Efficacy and safety of the coadministration of ezetimibe/simvastatin with fenofibrate in patients with mixed hyperlipidemia

Farnier, Michel; Roth, Eli M.; Gil‐Extremera, Blas; Méndez, Gustavo; Macdonell, Geraldine; Hamlin, C.; Perevozskaya, Inna; Davies, Michael J.; Kush, D.; Mitchel, Yale

doi:10.1016/j.ahj.2006.10.031

Cited by 73 publications

(80 citation statements)

References 17 publications

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“…In addition, and consistent with the well-known effects of fenofibrate on plasma TG, VLDL-C, and LDL-C subclass distributions, nearly 66% of the patients on either ezetimibe/simvastatin 1 fenofibrate or fenofibrate alone had a larger, more-buoyant LDL-C subclass pattern compared with fewer than 20% at baseline (16). The purpose of the analysis presented here was to evaluate the effects of ezetimibe/simvastatin and fenofibrate, both as monotherapy and in coadministration, in more detail by examining their effects on individual lipoprotein subclasses using the Vertical Auto Profile II (VAP II) and segmented gradient gel electrophoresis (S 3 GGE™) methods in patients with mixed hyperlipidemia.…”

mentioning

confidence: 52%

“…The effects of the combination of ezetimibe/simvastatin 1 fenofibrate were demonstrated to result in significantly greater reduction in LDL-C than for fenofibrate alone. This could be attributed mainly to the effect of ezetimibe/simvastatin, inasmuch as there was little or no incremental LDL-C reduction from baseline observed for the addition of fenofibrate (16). Similarly, the change in HDL-C could be attributed mainly to fenofibrate, inasmuch as there was little or no incremental change in the combination treatment compared with those observed for fenofibrate alone.…”

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confidence: 84%

“…The use of both cholesterol-lowering agents, simvastatin and ezetimibe, together with fenofibrate has also been reported (16). The effects of the combination of ezetimibe/simvastatin 1 fenofibrate were demonstrated to result in significantly greater reduction in LDL-C than for fenofibrate alone.…”

mentioning

confidence: 91%

“…The complete details of study design and patient entry criteria are published elsewhere (16). In brief, this was a multicenter, international, randomized, double-blind, placebo-controlled, parallelgroup study.…”

Section: Design and Methodsmentioning

confidence: 99%

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VAP II analysis of lipoprotein subclasses in mixed hyperlipidemic patients on treatment with ezetimibe/simvastatin and fenofibrate

Farnier¹,

Perevozskaya

Taggart

et al. 2008

Journal of Lipid Research

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This analysis evaluates the effects on lipoprotein subfractions and LDL particle size of ezetimibe/simvastatin with or without coadministration of fenofibrate in patients with mixed hyperlipidemia. This multicenter, double-blind, placebo-controlled, parallel-group study included 611 patients aged 18-79 years randomized in 1:3:3:3 ratios to one of four 12 week treatment groups: placebo; ezetimibe/simvastatin 10/20 mg/day; fenofibrate 160 mg/day; or ezetimibe/ simvastatin 10/20 mg/day 1 fenofibrate 160 mg/day. At baseline and study endpoint, cholesterol associated with VLDL, intermediate density lipoprotein (IDL), LDL, and HDL subfractions was quantified using the Vertical Auto Profile II method. LDL particle size was determined using segmented gradient gel electrophoresis. Whereas fenofibrate reduced cholesterol mass within VLDL and IDL, and shifted cholesterol from dense LDL subfractions into the more buoyant subfractions and HDL, ezetimibe/simvastatin reduced cholesterol mass within all apolipoprotein Bcontaining particles without significantly shifting the LDL particle distribution profile. When administered in combination, the effects of the drugs were complementary, with morepronounced reductions in VLDL, IDL, and LDL, preferential loss of more-dense LDL subfractions, and increased HDL, although the effects on most lipoprotein subfractions were not additive. Thus, ezetimibe/simvastatin 1 fenofibrate produced favorable effects on atherogenic lipoprotein subclasses in patients with mixed hyperlipidemia.-Farnier, M., I. Perevozskaya, W. V. Taggart, D. Kush, and Y. B. Mitchel. VAP II analysis of lipoprotein subclasses in mixed hyperlipidemic patients on treatment with ezetimibe/simvastatin and fenofibrate.

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confidence: 52%

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confidence: 84%

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confidence: 91%

Section: Design and Methodsmentioning

confidence: 99%

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VAP II analysis of lipoprotein subclasses in mixed hyperlipidemic patients on treatment with ezetimibe/simvastatin and fenofibrate

Farnier¹,

Perevozskaya

Taggart

et al. 2008

Journal of Lipid Research

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“…In a multicenter, randomized, double-blind, placebo-controlled trial 44) , eligible patients (n 611) with mixed hyperlipidemia (LDL-C 130-220 mg/dL, TG 150-500 mg/L) were randomized in a 3:3:3:1 ratio to one of 4 treatment arms for 12 weeks: ezetimibe/simvastatin 10/20 mg plus fenofibrate 160 mg, ezetimibe/simvastatin 10/20 mg, fenofibrate 160 mg, or placebo. Ezetimibe/simvastatin plus fenofibrate provided significantly (p 0.05) greater reductions in LDL-C ( 45.8%) vs fenofibrate ( 15.7%) or placebo ( 3.5%), but not vs ezetimibe/simvastatin ( 47.1%).…”

Section: Ezetimibe and Ezetimibe/simvastatin In Combination With Fenomentioning

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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Use of Lipid‐Lowering Agents in the Prevention of Cardiovascular Disease

Failor

Probstfield

2009

Evidence‐Based Cardiology

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Efficacy and safety of the coadministration of ezetimibe/simvastatin with fenofibrate in patients with mixed hyperlipidemia

Cited by 73 publications

References 17 publications

VAP II analysis of lipoprotein subclasses in mixed hyperlipidemic patients on treatment with ezetimibe/simvastatin and fenofibrate

VAP II analysis of lipoprotein subclasses in mixed hyperlipidemic patients on treatment with ezetimibe/simvastatin and fenofibrate

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

Use of Lipid‐Lowering Agents in the Prevention of Cardiovascular Disease

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