Cholesterol Absorption Inhibitors

Cholesterol absorption inhibitors block the intestinal sterol transporter NPC1L1 at the brush border of enterocytes, reducing uptake of dietary and biliary cholesterol. Ezetimibe is the only member in routine use. It lowers LDL cholesterol by 15% to 20% alone and by a further 15% to 25% when added to a statin, with further reduction in cardiovascular events after acute coronary syndrome.

Members. Ezetimibe, used alone or as a fixed-dose combination with a statin. Bempedoic acid, which acts in the liver, is a related non-statin option for statin intolerance and is noted for selection.

Mechanism. Reduced cholesterol delivery to the liver raises LDL receptor expression and lowers LDL cholesterol. Plant sterol absorption is also reduced, which is useful in sitosterolaemia.

Pharmacokinetics. Ezetimibe is absorbed and glucuronidated to an active metabolite, which undergoes enterohepatic recycling, giving a half-life of about 22 hours. It is taken once daily with or without food.

• Ezetimibe: 10 mg tablet; well tolerated; low cost as a generic.
• Ezetimibe with statin combinations: with atorvastatin, rosuvastatin or simvastatin, which improve adherence.
• Bempedoic acid: 180 mg daily, an ATP citrate lyase inhibitor; lowers LDL cholesterol by 15% to 25%; raises uric acid and risk of gout and tendon rupture.

• Add-on to a statin: ezetimibe 10 mg daily when LDL cholesterol is over target after 4 to 6 weeks of maximum tolerated statin.
• Early combination: in very high risk patients, starting with a statin plus ezetimibe achieves targets faster.
• Statin intolerance: ezetimibe alone, or with bempedoic acid.
• Chronic kidney disease: simvastatin 20 mg with ezetimibe 10 mg, or atorvastatin with ezetimibe.
• Sitosterolaemia: ezetimibe 10 mg daily is the main treatment.
• Selection: the first add-on after a statin because of cost and safety, before a PCSK9 inhibitor.

Contraindications. Hypersensitivity. With a statin: active liver disease or unexplained persistent liver enzyme elevation, and pregnancy and breastfeeding. Moderate or severe hepatic impairment (avoid ezetimibe).

Adverse effects. Diarrhoea, abdominal pain, fatigue, upper respiratory symptoms, myalgia, raised liver enzymes (more with a statin), and rarely angioedema, pancreatitis and rhabdomyolysis.

Interactions. Ciclosporin raises ezetimibe levels, with ciclosporin concentration monitoring. Cholestyramine and other bile acid sequestrants reduce absorption, so ezetimibe is taken at least 2 hours before or 4 hours after them. Fibrates raise ezetimibe levels and gallstone risk. Warfarin effect may change, so check INR.

Monitoring. Lipid profile at 4 to 12 weeks, liver enzymes at baseline and when combined with a statin, and symptoms.

Referral and escalation. Persistent LDL cholesterol over target on a statin and ezetimibe needs lipid specialist review for a PCSK9 inhibitor or inclisiran.

Special groups. Pregnancy and breastfeeding: avoid. Older adults: no dose change. Kidney disease: no dose change. Children: approved from age 6 years in some regions for familial hypercholesterolaemia.