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Published Version PUBLISHED VERSION Rose Q Do, Stephen J Nicholls and Gregory G Schwartz Evolving targets for lipid-modifying therapy EMBO Molecular Medicine, 2014; 6(10):1215-1230 © 2014 The Authors. Published under the terms of the CC BY 4.0 license Originally published at: http://doi.org/10.15252/emmm.201404000 PERMISSIONS http://creativecommons.org/licenses/by/4.0/ 15 November 2016 http://hdl.handle.net/2440/102156 Published online: August 29, 2014 Review Review series: Cardiovascular Diseases Evolving targets for lipid-modifying therapy Rose Q Do1,†, Stephen J Nicholls2 & Gregory G Schwartz1,*,† Abstract Targets for reduction of LDL and related atherogenic lipoproteins The pathogenesis and progression of atherosclerosis are integrally connected to the concentration and function of lipoproteins in Statin drugs have been the cornerstone of lipid-modifying therapy various classes. This review examines existing and emerging for more than a quarter century. Statins inhibit 3-hydroxy-3-methyl- approaches to modify low-density lipoprotein and lipoprotein (a), glutaryl coenzyme A (HMG CoA) reductase, which is the rate-limiting triglyceride-rich lipoproteins, and high-density lipoproteins, step for cholesterol synthesis. A reduction in hepatic cholesterol emphasizing approaches that have progressed to clinical evalua- synthesis and hepatocyte cholesterol concentration results in upreg- tion. Targeting of nuclear receptors and phospholipases is also ulation of LDL receptor expression on hepatocytes and enhanced discussed. clearance of LDL and other atherogenic lipoproteins from the circu- lation. Through this mechanism, statins can reduce concentrations Keywords atherosclerosis; cholesterol; lipoproteins; triglycerides of LDL-C by as much as 50–60%, with accompanying reductions of DOI 10.15252/emmm.201404000 | Received 28 April 2014 | Revised 26 June triglyceride-rich lipoproteins and modest increases in HDL-C. A 2014 | Accepted 23 July 2014 | Published online 29 August 2014 large body of data from controlled clinical trials indicates that each EMBO Mol Med (2014) 6: 1215–1230 1 mmol/l reduction in LDL-C produced by statin treatment is associ- ated with approximately 12% reduction in all-cause mortality and See also Glossary for abbreviations used in this article 20% reduction in cardiovascular morbidity (Baigent et al, 2005). At usual doses, statins reduce cardiovascular risk by 25–30%. Part of the clinical efficacy of statins may also be attributable to non-lipid, Introduction or ‘pleiotropic’ effects related to effects of HMG CoA reductase inhibition on isoprenoid intermediates in cholesterol biosynthesis Ischemic heart disease and cerebrovascular disease due to athero- (Davignon, 2004; Nohria et al, 2009; Zhou & Liao, 2010). However, sclerosis remain leading causes of death in the world. Lipoprotein substantial residual cardiovascular risk remains despite effective abnormalities play a key role in the pathogenesis of these diseases. statin treatment. The extent to which this residual risk is attribut- Low-density lipoprotein (LDL), triglyceride-rich lipoproteins, and able to lipoprotein abnormalities, and might be reduced by addi- high-density lipoprotein (HDL) may contribute to the development tional lipoprotein-modifying therapies, remains unknown. To date, and progression of atherosclerosis and its complications. Numerous no second lipid-modifying therapy, added to primary treatment with strategies to modify each of the principal classes of lipoproteins statins, has been proven to reduce cardiovascular risk. However, have been or are currently under investigation. This review primarily promising new targets and new approaches to established targets focuses on those approaches that have progressed to clinical are being investigated. evaluation or implementation. LDL, triglyceride-rich lipoproteins, and HDL comprise the Cholesterol absorption three principal lipoprotein classes. The primary function of LDL Interference with cholesterol absorption can lower circulating is to deliver essential cholesterol to peripheral tissues. Triglycer- concentrations of LDL-C. Bile acid sequestrants such as cholestyr- ide-rich lipoproteins carry a cargo of energy substrate (fatty amine lower LDL-C levels up to 25%. As monotherapy, cholestyr- acids) from intestine to liver and to peripheral tissues for fat amine was shown to reduce the risk of myocardial infarction (Lipid storage and oxidative metabolism. HDL participates in reverse Research Clinics Program, 1984). However, use of bile acid seques- cholesterol transport to remove excess cholesterol stores from trants is limited by gastrointestinal side effects, interference with peripheral sites for biliary excretion. Each lipoprotein class may absorption of other drugs, and exacerbation