Circulating PCSK9 levels are not associated with the conversion to type 2 diabetes
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Updated: Jan 2, 2026
A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Stéphane Ramin-Mangata1, Matthieu Wargny2, Matthieu Pichelin3
1Université La Réunion, Inserm UMR 1188 DéTROI, Sainte Clotilde, France.
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.
Insights
This study found no significant link between plasma PCSK9 levels and new-onset diabetes (NOD) risk. These findings suggest that inhibiting PCSK9 may not negatively impact glucose homeostasis.
Area of Science:
- Cardiovascular Research
- Metabolic Disorders
- Biochemistry
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of LDL receptor metabolism.
- Recent studies have questioned the potential diabetogenic risk associated with PCSK9 inhibitors.
Purpose of the Study:
- To investigate the association between plasma PCSK9 levels and the risk of new-onset diabetes (NOD).
Main Methods:
- Analysis of plasma PCSK9 levels using ELISA in two prospective cohorts (IT-DIAB and ELSA-Brasil).
- Longitudinal assessment of NOD incidence using multivariable Cox models.
- Exploration of associations with glucose homeostasis parameters and HOMA-IR.
Main Results:
- Plasma PCSK9 levels showed no significant association with NOD in either cohort.
- A positive association was observed between PCSK9 levels and worsening glucose homeostasis, including progression to prediabetes, in the ELSA-Brasil cohort.
- PCSK9 levels correlated positively with fasting plasma glucose changes and HOMA-IR in ELSA-Brasil.
Conclusions:
- Plasma PCSK9 levels are not significantly associated with the risk of developing new-onset diabetes.
- Inhibition of the PCSK9 pathway is unlikely to be detrimental to glucose homeostasis.
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