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

Abstract

Total word count (including tables and figure legends): 3927 Number of tables and figures : 4 ABSTRACT (Word count 250) Background and aims -PCSK9 is an endogenous inhibitor of 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=1,751; 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 multivariate 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.

Depression and cardiovascular risk—association among Beck Depression Inventory, PCSK9 levels and insulin resistance

“…This evidence was confirmed in the Dallas Heart Study, reporting that PCSK9 levels were significantly associated with glucose metabolism, including HOMA-IR [ 65 ]. These findings have been partially confirmed in prospective cohort studies in which plasma PCSK9 levels were positively correlated with HOMA-IR, but not with glucose homeostasis [ 66 ]. Finally, in patients with stable CVD, low PCSK9 plasma levels were associated with a metabolic pattern characterized by low HDL cholesterol, the metabolic syndrome, elevated BMI, insulin resistance and diabetes with diffuse non-obstructive coronary atherosclerosis [ 67 ].…”

Depression and Cardiovascular Risk - Association Among Beck Depression Inventory, PCSK9 Levels and Insulin Resistance

“…This evidence was con rmed in the Dallas Heart Study, reporting that PCSK9 levels were signi cantly associated with glucose metabolism, including HOMA-IR [65]. These ndings have been partially con rmed in prospective cohort studies in which plasma PCSK9 levels were positively correlated with HOMA-IR, but not with glucose homeostasis [66]. Finally, in patients with stable CVD, low PCSK9 plasma levels were associated with a metabolic pattern characterized by low HDL cholesterol, the metabolic syndrome, elevated BMI, insulin resistance and diabetes with diffuse non-obstructive coronary atherosclerosis [67].…”

Genome-wide association of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) plasma levels in the ELSA-Brasil study

“…It is positively associated with albumin, liver enzymes (ALT, ALP, AST, GGT) and with hepatic steatosis, although whether this association is confounded by or mediated by LDL-C is still unclear [18]. Another important point to be considered is that there is great interindividual variation in both PCSK9 levels and response to PCSK9 inhibitors [8,19,20]. In addition, only about 20% of circulating PCSK9 variance can be explained by clinical variables.…”

“…106 without cardiovascular, renal or hepatic diseases (exclusion criteria: self-reported history 107 of medical diagnosis of these pathologies), and who did not report prescription of lipid-108 lowering agents, were eligible for a PCSK9 ancillary and exploratory study. From the 109 1,751 randomly selected participants fulfilling the inclusion criteria for subsequent 110 PCSK9 plasma concentrations measurements [8], we have used the 810 who had…”