Long-term safety and, tolerability profiles andlipid-modifying efficacy of ezetimibe coadministered with ongoing simvastatin treatment: A multicenter, randomized, double-blind, placebo-controlled, 48-week extension study

Masana, Luís; Mata, Pedro; Gagné, Claude; Sirah, Waheeda; Cho, Meehyung; Johnson‐Levonas, Amy O.; Meehan, Alan G.; Troxell, John K.; Gumbiner, Barry M.

doi:10.1016/j.clinthera.2005.02.011

Cited by 57 publications

(21 citation statements)

References 12 publications

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“…Based on prior studies of the half-lives, time course to maximal lipid changes, and time course of their reversal upon withdrawal of therapy, it can be assumed that steady state, in terms of treatment effects, was achieved by the time the key measurements were performed during each period (16)(17)(18). This was supported by the absence of any observed carryover effects.…”

Section: Plasma Lipidsmentioning

confidence: 68%

Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men

Sudhop

Reber

Tribble

et al. 2009

Journal of Lipid Research

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available. It is known that combining lipid lowering agents with different modes of action may enhance the lipid altering effect, but the impact of the combined treatment effects on the major cholesterol balance mechanisms is only poorly understood.In addition to newer medications meant to treat hypercholesterolemia, there have been major improvements in the development of methods of measuring cholesterol balance. The use of nonradiolabeled isotope enrichment of tracer cholesterol and the nonabsorbed marker sitostanol and multiple selective ion monitoring gas chromatographymass spectroscopy (GC-MS) have made it possible to make repeated treatments within a study, whereas, previously, the number of treatments and measurements was limited by exposure to radiation and/or the ability to detect the isotopes. Numerous studies of cholesterol absorption have demonstrated that there are wide interindividual variations in the fraction of cholesterol absorbed with a range of about 15-70% in normal healthy individuals ( 1-5 ).This study investigated the infl uence of simvastatin and ezetimibe and the combination of simvastatin and ezetimibe on cholesterol balance by assessing fractional cholesterol absorption from the gastrointestinal tract by measuring the absorption of isotopic cholesterol compared with the nonabsorbed marker sitostanol ( 6 ) as well as cholesterol synthesis by mass balance ( 7 ).Simvastatin and ezetimibe are approved cholesterol lowering medications that are prescribed individually or together in patients in need of plasma cholesterol reduction. Simvastatin has been previously characterized as an inhibitor of HMG-CoA reductase and as an LDL receptor enhancer ( 8 ), and ezetimibe, an inhibitor of cholesterol absorption from the gastrointestinal tract, has been characterized as an inhibitor of the Niemann-Pick C1-Like 1 Abstract This study evaluates changes in cholesterol balance in hypercholesterolemic subjects following treatment with an inhibitor of cholesterol absorption or cholesterol synthesis or coadministration of both agents. This was a randomized, double blind, placebo-controlled, four-period crossover study to evaluate the effects of coadministering 10 mg ezetimibe with 20 mg simvastatin (ezetimibe/simvastatin) on cholesterol absorption and synthesis relative to either drug alone or placebo in 41 subjects. Each treatment period lasted 7 weeks. Ezetimibe and ezetimibe/simvastatin decreased fractional cholesterol absorption by 65% and 59%, respectively ( P < 0.001 for both relative to placebo). Simvastatin did not signifi cantly affect cholesterol absorption. Ezetimibe and ezetimibe/simvastatin increased fecal sterol excretion (corrected for dietary cholesterol), which also represents net steady state cholesterol synthesis, by 109% and 79%, respectively ( P < 0.001). Ezetimibe, simvastatin, and ezetimibe/simvastatin decreased plasma LDL-cholesterol by 20, 38, and 55%, respectively. The coadministered therapy was well tolerated.The decreases in net cholesterol synthesis and increased fecal sterol e...

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Section: Plasma Lipidsmentioning

confidence: 68%

Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men

Sudhop

Reber

Tribble

et al. 2009

Journal of Lipid Research

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“…Recently, ezetimibe, a new LDL cholesterol-lowering therapy described as a cholesterol absorption inhibitor, was developed, and it is now commercialized as a monotherapy or in combination with statins (9,10). One interest of combination therapy is to reach the goals recommended by the National Cholesterol Education Program Adult Treatment Panel III (11) and to limit the potential side effects observed with high doses of statins (12).…”

mentioning

confidence: 99%

Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine

Brusq

Ancellin

Grondin

et al. 2006

Journal of Lipid Research

308

197

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The alkaloid drug berberine (BBR) was recently described to decrease plasma cholesterol and triglycerides (TGs) in hypercholesterolemic patients by increasing expression of the hepatic low density lipoprotein receptor (LDLR). Using HepG2 human hepatoma cells, we found that BBR inhibits cholesterol and TG synthesis in a similar manner to the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide 1-b-ribofuranoside (AICAR). Significant increases in AMPK phosphorylation and AMPK activity were observed when the cells were incubated with BBR. Activation of AMPK was also demonstrated by measuring the phosphorylation of acetyl-CoA carboxylase, a substrate of AMPK, correlated with a subsequent increase in fatty acid oxidation. All of these effects were abolished by the mitogen-activated protein kinase kinase inhibitor PD98059. Treatment of hyperlipidemic hamsters with BBR decreased plasma LDL cholesterol and strongly reduced fat storage in the liver. These findings indicate that BBR, in addition to upregulating the LDLR, inhibits lipid synthesis in human hepatocytes through the activation of AMPK. These effects could account for the strong reduction of plasma TGs observed with this drug in clinical trials.-Brusq, J-M., N. Ancellin, P. Grondin, R. Guillard, S. Martin, Y. Saintillan, and M. Issandou. Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine.

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“…Another treatment option today is ezetimibe, which can be used alone, but is usually given as an add-on therapy to statins. The addition of ezetimibe to simvastatin treatment increased the attainment rate of the NCEP ATP III guidelines from 22% to 59% [46], and when combined with 10 mg of atorvastatin, LDL-C control rate increased from 7% to 22% among high-risk patients [47 ]. Coadministration of ezetimibe and rosuvastatin 40 mg can increase the attainment rate even further (data on file).…”

Section: Improving Drug Efficacymentioning

confidence: 95%

Beyond guidelines: achieving the optimum in LDL cholesterol control

Leibovitz

Bitzur²,

Harats³

et al. 2005

Current Opinion in Lipidology

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Long-term safety and, tolerability profiles andlipid-modifying efficacy of ezetimibe coadministered with ongoing simvastatin treatment: A multicenter, randomized, double-blind, placebo-controlled, 48-week extension study

Cited by 57 publications

References 12 publications

Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men

Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men

Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine

Beyond guidelines: achieving the optimum in LDL cholesterol control

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