of hypertriglyceridemia. affect the development and progression of atherosclerosis and A newer bile acid sequestrant, colesevelam, has a relatively low its complications. Numerous strategies to modify each of the incidence of gastrointestinal side effects (Davidson et al, 1999). principal classes of lipoproteins have been or are currently under A target for the inhibition of intestinal cholesterol absorption is investigation (Table 1, Fig 1). Niemann-Pick C1-like 1 (NPC1L1). Ezetimibe inhibits cholesterol 1 VA Medical Center, University of Colorado School of Medicine, Denver, CO, USA 2 South Australian Health and Medical Research Institute and University of Adelaide, Adelaide, SA, Australia *Corresponding author. Tel: +1 303 393 2826; Fax: +1 303 393 5054; E-mail: [email protected] †This article has been contributed to by US Government employees and their work is in the public domain in the USA ª 2014 The Authors. Published under the terms of the CC BY 4.0 license EMBO Molecular Medicine Vol 6 |No10 | 2014 1215 Published online: August 29, 2014 EMBO Molecular Medicine Evolving targets for lipid-modifying therapy Rose Q Do et al C-reactive protein levels by 25%. It progressed to evaluation in Glossary Phases 2 and 3 clinical trials. However, development of lapaquistat Apheresis a procedure used to remove a substance from was halted due to two cases of severe liver enzyme elevation, blood circulation. Whole blood is drawn from the body by large catheter and separated into coupled with evidence that the strategy might not reduce muscle different blood components. The desired toxicity (Stein et al, 2011). No other squalene synthase inhibitors substance can then be removed, with reinfusion have reached advanced stages of clinical development. of remaining blood products to the body. 100 Atherosclerosis the process of cholesterol plaque deposition and Expression of apolipoprotein B inflammation along arterial walls. It can result in Apolipoprotein (apo) B-containing lipoproteins include LDL, very obstruction to blood flow and a tendency to low-density lipoprotein (VLDL), and VLDL remnants. Because these thrombosis with sudden vessel occlusion. lipoproteins may promote atherosclerosis, strategies to prevent Chylomicrons large lipoprotein particle that carries dietary lipid expression of apoB are attractive. However, interference with and is rich in triglyceride. hepatic export of apoB-containing lipoproteins also has the potential to promote hepatic steatosis. Foam cells macrophages or immune cells containing excess 0 cholesterol, largely due to uptake of oxidized LDL. Mipomersen is a 20-base, 2 -O-(2-methoxy) ethyl-modified anti- sense oligonucleotide that targets mRNA encoding apoB100. It 1 High-density ApoA -containing lipoprotein; major function is reduces circulating levels of all lipoprotein species containing lipoprotein (HDL) reverse transport from peripheral sites to liver for apoB100 in humans. In Phases 2 and 3 clinical trials of mipomersen excretion. as monotherapy or added to statins in patients with familial hyper- Intermediate formed by action of lipases on very low-density cholesterolemia (FH), LDL-C reductions of up to 47% were observed density lipoproteins, resulting in increased cholesterol (Visser et al, 2012). Because mipomersen does not significantly lipoprotein and decreased triglyceride content and smaller affect intestinal apoB48 expression, intestinal fat absorption is unaf- size, compared with VLDL. fected and intestinal steatosis is avoided (Crooke et al, 2005). Lipoprotein particles consisting of surface proteins and However, treatment with mipomersen was associated with injection phospholipid and a neutral lipid core, functioning site reactions, flu-like symptoms, and hepatic steatosis with elevated to transport of lipids throughout the circulation. liver transaminases (Visser et al, 2012). Low-density ApoB-containing lipoprotein. Major carrier of Mipomersen is currently approved for the treatment of homozygous lipoprotein (LDL) cholesterol esters to peripheral cells. familial hypercholesterolemia. However, the long-term benefit/risk Myopathy muscle disease that in general describes muscle profile remains to be determined and might be influenced by weakness or pain. tolerability or hepatic safety. Other approaches to knockdown apoB100, including small interfering RNAs, are under investigation Hepatic steatosis caused by an imbalance of lipid uptake or et al synthesis compared with clearance from the liver. (Tadin-Strapps , 2011). Very low-density carries triglycerides and cholesterol from liver to VLDL assembly – ACAT and MTP lipoprotein peripheral tissue and contains apolipoproteins B, Another approach to reduce LDL is to prevent hepatic secretion of C, and E. its precursor lipoprotein, VLDL,
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