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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EDyslipidemia plays a critical role in cardiovascular (CV) risk. Strong evidence supports that lower low-density lipoprotein cholesterol is better, but there are more questions than answers on what to do about triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C). This article discusses high TGs and HDL-C, emerging CV disease risk factors, as well as novel therapeutic strategies for plasma lipid disorders.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ELipid Disorders\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ELipid Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EEndocrinology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes \u0026amp; Metabolic Syndrome\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EDyslipidemia plays a critical role in cardiovascular (CV) risk. Strong evidence supports that lower low-density lipoprotein cholesterol (LDL-C) is better, but there are more questions than answers on what to do about triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C). Anne Carol Goldberg, MD, Washington University of Medicine, St. Louis, Missouri, USA, addressed high TGs and HDL-C.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003ETG, lipid fractions used for energy storage, are intrinsically synthesized in the liver and derived from external sources through uptake in the intestine [Sarwar N et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2007]. Normal serum TG levels are \u0026lt;150 mg\/dL while levels \u0026gt;500 mg\/dL increase the risk of pancreatitis [Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. \u003Cem\u003EJAMA\u003C\/em\u003E 2001].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003ETG level is a significant CV disease (CVD) risk factor [Sarwar N et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2007]. An estimated 31% of the adult population in the United States has TG levels \u2265150 md\/dL, with no appreciable change between NHANES 1988\u20131994 and 1999\u20132008 [Miller M et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2011]. Subgroup analyses suggest that treatment of dyslipidemia defined as TG\u2265204 mg\/dL and HDL-C \u226434 mg\/dL may decrease CV risk [Sacks FM et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2010].\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EHDL is much more complicated than previously appreciated, with roles in lipid transport and exchange, inflammation, immunity, hemostasis, and complement. Recent trials have failed to show that raising HDL-C decreases CVD [Barter PJ et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2007; Schwartz GG et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2012; The AIM-HIGH Investigators. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2011]. Although some people may have HDL that is proatherogenic [Brewer HB, Jr. \u003Cem\u003EJ Clin Endocrinol Metab\u003C\/em\u003E 2011], HDL appears to decrease CV risk due to antiatherogenic effects, including regulation of glucose metabolism, endothelial repair, and anti-inflammatory and antithrombotic activities [Chapman MJ et al. \u003Cem\u003EEur Heart J\u003C\/em\u003E 2011].\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003ERobert H. Eckel, MD, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA, discussed emerging CVD risk factors. These include apolipoprotein B (apoB), lipoprotein (a), homocysteine, prothrombotic and proinflammatory factors, impaired fasting glucose, and assessment of subclinical atherosclerosis.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EA meta-analysis of prospective studies on apoB and coronary heart disease (CHD) gave a relative risk of 1.99 (95% CI, 1.65 to 2.39) in a comparison of individuals in the top third versus those in the bottom third of baseline values [Thompson A, Danesh J. \u003Cem\u003EJ Intern Med\u003C\/em\u003E 2006]. However, apoB should not replace lipid measurements but might have added value beyond non-HDL-C in patients with low levels of LDL-C \u00b1 statin who have elevated TG (\u0026gt;200 mg\/dL).\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003ESuk Danik et al. [\u003Cem\u003EJAMA\u003C\/em\u003E 2006] found that after adjusting for all pertinent variables, the hazard ratio associated with lipoprotein (a) levels exceeding the 90th percentile (\u226565.5 mg\/dL) was 1.66 (95% CI, 1.38 to 1.99); 95th percentile (\u226583 mg\/dL), 1.87 (95% CI, 1.50 to 2.34); and 99th percentile (\u2265130.7 mg\/dL), 1.99 (95% CI, 1.32 to 3.00), with almost no risk gradient at lower levels. Based on these and other findings, the suggested level of additional concern was when the lipoprotein (a) is \u0026gt;30 mg\/dL.