Perspectives in Cholesterol-Lowering Therapy

Bruckert, Éric; Giral, Philippe; Tellier, Philippe

doi:10.1161/01.cir.0000072345.98581.24

Cited by 94 publications

(37 citation statements)

References 19 publications

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“…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]. In patients with heart failure, 4 weeks of simvastatin but not ezetimibe treatment improved endothelial function and reduced oxidative stress, despite comparable reduction in serum cholesterol levels [32].…”

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

538

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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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

538

394

View full text Add to dashboard Cite

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“…Mean percent change from treated HMG-CoA reductase inhibitor therapy was -17% for total cholesterol, -25% for LDL-C, -14% for triglycerides, and +3% for HDL-C [1,2].…”

Section: Pharmacologymentioning

confidence: 94%

“…In patients with primary hypercholesterolemia, ezetimibe as monotherapy reduced LDL-C by 18%, reduced total cholesterol by 13%, reduced triglycerides by 9% and raised HDL by 1% [1,2].…”

Section: Pharmacologymentioning

confidence: 99%

“…It localizes to the brush border of the small intestine where it inhibits absorption of cholesterol thereby decreasing the delivery of intestinal cholesterol to the liver [1]. This decreases cholesterol stores within the liver and ultimately increases clearance of cholesterol from the blood.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

“…l Ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma (half-life of 22 hours for both) with biliary and renal excretion [1].…”

Section: Pharmacokineticsmentioning

confidence: 99%

See 2 more Smart Citations

Ezetimibe (Zetia)

Brar

2004

Medical Journal Armed Forces India

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Hypolipidemic Agents and Their Role in the Therapy of Diabetes Mellitus

Taskinen

2004

International Textbook of Diabetes Mellitus

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Coronary heart disease (CHD) is increasingly recognized as the major complication in people with type 2 diabetes. Recent data from large endpoint trials have provided convincing evidence that lowering of LDL cholesterol reduces cardiovascular disease events in people with type 2 diabetes. Consequently, the main target for therapy has been defined to be LDL cholesterol (goal <2.6 mmol/l). Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are recommended for first‐line therapy. Optimum therapy of diabetic dyslipidemia should specifically attack those lipid abnormalities that are most common for diabetic dyslipidemia: elevated triglycerides and low HDL cholesterol. In this regard, fibrates provide an option that produces greater changes of these abnormalities than do statins. Effective therapy will be crucial to reduce the excess risk of CHD beyond LDL cholesterol in people with type 2 diabetes. Ongoing trials performed specifically in people with diabetes will likely provide the data regarding how to optimize and individualize the management of diabetic dyslipidemia.

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Perspectives in Cholesterol-Lowering Therapy

Cited by 94 publications

References 19 publications

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Ezetimibe (Zetia)

Hypolipidemic Agents and Their Role in the Therapy of Diabetes Mellitus

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