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Canadian Journal of Cardiology

The Atherogenic Dyslipidemia Complex and Novel Approaches to Cardiovascular Disease Prevention in Diabetes

  • Priska Stahel
    Affiliations
    Department of Medicine, Department of Physiology, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada

    Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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  • Changting Xiao
    Affiliations
    Department of Medicine, Department of Physiology, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada

    Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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  • Robert A. Hegele
    Affiliations
    Robarts Research Institute and Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
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  • Gary F. Lewis
    Correspondence
    Corresponding author: Dr Gary F. Lewis, Toronto General Hospital, 200 Elizabeth St, EN12-218, Toronto, Ontario M5G 2C4, Canada. Tel.: +1-416-340-4270; fax: +1-416-340-3314.
    Affiliations
    Department of Medicine, Department of Physiology, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada

    Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
    Search for articles by this author
Published:December 14, 2017DOI:https://doi.org/10.1016/j.cjca.2017.12.007

      Abstract

      Despite the effectiveness of low-density lipoprotein (LDL)-lowering strategies for the treatment of diabetic dyslipidemia, significant residual risk of atherosclerotic cardiovascular disease remains. Residual risk might in part be explained by lipid abnormalities that go beyond LDL cholesterol elevation, collectively termed the “atherogenic dyslipidemia complex (ADC),” consisting of hypertriglyceridemia, elevated small dense LDL particles, reduced high-density lipoprotein cholesterol, and high-density lipoprotein particle numbers, increased remnant lipoproteins, and postprandial hyperlipidemia. In this review, we briefly discuss the pathophysiology of the typical dyslipidemia that occurs in insulin-resistant states including obesity, the metabolic syndrome, and type 2 diabetes. Lipid-modifying strategies including lifestyle modification, ezetimibe, statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors in treating ADC are discussed. With the advent of novel therapies involving antisense oligonucleotides and monoclonal antibodies, new targets can be specifically downregulated to potentially promote lipoprotein clearance or suppress production. We review novel approaches currently undergoing clinical testing and we speculate on their suitability for use in treating ADC for the prevention of atherosclerotic cardiovascular disease. In addition, future targets that might be considered for therapeutic development are discussed.

      Résumé

      Malgré l’efficacité des stratégies de réduction du taux de lipoprotéines de faible densité (LDL) dans le traitement de la dyslipidémie du diabétique, un important risque résiduel de maladie cardiovasculaire athéroscléreuse demeure. Ce risque résiduel pourrait être en partie expliqué par des anomalies lipidiques autres que la hausse du cholestérol LDL, collectivement appelées dyslipidémies athérogènes et comprenant l’hypertriglycéridémie, le taux élevé de petites particules LDL denses, la diminution du cholestérol à lipoprotéines de haute densité et de particules de lipoprotéines de haute densité, l’augmentation de lipoprotéines reliquats et l’hyperlipidémie postprandiale. Dans cette analyse, nous abordons brièvement la physiopathologie de la dyslipidémie type qui survient en cas d’insulinorésistance, observée en présence d’obésité, de syndrome métabolique et de diabète de type 2. Nous abordons les stratégies visant à corriger la lipidémie, comme la modification du mode de vie, l’ézétimibe, les statines, les fibrates, la niacine et les inhibiteurs de la protéine de transfert de l’ester de cholestéryle, pour traiter les dyslipidémies athérogènes. Avec la venue de nouveaux traitements comportant des oligonucléotides antisens et des anticorps monoclonaux, les nouvelles cibles peuvent être particulièrement abaissées pour potentiellement favoriser la clairance des lipoprotéines ou en supprimer la production. Nous étudions des méthodes novatrices impliquant des épreuves cliniques existantes et nous spéculons sur la possibilité de leur utilisation dans le traitement des dyslipidémies athérogènes pour prévenir la maladie cardiovasculaire athéroscléreuse. De plus, nous abordons de futures cibles qui pourraient être considérées dans la mise au point de traitements.
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