminases (when used with statins).

• Known hypersensitivity to ezetimibe or any component of the formulation.

• Pregnancy and breastfeeding: avoid combination with statins; monotherapy use should be risk-assessed.

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Precautions

• Baseline liver function tests when combined with statins; monitor periodically.

• Use with caution in moderate to severe hepatic impairment.

• Myopathy/rhabdomyolysis risk increases when used with statins or fibrates (especially gemfibrozil).

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Adverse Effects

• Common: Diarrhea, abdominal pain, fatigue, arthralgia.

• Less common: Myalgia, sinusitis, upper respiratory tract infection.

• Rare but serious: Hypersensitivity reactions (rash, angioedema), hepatitis, myopathy/rhabdomyolysis (more likely with statin co-use).

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Drug Interactions

• Bile acid sequestrants (cholestyramine, colesevelam, colestipol) decrease ezetimibe absorption; separate doses by ≥2–4 hours before or ≥4–6 hours after the sequestrant.

• Cyclosporine: Increases ezetimibe concentrations; monitor levels.

• Fibrates: Gemfibrozil increases ezetimibe exposure and risk of gallstones; use with caution.

• Warfarin: Small risk of increased INR; monitor after initiation or dose changes.