Dose-comparison Study of the Combination of Ezetimibe and Simvastatin (Vytorin) Versus Atorvastatin in Patients With Hypercholesterolemia: The Vytorin Versus Atorvastatin (VYVA) Study

Ballantyne, C.M.; Abate, Nicola; Yuan, Zuyi; King, Thomas; Palmisano, Joanne

doi:10.1016/j.accreview.2005.08.024

Cited by 43 publications

(88 citation statements)

References 9 publications

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“…All treatments were well tolerated 37) . In the VYtorin versus Atorvastatin (VYVA) trial 38) , ezetimibe/simvastatin was compared to atorvastatin at various fixed-doses. A total of 1,902 patients not at their NCEP ATP LDL-C goal were randomized to atorvastatin (10, 20, 40, or 80 mg) or to ezetimibe/simvastatin (10/10, 10/20, 10/40, or 10/80 mg).…”

Section: Ezetimibe/simvastatin Vs Atorvastatinmentioning

confidence: 99%

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/simvastatin Vs Atorvastatinmentioning

confidence: 99%

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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“…Highly expressed on the apical surface of absorptive enterocytes (1,3,4), NPC1L1 is a sterol-sensing domain-containing polytopic transmembrane protein (5) that appears to be the target of ezetimibe, a cholesterol absorption inhibitor. Ezetimibe, commercially known as Zetia, can effectively lower plasma LDL-cholesterol (6)(7)(8), presumably through its ability to inhibit NPC1L1 in enterocytes (1,9). However, unlike rodents, in which NPC1L1 is mainly expressed in the intestine, humans highly express NPC1L1 in the liver (1,2,5).…”

Section: Introductionmentioning

confidence: 99%

Hepatic Niemann-Pick C1–like 1 regulates biliary cholesterol concentration and is a target of ezetimibe

Temel

Tang²,

Ma³

et al. 2007

J. Clin. Invest.

326

363

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Niemann-Pick C1-like 1 (NPC1L1) is required for cholesterol absorption. Intestinal NPC1L1 appears to be a target of ezetimibe, a cholesterol absorption inhibitor that effectively lowers plasma LDL-cholesterol in humans. However, human liver also expresses NPC1L1. Hepatic function of NPC1L1 was previously unknown, but we recently discovered that NPC1L1 localizes to the canalicular membrane of primate hepatocytes and that NPC1L1 facilitates cholesterol uptake in hepatoma cells. Based upon these findings, we hypothesized that hepatic NPC1L1 allows the retention of biliary cholesterol by hepatocytes and that ezetimibe disrupts hepatic function of NPC1L1. To test this hypothesis, transgenic mice expressing human NPC1L1 in hepatocytes (L1-Tg mice) were created. Hepatic overexpression of NPC1L1 resulted in a 10-to 20-fold decrease in biliary cholesterol concentration, but not phospholipid and bile acid concentrations. This decrease was associated with a 30%-60% increase in plasma cholesterol, mainly because of the accumulation of apoE-rich HDL. Biliary and plasma cholesterol concentrations in these animals were virtually returned to normal with ezetimibe treatment. These findings suggest that in humans, ezetimibe may reduce plasma cholesterol by inhibiting NPC1L1 function in both intestine and liver, and hepatic NPC1L1 may have evolved to protect the body from excessive biliary loss of cholesterol.

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“…For example, in a study of subjects with metabolic syndrome, the mean reduction in LDL-C was 8% greater with ezetimibe/simvastatin 10/40 mg compared with atorvastatin 40 mg [13]. And in the Vytorin Versus Atorvastatin (VYVA) study, which assessed subjects with hypercholesterolemia and established CHD or CHD risk equivalent, ezetimibe/ simvastatin 10/40 mg resulted in a 9% greater decrease in LDL-C compared with atorvastatin 40 mg [17]. This variation between studies could be due to differences in study design or subject population; however, these differences may be mathematical in nature.…”

Section: Discussionmentioning

confidence: 99%

87 Ezetimibe/Simvastatin 10/40mg Versus Atorvastatin 40mg in High Cardiovascular Risk Patients With Primary Hypercholesterolemia: A Randomized, Double-Blind, Active-Controlled, Multicenter Study

Civeira

Dan

Hing

et al. 2011

Atherosclerosis Supplements

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Dose-comparison Study of the Combination of Ezetimibe and Simvastatin (Vytorin) Versus Atorvastatin in Patients With Hypercholesterolemia: The Vytorin Versus Atorvastatin (VYVA) Study

Cited by 43 publications

References 9 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

Hepatic Niemann-Pick C1–like 1 regulates biliary cholesterol concentration and is a target of ezetimibe

87 Ezetimibe/Simvastatin 10/40mg Versus Atorvastatin 40mg in High Cardiovascular Risk Patients With Primary Hypercholesterolemia: A Randomized, Double-Blind, Active-Controlled, Multicenter Study

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