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

Ballantyne, Christie M.; Houri, J.-J.; Notarbartoló, A; Melani, Lorenzo; Lipka, Leslie J.; Suresh, Ramachandran; Sun, Steven; LeBeaut, Alexandre; Sager, Philip T.; Veltri, Enrico P.

doi:10.1161/01.cir.0000068312.21969.c8

Cited by 631 publications

(392 citation statements)

References 16 publications

(15 reference statements)

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“…For example, aspirin (Husain et al 1998) and the selective COX-2 inhibitor celecoxib (Widlansky et al 2003b) have both been shown to improve endothelium-dependent dilation. It is well established that cholesterol-lowering therapy also reduces systemic markers of inflammation, including CRP (Ballantyne et al 2003). On this basis, investigators have argued that the beneficial effects of statins on endothelial function in patients might also be attributable to pleiotropic anti-inflammatory effects (Bonetti et al 2003).…”

Section: Human Studies Of Systemic Inflammation and Endothelial Dysfumentioning

confidence: 99%

Effects of Systemic Inflammation on Endothelium-Dependent Vasodilation

Huang

Vita

2006

Trends in Cardiovascular Medicine

115

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The importance of inflammation in the pathogenesis of atherosclerosis is well established. The vascular endothelium contributes to and is affected by the inflammatory process. For example, a variety of cytokines have the ability to "activate" the endothelium and thereby promote expression of adhesion molecules and chemotactic factors that accelerate the inflammatory process and direct accumulation of leukocytes to specific sites in the arterial tree. In experimental systems, activation of endothelial cells is also associated with a loss of the biologic activity of endothelium-derived nitric oxide, an effect that accelerates the inflammatory process and also promotes local thrombosis and impairs local control of vasomotor tone. Consistent with these experimental studies, recent studies have provided evidence that inflammation is associated with an impairment of nitric oxide-dependent responses in human subjects. This article will review the experimental and clinical studies that support the relevance of inflammation to nitric oxide bioactivity in human atherosclerosis.It is now well recognized that atherosclerosis is an inflammatory disease (Ross 1999). Systemic risk factors induce a state of inflammation that contributes to all stages of atherosclerosis from the initiating events in lesion formation to the latest phase when plaques rupture, thrombose, and produce clinical syndromes such as myocardial infarction or stroke (Libby et al. 2002). The importance of inflammation in atherosclerosis is supported by recent studies showing that elevated levels of inflammatory markers identify individuals with increased risk for cardiovascular events (Pearson et al. 2003). In particular, the acute phase reactant C-reactive protein (CRP) shows promise as a clinically useful marker of cardiovascular risk (Ridker 2003).The vascular endothelium is both affected by and contributes to the inflammatory process that leads to atherosclerosis. For example, proinflammatory factors "activate" endothelial cells to promote an atherogenic phenotype. The activated endothelium, in turn, expresses adhesion molecules and chemotactic factors that accelerate and localize the inflammatory process. An important consequence of endothelial activation is loss of the biologic activity of endotheliumderived nitric oxide. Investigators have argued that a broad alteration of endothelial function, including loss of nitric oxide under proinflammatory conditions, might be a critical mechanism that links systemic states of inflammation to atherosclerosis (Vallance et al. 1997). This article will review the recent studies that support the relevance of systemic inflammation to nitric oxide bioactivity in human subjects. The Endothelium as a Regulator of Vascular HomeostasisThe endothelium regulates vasomotor tone, blood fluidity, growth of vascular smooth muscle cells, and local inflammation by elaborating a number of paracrine factors, including nitric oxide (Widlansky et al. 2003a). Endothelium-derived nitric oxide is a potent vasodilator and acts ...

