Ezetimibe — Indications, Mode of Action, Metabolism, Excretion, Side Effects and Dosage

Ezetimibe is a selective inhibitor of intestinal cholesterol absorption — it is not a statin and does not inhibit HMG-CoA reductase.

It acts on the Niemann-Pick C1-Like 1 (NPC1L1) transporter on the brush border of jejunal enterocytes, blocking uptake of both dietary and biliary cholesterol and plant sterols.

Reduced cholesterol delivery to the liver depletes hepatic cholesterol stores, which upregulates LDL receptors and increases clearance of LDL from the blood.

It does not affect absorption of triglycerides, fatty acids, bile acids, or fat-soluble vitamins A, D, E and K.

This complementary mechanism to statins — blocking absorption while the statin blocks synthesis — is the basis of combination therapy.

Monotherapy lowers LDL-C by about 18–20%, with minimal effect on HDL-C and triglycerides.

Added to a statin, ezetimibe produces a further LDL-C reduction of about 20% — equivalent to roughly three doublings of the statin dose.

This makes it the preferred first add-on when a statin alone does not achieve target, or when high-intensity statin is not tolerated.

Adjunct to statin therapy in primary hypercholesterolaemia when LDL-C targets are not reached on maximally tolerated statin.

Monotherapy in patients who are statin-intolerant or in whom statins are contraindicated.

Secondary prevention of ASCVD — ACC/AHA guidance: in patients on maximal statin with LDL-C ≥70 mg/dl, adding ezetimibe is reasonable in very-high-risk ASCVD (Class IIa) and may be reasonable in others (Class IIb).

Before adding a PCSK9 inhibitor — guidelines specify that ezetimibe should be added to maximal statin therapy before a PCSK9 inhibitor is considered (Class I).

Homozygous familial hypercholesterolaemia, as an adjunct to statin ± LDL apheresis.

Homozygous sitosterolaemia (phytosterolaemia) — a specific licensed indication, because ezetimibe also blocks plant sterol absorption.

Mixed dyslipidaemia, in combination with fenofibrate.

Absorption: rapidly absorbed after oral dosing; can be taken with or without food. Time to peak concentration is about 4–12 hours for the active metabolite.

Metabolism: undergoes extensive glucuronidation in the small intestinal wall and liver by UGT enzymes, forming ezetimibe-glucuronide, which is pharmacologically active and accounts for most of the drug effect. Cytochrome P450 is not significantly involved, which is why ezetimibe has few drug interactions — a real advantage in polypharmacy.

Enterohepatic recirculation of the glucuronide delivers drug repeatedly to its site of action and gives a long half-life of about 22 hours.

Excretion: approximately 78% in faeces (mainly as unchanged ezetimibe) and about 11% in urine (mainly as the glucuronide).

No dose adjustment is required for mild hepatic impairment, renal impairment, or in the elderly. It should be avoided in moderate to severe hepatic impairment (Child-Pugh ≥7), where drug exposure rises several-fold.

10 mg once daily, orally, with or without food, at any time of day. There is no dose titration — 10 mg is the only dose.

Fixed-dose combinations are widely available (ezetimibe with simvastatin, atorvastatin, or rosuvastatin) and improve adherence.

If given with a bile acid sequestrant, administer ezetimibe at least 2 hours before or 4 hours after the sequestrant, because binding resins reduce its absorption.

Generally very well tolerated. Common: diarrhoea, abdominal pain, flatulence, fatigue, arthralgia, upper respiratory tract infection.

Myalgia and myopathy occur, and the risk of rhabdomyolysis increases when combined with a statin — though the incremental risk is small.

Elevated transaminases, particularly in combination with a statin; check liver function before starting combination therapy.

Rare: hypersensitivity reactions including angioedema and rash, hepatitis, cholelithiasis and cholecystitis, pancreatitis, and thrombocytopenia.

Interactions: ciclosporin raises ezetimibe levels (and ezetimibe raises ciclosporin levels) — monitor levels; fibrates increase biliary cholesterol and the risk of gallstones; cholestyramine reduces efficacy.

IMPROVE-IT — in post-ACS patients on simvastatin 40 mg, adding ezetimibe 10 mg gave a further 22% decrease in LDL-C, a 6.4% relative and 2% absolute reduction in the primary composite endpoint (cardiovascular death, MI, unstable angina, coronary revascularisation, stroke) over six years. This was the first trial to prove that a non-statin LDL-lowering drug reduces events, validating the “LDL hypothesis”.

EWTOPIA 75 — an open-label trial of ezetimibe monotherapy in Japanese patients aged 75 and over with LDL-C ≥140 mg/dl, showing reduction in cardiovascular events. It carries considerable weight in meta-analyses of lipid lowering in the very old.

PRECISE-IVUS — ezetimibe plus atorvastatin produced greater coronary plaque regression on intravascular ultrasound than atorvastatin alone.