Stéphane Ramin-Mangata1, Matthieu Wargny2, Matthieu Pichelin3, Cédric Le May4, Aurélie Thédrez4, Valentin Blanchard1, Brice Nativel1, Raul D Santos5, Isabela M Benseñor6, Paulo A Lotufo6, Gilles Lambert7, Bertrand Cariou8. 1. Université La Réunion, Inserm UMR 1188 DéTROI, Sainte Clotilde, France. 2. 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. 3. L'institut Du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France; L'institut Du Thorax, Department of Endocrinology, CIC 1413 INSERM, CHU Nantes, Nantes, France. 4. L'institut Du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France. 5. 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. 6. Center of Clinical and Epidemiologic Research, University of São Paulo, São Paulo, Brazil. 7. Université La Réunion, Inserm UMR 1188 DéTROI, Sainte Clotilde, France. Electronic address: gilles.lambert@univ-reunion.fr. 8. L'institut Du Thorax, INSERM, CNRS, UNIV Nantes, Nantes, France; L'institut Du Thorax, Department of Endocrinology, CIC 1413 INSERM, CHU Nantes, Nantes, France. Electronic address: bertrand.cariou@univ-nantes.fr.
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.
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.
Authors: Francesco Spannella; Federico Giulietti; Roberta Galeazzi; Anna Passarelli; Serena Re; Chiara Di Pentima; Massimiliano Allevi; Paolo Magni; Riccardo Sarzani Journal: Biomedicines Date: 2022-08-12
Authors: C Macchi; C Favero; A Ceresa; L Vigna; D M Conti; A C Pesatori; G Racagni; A Corsini; N Ferri; C R Sirtori; M Buoli; V Bollati; M Ruscica Journal: Cardiovasc Diabetol Date: 2020-11-03 Impact factor: 8.949