Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia

Davidson, Michael; McGarry, Thomas; Bettis, Robert; Melani, Lorenzo; Lipka, Leslie J.; LeBeaut, Alexandre; Suresh, Ramachandran; Sun, Steven; Veltri, Enrico P.

doi:10.1016/s0735-1097(02)02610-4

Cited by 510 publications

(331 citation statements)

References 18 publications

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“…13 The apparent attenuation in incremental LDL-C lowering observed at the highest dose (80 mg) in the present study may be related to the method of calculation. Although high-dose statin can reduce cholesterol excretion into bile, 14 which may theoretically lessen the effect of ezetimibe, this has not been observed with simvastatin (80 mg), 15 and further reductions in LDL-C were observed with ezetimibe plus atorvastatin (80 mg) in the present study.…”

Section: Discussioncontrasting

confidence: 65%

“…Ezetimibe has also been shown to be efficacious when coadministered with simvastatin. In a similarly designed study, 15 the combination of ezetimibe (10 mg/d) and simvastatin (pooled doses of 10, 20, 40, and 80 mg/d) provided significantly greater reductions in LDL-C (13.8%) and triglyceride (7.5%) and increases in HDL-C (2.4%) than simvastatin alone (PϽ0.01). Combining the different mechanisms of action of these agents (inhibition of cholesterol synthesis by the statin and inhibition of cholesterol absorption across the intestinal wall by ezetimibe) appears to provide substantial incremental reductions in LDL-C, with additional favorable changes in total cholesterol, triglycerides, apo B, and HDL-C. …”

Section: Discussionmentioning

confidence: 99%

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Effect of Ezetimibe Coadministered With Atorvastatin in 628 Patients With Primary Hypercholesterolemia

et al. 2003

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Background-Despite the established efficacy of statins, many patients do not achieve recommended LDL cholesterol (LDL-C) goals. Contributing factors may be inadequate dosing, increased risk for adverse effects with high-dose monotherapy, and increased potential for intolerance and adverse effects with combinations of available agents. Methods and Results-In a double-blind study, 628 patients with baseline LDL-C 145 to 250 mg/dL and triglycerides Յ350 mg/dL were randomly assigned to receive 1 of the following for 12 weeks: ezetimibe ( Coadministration of ezetimibe provided a significant additional 12% LDL-C reduction, 3% HDL-C increase, 8% triglyceride reduction, and 10% hs-CRP reduction versus atorvastatin alone. Ezetimibe plus atorvastatin provided LDL-C reductions of 50% to 60%, triglyceride reductions of 30% to 40%, and HDL-C increases of 5% to 9%, depending on atorvastatin dose. LDL-C reductions with ezetimibe plus 10 mg atorvastatin (50%) and 80 mg atorvastatin alone (51%) were similar. Conclusions-Ezetimibe plus atorvastatin was well tolerated, with a safety profile similar to atorvastatin alone and to placebo. When coadministered with atorvastatin, ezetimibe provided significant incremental reductions in LDL-C and triglycerides and increases in HDL-C. Coadministration of ezetimibe and atorvastatin offers a well-tolerated and highly efficacious new treatment option for patients with hypercholesterolemia. (Circulation. 2003;107:2409-2415.)

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Section: Discussioncontrasting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Effect of Ezetimibe Coadministered With Atorvastatin in 628 Patients With Primary Hypercholesterolemia

et al. 2003

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“…Ezetimibe is a potent cholesterol and phytosterol uptake inhibitor (2,3) and is used for the treatment of hypercholesterolemia. Ezetimibe effectively lowers circulating plasma cholesterol in humans by 15-20% (4-6), and coadministration of ezetimibe with 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors (statins), inhibitors of cholesterol synthesis, results in additive effects on cholesterol reduction (7)(8)(9)(10)(11).…”

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confidence: 99%

The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1)

