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Brinton E.A.,Utah Foundation for Biomedical Research | Ballantyne C.M.,Baylor College of Medicine | Bays H.E.,Louisville Metabolic and Atherosclerosis Research Center | Braeckman R.A.,Amarin | Soni P.N.,Amarin
Cardiovascular Diabetology | Year: 2013

Background: Icosapent ethyl (IPE) is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. ANCHOR was a 12-week, phase 3 study that evaluated the efficacy and safety of IPE in patients (N = 702) with residual high fasting TG levels (≥200 and <500 mg/dL) despite having optimized low-density lipoprotein cholesterol (LDL-C) levels (≥40 and <100 mg/dL) on statin therapy. Among patients randomized to IPE (4 g/day or 2 g/day) or placebo, 514 (73%) had diabetes mellitus.Methods: A post hoc subgroup analysis of the ANCHOR study was conducted to assess the effects of IPE on median placebo-adjusted percent change from baseline in efficacy end point parameters in 3 subgroups: total (all subjects with diabetes-overall median baseline glycosylated hemoglobin A1c [A1c] = 6.8%), better-controlled diabetes (below median baseline A1c), and less-controlled diabetes (above median baseline A1c).Results: Baseline efficacy parameters were similar among all groups except high-sensitivity C-reactive protein (hsCRP), which was higher in the total and less-controlled diabetes groups. Compared with placebo, IPE 4 g/day significantly reduced TG, non-high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol (VLDL-C), lipoprotein-associated phospholipase A2, apolipoprotein B (Apo B), total cholesterol, high-density lipoprotein cholesterol, VLDL-TG, oxidized LDL, and remnant-like particle cholesterol in all 3 diabetes groups, LDL-C in the total diabetes group, and hsCRP in the total and less-controlled diabetes groups. Decreases in hsCRP and Apo B were much greater in patients with less-controlled diabetes. There were no significant increases in fasting plasma glucose, A1c, insulin, or homeostasis model assessment-estimated insulin resistance in any group.Conclusion: IPE 4 g/day significantly improved lipid and lipid-related parameters without worsening glycemic control in patients with diabetes and mixed dyslipidemia, with possibly greater effects among those with less-controlled diabetes.Trial registration: Clinicaltrials.gov Identifier NCT01047501. © 2013 Brinton et al.; licensee BioMed Central Ltd.

Verma D.R.,University of Utah | Brinton E.A.,Utah Foundation for Biomedical Research
Reviews in Cardiovascular Medicine | Year: 2014

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability in the United States and other developed nations, and is rising rapidly in the rest of the world. Low-density lipoprotein (LDL) is the major atherogenic particle in most patients at high risk for ASCVD events, and statin-based LDL-lowering treatment is the major focus of treatment for prevention of ASCVD. Despite this, an estimated 57 million US adults (25%) still have moderately elevated levels of LDL-cholesterol (LDL-C) > 160 mg/dL, and many others have an LDL-C above the level considered appropriate for their high-risk status. Although statins are very effective for lowering LDL-C, and other classes of LDL-lowering medications are available, many patients still cannot achieve adequate LDL-lowering with maximal tolerated doses of US Food and Drug Administration-approved treatments. Thus, there is an unmet medical need for statin adjuncts in these patients, as well as for statin alternatives in statin-intolerant patients. A recently discovered human protein, proprotein convertase subtilisin/kexin type 9 (PCSK9), plays an important role in LDL metabolism by promoting degradation of the LDL receptor, and thus reducing clearance of LDL and increasing LDL-C levels. Accordingly, inhibition of PCSK9 activity has become an attractive target for drug development for lowering LDL-C, and human monoclonal antibodies against PCSK9, are now in late-stage clinical development. These antibodies are at least as effective as statins for LDL-C lowering (or more so), and their effects are additive to those of statins. To date, they have been well tolerated and apparently safe in clinical trials. Long-term randomized, controlled trials of their safety, tolerability, and ability to reduce ASCVD are now underway. © 2014 MedReviews , LLC.

