Pleiotropic Effects of Statins: Benefit Beyond Cholesterol Reduction?

Robinson, Jennifer G.; Smith, Brian J.; Maheshwari, Nidhi; Schrott, Helmut G.

doi:10.1016/j.jacc.2005.05.085

Cited by 375 publications

(212 citation statements)

References 93 publications

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“…Lowering LDL-C levels has been shown to reduce the risk of CVD events in several interventional and epidemiologic studies [11–13,37–39]; that holds for both statin [40,41] and non-statin therapies [42,43]. The evolocumab CV outcomes trial, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) [16], demonstrated that the addition of evolocumab to SoC is associated with a reduced incidence of major CVD events.…”

Section: Methodsmentioning

confidence: 99%

Cost-effectiveness of evolocumab in treatment of heterozygous familial hypercholesterolaemia in Bulgaria: measuring health benefit by effectively treated patient-years*

Borissov¹,

Urbich

Georgieva³

et al. 2017

Journal of Market Access & Health Policy

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Background: An elevated level of low-density lipoprotein cholesterol (LDL-C) constitutes one of the most important modifiable risk factors for cardiovascular disease (CVD). Individuals with heterozygous familial hypercholesterolaemia (HeFH) are particularly vulnerable to CVD events. The addition of evolocumab to statins has shown marked reductions in LDL-C levels. The objective of this analysis is to demonstrate the clinical and economic value of LDL-C lowering with evolocumab from the Bulgarian public health care perspective. Methods: A disease-specific measure of health benefit was devised: Effectively treated patient-years (ETPYs) combine length of life with the likelihood of attaining best-practice recommendations on LDL-C lowering. “Effective treatment” was defined as a reduction in LDL-C levels of ≥50%. A Markov cohort state-transition model was adapted, considering a life-long treatment duration. Demographics, baseline characteristics and efficacy data were taken from the RUTHERFORD-2 trial. The model uses the relationship between LDL-C lowering and reduced CVD event rates observed in the meta-analyses conducted by the Cholesterol Treatment Trialists’ Collaboration. Outcomes and costs (from year 2015) were discounted at an annual rate of 5%. Sensitivity analyses were conducted to assess uncertainty surrounding the results. Results: The total incremental costs of evolocumab added to statins versus statins alone are BGN 120,329 while adding 9.30 ETPYs over lifetime. These results imply an incremental cost per ETPY of BGN 12,937 (US$ 7,215; € 6,604). The use of evolocumab is associated with a relative reduction in the CVD event rate by 38% (18% per 1 mmol/L). Conclusions: Adding evolocumab to statins may be considered cost-effective in light of an additional expense per patient-year gained in which individuals with HeFH receive effective treatment under the terms of international prevention guidelines. ETPYs are an intuitive and clinically meaningful measure of patient benefit that, in relation to costs, can support health care decision-making that considers quality of care.

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Section: Methodsmentioning

confidence: 99%

Cost-effectiveness of evolocumab in treatment of heterozygous familial hypercholesterolaemia in Bulgaria: measuring health benefit by effectively treated patient-years*

Borissov¹,

Urbich

Georgieva³

et al. 2017

Journal of Market Access & Health Policy

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“…Therefore, lowering of oxLDL levels by statins might contribute to some of the cholesteroldependent effects of statins. Furthermore, data from meta-analysis of lipid-lowering trials suggest that lipid modification alone accounts for the clinical benefits associated with statin therapy [18]. However, both the level of efficacy and early treatment benefits as a result of statin therapy have so far been greater than the beneficial effects of non-statin lipid-lowering therapies.…”

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

537

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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“…Ridker et al (90) observed that patients whose statin therapy reduced LDL-cholesterol to <70 mg/dl (<1·81 mM/dl), had a reduced rate of recurrent myocardial infarction or death from coronary events (2·7 events per 100 person-years), than individuals whose statin therapy did not reach this goal (4·0 events per 100 person-years). However, it has also been demonstrated non-statin therapy (diet, bile acid sequesterants and ileal bypass surgery) reduced CHD risk equally to that of statins, with each 1 % reduction in LDLcholesterol corresponding to a 1 % decrease in CHD risk (10) . Statins can also be used in combination with drugs such as Ezetimbibe, which targets NPC1L1 to lower cholesterol absorption.…”

Section: Pharmacological Interventionmentioning

confidence: 99%

“…It is likely that these alterations play a role in the accumulation of LDL-cholesterol and disease pathogenesis. The accumulation of plasma cholesterol can also be moderated by diet, while pharmaceutical and pre-and probiotic administration have largely been associated with reduced LDLcholesterol levels and CVD risk (9)(10)(11)(12)(13) .…”

mentioning

confidence: 99%

Investigating cholesterol metabolism and ageing using a systems biology approach

et al. 2016

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CVD accounted for 27 % of all deaths in the UK in 2014, and was responsible for 1·7 million hospital admissions in 2013/2014. This condition becomes increasingly prevalent with age, affecting 34·1 and 29·8 % of males and females over 75 years of age respectively in 2011. The dysregulation of cholesterol metabolism with age, often observed as a rise in LDL-cholesterol, has been associated with the pathogenesis of CVD. To compound this problem, it is estimated by 2050, 22 % of the world's population will be over 60 years of age, in culmination with a growing resistance and intolerance to pre-existing cholesterol regulating drugs such as statins. Therefore, it is apparent research into additional therapies for hypercholesterolaemia and CVD prevention is a growing necessity. However, it is also imperative to recognise this complex biological system cannot be studied using a reductionist approach; rather its biological uniqueness necessitates a more integrated methodology, such as that offered by systems biology. In this review, we firstly discuss cholesterol metabolism and how it is affected by diet and the ageing process. Next, we describe therapeutic strategies for hypercholesterolaemia, and finally how the systems biology paradigm can be utilised to investigate how ageing interacts with complex systems such as cholesterol metabolism. We conclude by emphasising the need for nutritionists to work in parallel with the systems biology community, to develop novel approaches to studying cholesterol metabolism and its interaction with ageing.

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Pleiotropic Effects of Statins: Benefit Beyond Cholesterol Reduction?

Abstract: The pleiotropic effects of statins do not seem to contribute an additional cardiovascular risk reduction benefit beyond that expected from the degree of LDL-C lowering observed in other trials that primarily lowered LDL-C.

Cited by 375 publications

References 93 publications

Cost-effectiveness of evolocumab in treatment of heterozygous familial hypercholesterolaemia in Bulgaria: measuring health benefit by effectively treated patient-years*

Cost-effectiveness of evolocumab in treatment of heterozygous familial hypercholesterolaemia in Bulgaria: measuring health benefit by effectively treated patient-years*

Pleiotropic effects of statin therapy: molecular mechanisms and clinical results

Investigating cholesterol metabolism and ageing using a systems biology approach

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