García‐Calvo

Lisnock

Bull

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

704

462

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Ezetimibe is a potent inhibitor of cholesterol absorption that has been approved for the treatment of hypercholesterolemia, but its molecular target has been elusive. Using a genetic approach, we recently identified Niemann-Pick C1-Like 1 (NPC1L1) as a critical mediator of cholesterol absorption and an essential component of the ezetimibe-sensitive pathway. To determine whether NPC1L1 is the direct molecular target of ezetimibe, we have developed a binding assay and shown that labeled ezetimibe glucuronide binds specifically to a single site in brush border membranes and to human embryonic kidney 293 cells expressing NPC1L1. Moreover, the binding affinities of ezetimibe and several key analogs to recombinant NPC1L1 are virtually identical to those observed for native enterocyte membranes. KD values of ezetimibe glucuronide for mouse, rat, rhesus monkey, and human NPC1L1 are 12,000, 540, 40, and 220 nM, respectively. Last, ezetimibe no longer binds to membranes from NPC1L1 knockout mice. These results unequivocally establish NPC1L1 as the direct target of ezetimibe and should facilitate efforts to identify the molecular mechanism of cholesterol transport.cholesterol ͉ intestinal brush border membranes

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“…40,46,47 Together, these data clearly demonstrate that the dual inhibition of both cholesterol synthesis and absorption is an attractive new strategy for the treatment of primary hypercholesterolemia.…”

Section: Efficacy Of Combination Therapy Using Ezetimibe With a Statinmentioning

confidence: 79%

Cholesterol metabolism and therapeutic targets: Rationale for targeting multiple metabolic pathways

Turley

2004

Clin Cardiol

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The liver is the major regulator of the plasma low density lipoprotein cholesterol (LDL‐C) concentration because it is not only the site of formation of very low density lipoproteins (VLDL), the precursors of most LDL in the circulation, but it is also the organ where the bulk of receptor‐mediated clearance of LDL takes place. The liver also initially clears all the cholesterol that is absorbed from the small intestine. The absorption of excess cholesterol can potentially increase the amount of cholesterol stored in the liver. This, in turn, can result in increased VLDL secretion, and hence LDL formation, and also downregulation of hepatic LDL receptor activity. Such events will potentially increase plasma LDL‐C levels. The converse situation occurs when cholesterol absorption is inhibited. Cholesterol enters the lumen of the small intestine principally from bile and diet. The major steps involved in the absorption process have been characterized. On average, about half of all cholesterol entering the intestine is absorbed, but the fractional absorption rate varies greatly among individuals. While the basis for this variability is not understood, it may partly explain why some patients respond poorly or not at all to statins and other classes of lipid‐lowering drugs. There are few data relating to racial differences in cholesterol absorption. One study reported a significantly higher rate in African Americans compared with non‐African Americans. Multiple lipid‐lowering drugs that target pathways involving the absorption, synthesis, transport, storage, catabolism, and excretion of cholesterol are available. Ezetimibe selectively blocks cholesterol absorption and lowers plasma LDL‐C levels by an average of 18%. When ezetimibe is coadministered with lower doses of statins, there is an additive reduction in LDL‐C level, which equals the reduction achieved with maximal doses of statins alone. Dual inhibition of cholesterol synthesis and absorption is an effective new strategy for treating hypercholesterolemia.

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Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia

Abstract: When coadministered with simvastatin, ezetimibe provided significant incremental reductions in LDL-C and TG, as well as increases in HDL-C. Coadministration of ezetimibe with simvastatin was well tolerated and comparable to statin alone.

Cited by 510 publications

References 18 publications

Effect of Ezetimibe Coadministered With Atorvastatin in 628 Patients With Primary Hypercholesterolemia

Effect of Ezetimibe Coadministered With Atorvastatin in 628 Patients With Primary Hypercholesterolemia

The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1)

Cholesterol metabolism and therapeutic targets: Rationale for targeting multiple metabolic pathways

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