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Circulating PCSK9 levels are not associated with the conversion to type 2 diabetes

  • Author Footnotes
    1 These authors contributed equally as co-first authors.
    Stéphane Ramin-Mangata
    Footnotes
    1 These authors contributed equally as co-first authors.
    Affiliations
    Université La Réunion, Inserm UMR 1188 DéTROI, Sainte Clotilde, France
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  • Author Footnotes
    1 These authors contributed equally as co-first authors.
    Matthieu Wargny
    Footnotes
    1 These authors contributed equally as co-first authors.
    Affiliations
    L'institut Du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France

    L'institut Du Thorax, Department of Endocrinology, CIC 1413 INSERM, CHU Nantes, Nantes, France

    CHU de Nantes, INSERM, CIC 1413, Pôle Hospitalo-Universitaire 11: Santé Publique, Clinique des Données, Nantes, F-44093, France
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  • Matthieu Pichelin
    Affiliations
    L'institut Du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France

    L'institut Du Thorax, Department of Endocrinology, CIC 1413 INSERM, CHU Nantes, Nantes, France
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  • Cédric Le May
    Affiliations
    L'institut Du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
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  • Aurélie Thédrez
    Affiliations
    L'institut Du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
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  • Valentin Blanchard
    Affiliations
    Université La Réunion, Inserm UMR 1188 DéTROI, Sainte Clotilde, France
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  • Brice Nativel
    Affiliations
    Université La Réunion, Inserm UMR 1188 DéTROI, Sainte Clotilde, France
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  • Raul D. Santos
    Affiliations
    Lipid Clinic Heart Institute (InCor), University of Sao Paulo Medical School Hospital, São Paulo, Brazil

    Hospital Israelita Albert Einstein, São Paulo, Brazil

    Center of Clinical and Epidemiologic Research, University of São Paulo, São Paulo, Brazil
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  • Isabela M. Benseñor
    Affiliations
    Center of Clinical and Epidemiologic Research, University of São Paulo, São Paulo, Brazil
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  • Paulo A. Lotufo
    Affiliations
    Center of Clinical and Epidemiologic Research, University of São Paulo, São Paulo, Brazil
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  • Author Footnotes
    2 These authors contributed equally as co-last authors.
    Gilles Lambert
    Correspondence
    Corresponding author. Inserm UMR 1188 DéTROI, Plateforme CYROI, 2 Rue Maxime Rivière, 97490 Sainte Clotilde, France.
    Footnotes
    2 These authors contributed equally as co-last authors.
    Affiliations
    Université La Réunion, Inserm UMR 1188 DéTROI, Sainte Clotilde, France
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  • Author Footnotes
    2 These authors contributed equally as co-last authors.
    Bertrand Cariou
    Correspondence
    Corresponding author. Clinique d’Endocrinologie, Hôpital Guillaume & René Laennec, Boulevard Jacques Monod, Saint-Herblain, 44093, Nantes Cedex 1, France.
    Footnotes
    2 These authors contributed equally as co-last authors.
    Affiliations
    L'institut Du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France

    L'institut Du Thorax, Department of Endocrinology, CIC 1413 INSERM, CHU Nantes, Nantes, France
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally as co-first authors.
    2 These authors contributed equally as co-last authors.

      Highlights

      • Like statins, PCSK9 inhibitors have been proposed to increase the risk of new onset diabetes (NOD).
      • We show that PCSK9 levels do not predict the transition from prediabetes to NOD.
      • Inhibiting circulating PCSK9 should be safe for glucose homeostasis.

      Abstract

      Background and aims

      PCSK9 is an endogenous inhibitor of the LDL receptor pathway. Recently, Mendelian randomization studies have raised a doubt about the diabetogenic risk of PCSK9 inhibitors. Here, we assessed the relationship between plasma PCSK9 levels and the risk of new onset diabetes (NOD).

      Methods

      Fasting plasma PCSK9 levels were measured at baseline by ELISA in subjects without lipid lowering treatment in IT-DIAB (n = 233 patients with prediabetes, follow-up 5 years) and ELSA-Brasil (n = 1751; 27.5% with prediabetes, follow-up 4 years) prospective cohorts. The primary outcome in both studies was the incidence of NOD. The association of NOD with plasma PCSK9 levels was studied using multivariable Cox models.

      Results

      Plasma PCSK9 levels were not significantly associated with NOD in IT-DIAB (HR (+1SD) 0.96, CI95% [0.76; 1.21]) and ELSA-Brasil (OR (+1SD) 1.13 [0.89; 1.42]). In ELSA-Brasil, a significant positive association between PCSK9 and worsening of glucose homeostasis, including the progression from normoglycemia to prediabetes, was found (OR (+1SD) 1.17 [1.04; 1.30], p = 0.0074). Plasma PCSK9 concentration was also positively associated with the change in fasting plasma glucose between the first and second visit in ELSA-Brasil (β = 0.053, CI95% [0.006; 0.10], p = 0.026). Plasma PCSK9 levels positively correlated with total cholesterol in IT-DIAB and ELSA-Brasil, but not with glucose homeostasis parameters, except for a positive correlation with HOMA-IR in ELSA-Brasil.

      Conclusions

      Plasma PCSK9 levels were not significantly associated with NOD risk in longitudinal analyses. These data suggest that inhibition of the PCSK9 extra-cellular pathway should not be deleterious for glucose homeostasis.

      Graphical abstract

      Keywords

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