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Section: Human Studies Of Systemic Inflammation and Endothelial Dysfumentioning

confidence: 99%

Effects of Systemic Inflammation on Endothelium-Dependent Vasodilation

Huang

Vita

2006

Trends in Cardiovascular Medicine

115

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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: 77%

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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“…In this study, 628 patients with baseline LDL-C 145-250 mg/dl were randomly assigned to receive one of the following for 12 weeks: ezetimibe 10 mg/day, atorvastatin (10, 20, 40, or Adding EZE to ATO 20 mg resulted in significantly greater reductions in LDL-C and significantly more pts achieving LDL-C \100 mg/dl Stein et al [48] 621 high-risk pts with LDL-C C130 mg/dl despite treatment with ATO 10 mg/day EZE 10 mg/day ? ATO 10 mg/day followed by response-based ATO dose titration up to 40 mg/day vs. monotherapy with ATO 20 mg/day with response-based ATO dose titration up to 80 mg/day Adding EZE to ATO 10 mg/day followed by ATO dose titration was more effective in reducing LDL-C and significantly increased the proportion of pts achieving LDL-C B100 mg/dl Ballantyne et al [49] 628 pts with primary hypercholesterolemia and baseline LDL-C 145-250 mg/dl [49]. Depending on atorvastatin dose, the ezetimibe-atorvastatin combination provided LDL-C reductions of 50-60%, triglyceride reductions of 30-40%, and HDL-C increases of 5-9%.…”

Section: Lipid-lowering Efficacy Of the Ezetimibe/ Atorvastatin Combimentioning

confidence: 99%

“…Despite some isolated reports of myopathy attributable to ezetimibe [73], the adverse event profile in several large trials was similar to that of placebo [74]. Studies assessing specifically the short-term safety of the atorvastatinezetimibe combination showed similar results, with no significant differences in the incidences of laboratory and clinical adverse events, including gastrointestinal, liver, or muscle effects [46][47][48][49][50]. Concerns that ezetimibe could increase the risk of cancer were raised by the SEAS trial.…”

Section: Safety Of the Ezetimibe-atorvastatin Combinationmentioning

confidence: 99%

Defining the Place of Ezetimibe/Atorvastatin in the Management of Hyperlipidemia

Ferreira

Silva

2016

Am J Cardiovasc Drugs

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Statin-ezetimibe combinations are a potentially advantageous therapeutic option for high-risk patients who need additional lowering of low-density lipoprotein cholesterol (LDL-C). These combinations may overcome some of the limitations of statin monotherapy by blocking both sources of cholesterol. Recently, a fixed-dose combination with atorvastatin, one of the most extensively studied statins, was approved and launched in several countries, including the USA. Depending on atorvastatin dose, this combination provides LDL-C reductions of 50-60%, triglyceride reductions of 30-40%, and highdensity lipoprotein cholesterol (HDL-C) increases of 5-9%. Studies comparing the lipid-lowering efficacy of the atorvastatin-ezetimibe combination with the alternatives of statin dose titration or switching to a more potent statin consistently showed that combination therapy provided greater LDL-C reduction, translating into a greater proportion of patients achieving lipid goals. Simvastatinezetimibe combinations have been shown to reduce the incidence of major atherosclerotic events in several clinical settings to a magnitude that seems similar to that observed with statins for the same degree of absolute LDL-C lowering. The atorvastatin-ezetimibe combination has also been shown to induce the regression of coronary atherosclerosis measured by intravascular ultrasound in a significantly greater proportion of patients than atorvastatin alone. Atorvastatin-ezetimibe combinations are generally well tolerated. Previous concerns of a possible increase in the incidence of cancer with ezetimibe were dismissed in large trials with long follow-up periods. In this paper, we examine the rationale for an atorvastatin-ezetimibe combination, review the evidence supporting it, and discuss its potential role in the management of dyslipidemia. Key PointsStatin-ezetimibe combinations are a realistic treatment option for patients who do not achieve low-density lipoprotein cholesterol (LDL-C) targets while receiving statin monotherapy and for patients prone to dose-dependent statin side effects.The IMPROVE-IT trial was the first to demonstrate a reduction in cardiovascular events with ezetimibe.Recently, combination therapy with atorvastatin plus ezetimibe was also associated with greater coronary plaque regression than atorvastatin alone.

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

Cited by 631 publications

References 16 publications

Effects of Systemic Inflammation on Endothelium-Dependent Vasodilation

Effects of Systemic Inflammation on Endothelium-Dependent Vasodilation

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

Defining the Place of Ezetimibe/Atorvastatin in the Management of Hyperlipidemia

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