Efficacy and Safety of Ezetimibe Coadministered With Simvastatin in Patients With Primary Hypercholesterolemia: A Randomized, Double-Blind, Placebo-Controlled Trial

Goldberg, Anne C.; Sapre, Aditi; Liu, J. I.; Capece, Rachel; Mitchel, Yale

doi:10.4065/79.5.620

Cited by 176 publications

(144 citation statements)

References 18 publications

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“…In addition, C-reactive protein (CRP), an inflammatory marker which may be a risk factor for atherosclerosis, was found to be reduced nearly two fold greater in the ezetimibe plus simvastatin pooled groups compared to the simvastatin alone pooled groups ( 33.3% vs 14.3%; p 0.01) 34) . Considerable LDL-C reductions with the coadministration of ezetimibe and simvastatin compared with simvastatin were also reported by Goldberg et al 35) . Ezetimibe plus simvastatin reduced LDL-C by 46.2% to 60.8% over the 10-to 80-mg dose range, compared with 31.3% to 45.6% with 10 to 80 mg simvastatin alone.…”

Section: Ezetimibe In Combination With Statinsmentioning

confidence: 54%

Zetia: Inhibition of Niemann-Pick C1 Like 1 (NPC1L1) to Reduce Intestinal Cholesterol Absorption and Treat Hyperlipidemia

Davis¹,

Veltri²

2007

J Atheroscler Thromb

145

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Zetia (ezetimibe) is a selective cholesterol absorption inhibitor, which potently inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids. Ezetimibe reduces the small intestinal enterocyte uptake and absorption of cholesterol by binding to Niemann-Pick C1 Like 1 (NPC1L1), which keeps cholesterol in the intestinal lumen for excretion. Ezetimibe undergoes glucuronidation to a single metabolite and localizes at the intestinal wall, where it binds with higher affinity for NPC1L1 than ezetimibe to prevent cholesterol absorption. Enterohepatic recirculation of ezetimibe and/or its glucuronide ensures repeated delivery to the intestinal site of action and limited peripheral exposure. Ezetimibe has no effect on the activity of major drug metabolizing enzymes (CYP450), which reduces any potential drug-drug interactions with other medications. Ezetimibe (10 mg/day) was found to inhibit cholesterol absorption by an average of 54% in hypercholesterolemic individuals and by 58% in vegetarians. Ezetimibe alone reduced plasma total and LDL-Cholesterol (18%) levels in patients with primary hypercholesterolemia. When ezetimibe was added to on-going statin treatment, an additional 25% reduction in LDL-C was found in patients with primary hypercholesterolemia and an additional 21% reduction in LDL-C in homozygous familial hypercholesterolemia. Ezetimibe in combination with statins produces additional reductions in plasma cholesterol levels and allows for more patients to achieve their LDL-C goals. . Zetia was identified through the characterization of the active biliary metabolites of its predecessor, SCH 48461, and extensive structure-activity relationship information obtained from a seven day cholesterol-fed hamster model 2) . Ezetimibe dose-dependently inhibited diet-induced hypercholesterolemia in hamsters with an ED50 of 0.04 mg/kg. In an acute model of intestinal absorption using radiolabeled cholesterol in rats, ezetimibe inhibited the appearance of radiolabeled cholesterol in plasma with an ED50 of 0.0015 mg/kg ninety minutes after dosing, indicating that the onset of activity was rapid 3) . Ezetimibe has proven to be most potent pre-clinically in cholesterol-fed rhesus monkeys with an ED50 0.0005 mg/kg/day. A single dose of the ezetimibe analog, SCH 48461, administered to cynomolgus monkeys fed a single cholesterol-containing meal caused a significant reduction of cholesterol in chylomicrons and chylomicron remnants during the postprandial phase without affecting triglyceride content 4) . Ezetimibe selectively inhibits the transport of cholesterol across the intestinal wall. Ezetimibe does not affect intestinal cholesteryl ester hydrolysis and the absorption of fatty acids thus generated. The free cholesterol from this hydrolysis, however, was not absorbed J Atheroscler

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Section: Ezetimibe In Combination With Statinsmentioning

confidence: 54%

Zetia: Inhibition of Niemann-Pick C1 Like 1 (NPC1L1) to Reduce Intestinal Cholesterol Absorption and Treat Hyperlipidemia

Davis¹,

Veltri²

2007

J Atheroscler Thromb

145

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“…13,14,20, 21 When effectiveness for lowering LDL-C levels was compared among the 4 subgroups according to whether their respective levels of cholesterol absorption and synthesis markers were higher or lower than the median values at baseline, the decrease in LDL-C levels was greatest in patients with high absorption and low synthesis of cholesterol and lowest in patients with low absorption and high synthesis of cholesterol in the ezetimibe + statin group. In contrast, the decrease in LDL-C levels did not differ among the 4 subgroups in the double-dose statin group.…”

Section: Discussionmentioning

confidence: 99%

Clinical Usefulness of Additional Treatment With Ezetimibe in Patients With Coronary Artery Disease on Statin Therapy - From the Viewpoint of Cholesterol Metabolism -

Okada

Kimura

Iwahashi

et al. 2011

Circ J

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“…Previous data suggest that ezetimibe reduces hs-CRP when given in combination with other agents only 9) ; however, recent studies have reported that ezetimibe monotherapy also has an anti-inflammatory effect 39,40) . There was no correlation between the reduction of hs-CRP and LDL-C in the present study (data not shown), which was also reported previously 39) . This effect of ezetimibe is pleiotropic, because it is not absorbed into the circulation but acts locally by inhibiting cholesterol absorption from the small intestine.…”

Section: Discussionmentioning

confidence: 96%

Effects of Ezetimibe on Remnant-Like Particle Cholesterol, Lipoprotein (a), and Oxidized Low-Density Lipoprotein in Patients with Dyslipidemia

Nozue

Michishita

Mizuguchi

2010

JAT

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Efficacy and Safety of Ezetimibe Coadministered With Simvastatin in Patients With Primary Hypercholesterolemia: A Randomized, Double-Blind, Placebo-Controlled Trial

Cited by 176 publications

References 18 publications

Zetia: Inhibition of Niemann-Pick C1 Like 1 (NPC1L1) to Reduce Intestinal Cholesterol Absorption and Treat Hyperlipidemia

Zetia: Inhibition of Niemann-Pick C1 Like 1 (NPC1L1) to Reduce Intestinal Cholesterol Absorption and Treat Hyperlipidemia

Clinical Usefulness of Additional Treatment With Ezetimibe in Patients With Coronary Artery Disease on Statin Therapy - From the Viewpoint of Cholesterol Metabolism -

Effects of Ezetimibe on Remnant-Like Particle Cholesterol, Lipoprotein (a), and Oxidized Low-Density Lipoprotein in Patients with Dyslipidemia

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