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Eze4.4

Ezetimibe (Zetia) Research

Mostly mechanism / observationalModerate safety

7 peer-reviewed studies

What the evidence says

Mostly mechanism / observational

Most Ezetimibe (Zetia) studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.

Most evidence is from medium-quality randomised trials published 2003–2018 with a typical study size of 9,438 participants.

Based on 7 studies · 4 RCTs · 29,455 total participants

Confidence

Moderate

By outcome

LDL & lipid lowering
Mostly mechanism / observational5 studies
Cardiovascular events
Mostly mechanism / observational3 studies
Glucose & metabolic
Mostly mechanism / observational3 studies

Older research base

Newest study from 2018

200320102018

1RCTn=18,144 · very large study2015

Ezetimibe added to simvastatin significantly reduced cardiovascular events after acute coronary syndromes — the first proof that a non-statin LDL-lowering drug improves outcomes.

Cannon, Blazing, Giugliano, McCagg, White, Theroux · The New England journal of medicine (2015)

IMPROVE-IT randomized trial: ~18,000 patients stabilized after acute coronary syndromes
Ezetimibe + simvastatin lowered LDL-C further and reduced major cardiovascular events vs simvastatin alone
First demonstration that adding a non-statin LDL-lowering drug improves clinical outcomes

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2RCTn=9,438 · very large study2011

Simvastatin plus ezetimibe safely reduced major atherosclerotic events in patients with chronic kidney disease.

Baigent, Landray, Reith, Emberson, Wheeler, Tomson · Lancet (London, England) (2011)

SHARP randomized placebo-controlled trial in chronic kidney disease (n≈9,400)
Simvastatin + ezetimibe reduced major atherosclerotic events vs placebo
Established LDL lowering with the combination as safe and beneficial in CKD

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3RCTn=1,873 · large study2008

Simvastatin plus ezetimibe lowered LDL cholesterol but did not slow progression of aortic stenosis, though ischemic cardiovascular events were reduced.

Rossebø, Pedersen, Boman, Brudi, Chambers, Egstrup · The New England journal of medicine (2008)

SEAS randomized trial in patients with mild-to-moderate aortic stenosis
Combination markedly lowered LDL-C but did not reduce the primary aortic-valve outcome
Reduced ischemic cardiovascular events as a secondary finding

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4Systematic Review2018

Adding ezetimibe to statins probably reduces the risk of major cardiovascular events compared with statins alone.

Zhan, Tang, Liu, Xia, Shu, Wu · Cochrane Database of Systematic Reviews (2018)

Cochrane systematic review of ezetimibe randomized trials
Ezetimibe added to statins modestly reduced major cardiovascular events
Little effect on all-cause or cardiovascular mortality; benefit driven by non-fatal events

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5RCT2003

Ezetimibe 10 mg significantly reduced LDL cholesterol versus placebo in patients with primary hypercholesterolemia.

Knopp, Gitter, Truitt, Bays, Manion, Lipka · European heart journal (2003)

Randomized, double-blind, placebo-controlled monotherapy trial
Ezetimibe 10 mg/day lowered LDL-C ~17–18% versus placebo
Well tolerated with a safety profile similar to placebo

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6Animal2004

NPC1L1 is critical for intestinal cholesterol absorption and is the molecular site of action of ezetimibe.

Altmann, Davis, Zhu, Yao, Hoos, Tetzloff · Science (2004)

Identified NPC1L1 as the intestinal sterol transporter required for cholesterol absorption
NPC1L1-knockout mice had markedly reduced cholesterol absorption
Ezetimibe was ineffective in NPC1L1-null mice — pinpointing the drug's target

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7In Vitro2005

Radiolabeled ezetimibe bound specifically to NPC1L1, confirming it as the direct molecular target of the drug.

Garcia-Calvo, Lisnock, Bull, Hawes, Burnett, Braun · Proceedings of the National Academy of Sciences of the United States of America (2005)

Demonstrated direct, specific binding of ezetimibe to NPC1L1
Binding was absent in NPC1L1-deficient tissue
Confirms NPC1L1 as the molecular target of ezetimibe at the biochemical level

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View in Research Library

Ezetimibe (Zetia) Research

Mostly mechanism / observational

Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes.

The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial.

Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.

Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events.

Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia.

Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.

The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1).