A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia

Bays, Harold; Ose, Leiv; Fraser, Neil; Tribble, Diane L.; Quinto, Katherine; Reyes, Reinabelle; Johnson‐Levonas, Amy O.; Sapre, Aditi; Donahue, Steven

doi:10.1016/j.clinthera.2004.11.016

Cited by 165 publications

(134 citation statements)

References 42 publications

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“…In a study by Bays et al 36) , the efficacy of the ezetimibe/simvastatin tablet was consistent with coadministration studies, with LDL-C reductions of 44.8% to 60.2% over the 10 to 80 mg dose range. Ezetimibe/ simvastatin was also associated with significantly greater reductions in CRP and remnant-like particle-cholesterol than simvastatin alone (p 0.001).…”

Section: Ezetimibe In Combination With Statinsmentioning

confidence: 69%

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

Davis¹,

Veltri²

2007

J Atheroscler Thromb

143

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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: 69%

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

Davis¹,

Veltri²

2007

J Atheroscler Thromb

143

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“…The majority of clinical studies do not show an effect of NPC1L1 inhibition by ezetimibe on weight gain, body mass index, or waist circumference ( 7,52,53 ). In these studies, many factors may have confounded the results, including genetic background, ethnic groups, and exercise.…”

Section: Long-term Hfd Study: L1-ko Mice On the Low-cholesterol Hfd Hmentioning

confidence: 99%

Dietary cholesterol reverses resistance to diet-induced weight gain in mice lacking Niemann-Pick C1-Like 1

Lin

Liu

et al. 2010

Journal of Lipid Research

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“…Thus, combining ezetimibe and a statin would enhance LDL-cholesterol lowering, through complementary mechanisms of action (8,20). The combination enhances LDL-cholesterol reductions in dogs (12), and in clinical trials, combination therapy decreases LDL-cholesterol to a significantly greater extent than does either agent alone (21,22). However, the mechanism whereby this combination modulates the kinetics of apoB metabolism has not been investigated.…”

mentioning

confidence: 99%

The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin

Telford

Sutherland

Edwards

et al. 2007

Journal of Lipid Research

107

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The combination of ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein (NPC1L1), and an HMGCoA reductase inhibitor decreases cholesterol absorption and synthesis. In clinical trials, ezetimibe plus simvastatin produces greater LDL-cholesterol reductions than does monotherapy. The molecular mechanism for this enhanced efficacy has not been defined. Apolipoprotein B-100 (apoB-100) kinetics were determined in miniature pigs treated with ezetimibe (0.1 mg/kg/day), ezetimibe plus simvastatin (10 mg/kg/day), or placebo (n 5 7/group). Ezetimibe decreased cholesterol absorption (279%) and plasma phytosterols (291%), which were not affected further by simvastatin. Ezetimibe increased plasma lathosterol (165%), which was prevented by addition of simvastatin. The combination decreased total cholesterol (235%) and LDL-cholesterol (247%). VLDL apoB pool size decreased 26%, due to a 35% decrease in VLDL apoB production. LDL apoB pool size decreased 34% due to an 81% increase in the fractional catabolic rate, both of which were significantly greater than monotherapy. Combination treatment decreased hepatic microsomal cholesterol (229%) and cholesteryl ester (265%) and increased LDL receptor (LDLR) expression by 240%. The combination increased NPC1L1 expression in liver and intestine, consistent with increased SREBP2 expression. Ezetimibe plus simvastatin decreases VLDL and LDL apoB-100 concentrations through reduced VLDL production and upregulation of LDLR-mediated LDL clearance.-Telford,

show abstract

A multicenter, randomized, double-blind, placebo-controlled, factorial design study to evaluate the lipid-altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia

Cited by 165 publications

References 42 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

Dietary cholesterol reverses resistance to diet-induced weight gain in mice lacking Niemann-Pick C1-Like 1

The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin

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