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EClarke et al. [\u003Cem\u003EArch Intern Med\u003C\/em\u003E 2010] evaluated homocysteine as a marker of CVD risk in a meta-analysis of eight randomized trials involving 37,485 individuals. They found that although dietary supplementation with folic acid yielded an average 25% reduction in homocysteine levels, there were no significant effects on vascular outcomes within 5 years.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EIn a primary prevention trial, [Antithrombotic Trialists\u0027 Collaboration. \u003Cem\u003ELancet\u003C\/em\u003E 2009] aspirin yielded a 12% proportional reduction in serious vascular events (0.51% aspirin vs 0.57% control per year; p=0.0001), mainly due to a reduction of about a fifth in nonfatal myocardial infarction (0.18% vs 0.23% per year; p\u0026lt;0.0001). It also increased major gastrointestinal and extracranial bleeds (0.10% vs 0.07% per year; p\u0026lt;0.0001). According to Dr. Eckel, aspirin reduces CHD in high risk men and ischemic CV accidents in high-risk women. It also has borderline benefit in patients with diabetes without known CVD. Patients with diabetes and CVD should be on aspirin unless contraindicated.\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003EOther emerging CVD risk factors include C-reactive protein (CRP), impaired fasting glucose (IFG), and subclinical atherosclerosis. CRP concentration has continuous associations with the risk of coronary disease, ischemic stroke, and vascular mortality [Kaptoge S et al. \u003Cem\u003ELancet\u003C\/em\u003E 2010]. Among those with prediabetes, impaired glucose tolerance increases the risk for CVD events, whereas IFG does not. Budoff et al. [\u003Cem\u003EJ Am Coll Cardiol\u003C\/em\u003E 2007] found that coronary artery calcium was an independent predictor of mortality (model chi-square=2107; p\u0026lt;0.0001).\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EThomas P. Bersot, MD, PhD, University of California, San Francisco, San Francisco, California, USA, discussed novel therapeutic strategies for plasma lipid disorders, in particular homozygous familial hypercholesterolemia (HoFH).\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EHoFH is an extremely rare, refractory, inherited disorder that affects approximately one in a million people in the United States. Those with the disease often suffer myocardial infarction and death before the age of 30. Patients with HoFH respond poorly to currently available therapies.\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003ETreatment strategies focus on reducing very low density lipoprotein (VLDL) and\/or LDL levels through the use of novel drugs. Lomitapide is an inhibitor of microsomal TG transfer protein (MTP) in the gut and liver; mipomersen is an antisense oligonucleotide that prevents translation of apoB100 mRNA in the liver. Monoclonal antibodies that neutralize proprotein convertase subtilisin kexin9 (PCSK9), a crucial protein in LDL-C metabolism [Lambert G. \u003Cem\u003EJ Lipid Res\u003C\/em\u003E 2012], are also being explored.\u003C\/p\u003E\u003Cp id=\u0022p-15\u0022\u003EMTP is required for secretion of VLDL, the precursor to LDL. Lomitapide is an inhibitor of MTP. In a single-arm, open-label, Phase 3 study of the drug, 29 men and women with HoFH, aged \u226518 years, were recruited from 11 centers in 4 countries (USA, Canada, South Africa, and Italy); 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks) [Cuchel M et al. \u003Cem\u003ELancet\u003C\/em\u003E 2013]. The mean dosage of lomitapide was 40 mg daily.\u003C\/p\u003E\u003Cp id=\u0022p-16\u0022\u003ELDL-C was reduced by a mean of 50% (95% CI, \u221262 to \u221239) from baseline (mean 8.7 mmol\/L [SD 2.9]) to Week 26 (4.3 mmol\/L [2.5]; p\u0026lt;0.0001). Concentrations of LDL-C stayed reduced by 44% (95% CI, \u221257 to \u221231; p\u0026lt;0.0001) at Week 56 and 38% (95% CI, \u221252 to \u221224; p\u0026lt;0.0001) at Week 78.\u003C\/p\u003E\u003Cp id=\u0022p-17\u0022\u003EMipomersin sodium, a once-weekly subcutaneous injection, is a first-in-class antisense oligonucleotide inhibitor that targets ApoB-100. Used in addition to maximally tolerated lipid-lowering therapy, it further reduces LDL-C as well as other lipids, including apoB, TG, and non-HDL-C.\u003C\/p\u003E\u003Cp id=\u0022p-18\u0022\u003EPCSK9 inhibition has emerged as one of the most active lines of investigation in cholesterol research, with promising results in a number of Phase 2 trials. Approaches to inhibit PCSK9 include antibodies, RNA interference, and antisense therapy. Currently, 10 pharmaceutical firms have PCSK9-directed therapies in development.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2013 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/13\/10\/16.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nznogp\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}