Inhibition of Intestinal Cholesterol Absorption by Ezetimibe in Humans

Sudhop, Thomas; Lütjohann, Dieter; Kodal, Annette; Igel, Michael; Tribble, Diane L.; Shah, Sukrut; Perevozskaya, Inna; Bergmann, Klaus von

doi:10.1161/01.cir.0000034044.95911.dc

Cited by 613 publications

(370 citation statements)

References 26 publications

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“…However, previous experiments in metabolism of cholesterol indicate the potential for a reciprocal relationship in absorption and synthesis where change in one parameter oppositely affects the other. 19,[34][35][36][37][38] A paucity of trials exists which measure the effects of weight loss on both absorption and synthesis. The only research found was in subjects with type 2 diabetes mellitus (DM) using plant sterol and cholesterol precursors as indicators of absorption and synthesis.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol metabolism and body composition in women: the effects of moderate weight loss

et al. 2007

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Objective: To determine how moderate weight loss protocol through diet and exercise may affect changes in body composition, to determine the effects of weight loss on cholesterol metabolism and to examine the relationship between cholesterol metabolism and changes in body composition. Design: Thirty-five otherwise healthy, hypercholesterolemic women completed a 24-week weight loss study. A 20% decrease in energy intake through diet and a 10% increase in energy expenditure by exercise were combined with motivational strategies to encourage weight loss. The diet was self-selected and comprised of 50-60% carbohydrates, 20% protein and o30% fat. Results: Participants lost an average of 11.772.5 kg (Po0.001). Whole body and regional losses in tissue mass occurred after weight loss. After weight loss, cholesterol fractional synthesis rate (FSR) decreased (P ¼ 0.003) 3.8679.33%, whereas rates of cholesterol absorption and turnover did not change (3.31719.4%, P ¼ 0.32 and À0.0176.20%, P ¼ 0.75, respectively). Changes in cholesterol turnover were positively correlated (r ¼ 0.44, P ¼ 0.01) with changes in FSR. Reductions in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were predictive (b ¼ À5.04, r ¼ 0.38; P ¼ 0.03, and b ¼ À147, r ¼ 0.40; P ¼ 0.03, respectively) of increases in cholesterol turnover. Losses in skeletal muscle (SM) and upper-body SM predicted (b ¼ 6.82, r ¼ 0.36; P ¼ 0.04 and b ¼ 14.7, r ¼ 0.41; P ¼ 0.01, respectively) decreases in cholesterol absorption. Conclusions: Decreases in cholesterol synthesis after moderate weight loss are not compensated for by changes in cholesterol absorption or turnover. Changes in regional body composition were associated with variations in cholesterol metabolism. Understanding how weight loss affects cholesterol metabolism will help identify more effective treatment routes for overweight individuals undergoing weight loss resulting in earlier and more intensive therapy for the associated dyslipidemia.

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Section: Discussionmentioning

confidence: 99%

Cholesterol metabolism and body composition in women: the effects of moderate weight loss

et al. 2007

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“…Recently, two clinical trials with ezetimibe support the notion of statin pleiotropy in humans. Ezetimibe is a lipid-lowering agent, which acts by decreasing cholesterol absorption in the intestine [30]. It is used alone or in combination with statin therapy to enhance lipid lowering [31].…”

Section: Clinical Trials With Statinsmentioning

confidence: 99%

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Wang

Liu

Liao

2008

Trends in Molecular Medicine

532

394

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Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is required for cholesterol biosynthesis, and are beneficial in the primary and secondary prevention of cardiovascular disease. Most of the benefits of statin therapy are owing to the lowering of serum cholesterol levels. However, by inhibiting HMG-CoA reductase, statins can also inhibit the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. Therefore, it is possible that statins might exert cholesterol-independent or 'pleiotropic' effects through direct inhibition of these small GTP-binding proteins. Recent studies have shown that statins might have important roles in diseases that are not mediated by cholesterol. Here, we review data from recent clinical trials that support the concept of statin pleiotropy and provide a rationale for their clinical importance. [6], have demonstrated the beneficial effects of statin therapy for primary and secondary prevention of cardiovascular disease. Because 60-70% of serum cholesterol is derived from hepatic synthesis and HMG-CoA reductase is the crucial, rate-limiting enzyme in the cholesterol biosynthetic pathway, inhibition of this enzyme by statins results in a dramatic reduction in circulating low-density lipoprotein (LDL)-cholesterol (Figure 1). In addition, reduction of LDL-cholesterol leads to upregulation of the LDL receptor and increased LDL clearance. The lowering of serum cholesterol levels is therefore thought to be the primary mechanism underlying the therapeutic benefits of statin therapy in cardiovascular disease [1]. Pleiotropy of statins: beyond cholesterol loweringStatins, however, might also exert cholesterol-independent or pleiotropic effects. By inhibiting the conversion of HMG-CoA to L-mevalonic acid, statins prevent the synthesis of important isoprenoids, such as farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP), which are precursors of cholesterol biosynthesis [7] (Figure 1). These intermediates serve as important lipid attachments for the post-translational modification of proteins, such as nuclear lamins, Ras, Rho, Rac and Rap [8]. These isoprenylated proteins constitute approximately 2% of total cellular proteins [9]. Protein isoprenylation (see Glossary) enables proper subcellular localization and trafficking of intracellular proteins. Given that isoprenylated proteins might

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“…Ezetimibe monotherapy (10 mg per day) significantly reduces LDL-C levels by roughly 20% compared with placebo [43,44]. When added to statins, ezetimibe also provides statistically significant improvements in triglycerides, HDL-C, non-HDL-C, apolipoprotein B (ApoB), and high-sensitivity C-reactive protein (hsCRP).…”

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

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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Inhibition of Intestinal Cholesterol Absorption by Ezetimibe in Humans

Cited by 613 publications

References 26 publications

Cholesterol metabolism and body composition in women: the effects of moderate weight loss

Cholesterol metabolism and body composition in women: the effects of moderate weight loss

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

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

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