Martin S.S.,Johns Hopkins Hospital | Blaha M.J.,Johns Hopkins Hospital | Elshazly M.B.,Johns Hopkins Hospital | Brinton E.A.,Utah Foundation for Biomedical Research | And 11 more authors.
Journal of the American College of Cardiology | Year: 2013

Objectives: The aim of this study was to compare Friedewald-estimated and directly measured low-density lipoprotein cholesterol (LDL-C) values. Background: LDL-C is routinely estimated by the Friedewald equation to guide treatment; however, compatibility with direct measurement has received relatively little scrutiny, especially at levels <70 mg/dl now targeted in high-risk patients. Methods: We examined 1,340,614 U.S. adults who underwent lipid profiling by vertical spin density gradient ultracentrifugation (Atherotech, Birmingham, Alabama) from 2009 to 2011. Following standard practice, Friedewald LDL-C was not estimated if triglyceride levels were ≥400 mg/dl (n = 30,174), yielding 1,310,440 total patients and 191,333 patients with Friedewald LDL-C <70 mg/dl. Results: Patients were 59 ± 15 years of age and 52% were women. Lipid distributions closely matched those in the National Health and Nutrition Examination Survey. A greater difference in the Friedewald-estimated versus directly measured LDL-C occurred at lower LDL-C and higher triglyceride levels. If the Friedewald-estimated LDL-C was <70 mg/dl, the median directly measured LDL-C was 9.0 mg/dl higher (5th to 95th percentiles, 1.8 to 15.4 mg/dl) when triglyceride levels were 150 to 199 mg/dl and 18.4 mg/dl higher (5th to 95th percentiles, 6.6 to 36.0 mg/dl) when triglyceride levels were 200 to 399 mg/dl. Of patients with a Friedewald-estimated LDL-C <70 mg/dl, 23% had a directly measured LDL-C ≥70 mg/dl (39% if triglyceride levels were concurrently 150 to 199 mg/dl; 59% if triglyceride levels were concurrently 200 to 399 mg/dl). Conclusions: The Friedewald equation tends to underestimate LDL-C most when accuracy is most crucial. Especially if triglyceride levels are ≥150 mg/dl, Friedewald estimation commonly classifies LDL-C as <70 mg/dl despite directly measured levels ≥70 mg/dl, and therefore additional evaluation is warranted in high-risk patients. © 2013 American College of Cardiology Foundation.

Lu J.,Hoffmann-La Roche | Hubner K.,University of Heidelberg | Nanjee M.N.,University of Utah | Brinton E.A.,Utah Foundation for Biomedical Research | Mazer N.A.,Hoffmann-La Roche
PLoS Computational Biology | Year: 2014

High-density lipoprotein (HDL) is believed to play an important role in lowering cardiovascular disease (CVD) risk by mediating the process of reverse cholesterol transport (RCT). Via RCT, excess cholesterol from peripheral tissues is carried back to the liver and hence should lead to the reduction of atherosclerotic plaques. The recent failures of HDL-cholesterol (HDL-C) raising therapies have initiated a re-examination of the link between CVD risk and the rate of RCT, and have brought into question whether all target modulations that raise HDL-C would be atheroprotective. To help address these issues, a novel in-silico model has been built to incorporate modern concepts of HDL biology, including: the geometric structure of HDL linking the core radius with the number of ApoA-I molecules on it, and the regeneration of lipid-poor ApoA-I from spherical HDL due to remodeling processes. The ODE model has been calibrated using data from the literature and validated by simulating additional experiments not used in the calibration. Using a virtual population, we show that the model provides possible explanations for a number of well-known relationships in cholesterol metabolism, including the epidemiological relationship between HDL-C and CVD risk and the correlations between some HDL-related lipoprotein markers. In particular, the model has been used to explore two HDL-C raising target modulations, Cholesteryl Ester Transfer Protein (CETP) inhibition and ATP-binding cassette transporter member 1 (ABCA1) up-regulation. It predicts that while CETP inhibition would not result in an increased RCT rate, ABCA1 up-regulation should increase both HDL-C and RCT rate. Furthermore, the model predicts the two target modulations result in distinct changes in the lipoprotein measures. Finally, the model also allows for an evaluation of two candidate biomarkers for in-vivo whole-body ABCA1 activity: the absolute concentration and the % lipid-poor ApoA-I. These findings illustrate the potential utility of the model in drug development. © 2014 Lu et al.

Brinton E.A.,Utah Foundation for Biomedical Research
Current Atherosclerosis Reports | Year: 2012

These review discuses the effects of ethanol on lipoprotein levels and function as related to atherosclerosis and cardiovascular disease (CVD), with special emphasis on recent publications. Ethanol's effects on high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), triglycerides (TG), and other CVD risk factors recently have been explored. Other new data address genetic and demographic predictors and mechanisms of these responses. Not surprisingly, the results of some recent studies corroborate, whereas others differ from, earlier seemingly well-established findings. Prior and recent evidence shows favorable changes in HDL, other CVD risk factors, and CVD event rates with moderate, regular ethanol intake, and recent publications have explored the mechanisms of this relationship. Application of these findings in clinical practice remains problematic, however, due to the lack of randomized, controlled clinical trials of ethanol and due to the potential hazards of ethanol consumption. © Springer Science+Business Media, LLC 2012.

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