Lipid-lowering effects of PCSK9 lost in uncontrolled diabetes
MedWire News: The link between plasma pro-protein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein (LDL) catabolism is different in patients with Type 2 diabetes than in those without the condition, French researchers report.
PCKS9 can impact on the catabolism of LDL in nondiabetic individuals, but not in patients with uncontrolled Type 2 diabetes, they say.
PCSK9 is an inhibitor of the LDL receptor and PCKS9 inhibition is thought to be a promising therapeutic way of achieving low levels of LDL-cholesterol in combination with statins. However, the association between PCSK9 concentrations and insulin sensitivity is unclear, say the authors.
As reported in the journal Atherosclerosis, Bruno Verges (INSERM, Dijon, France) and team carried out a kinetic study of LDL-apolipoprotein B100 (LDL-apoB100) in 38 individuals, 15 of whom had Type 2 diabetes.
The researchers found that PCSK9 was negatively correlated with LDL-apoB100 fractional catabolism rate (FCR) in nondiabetic patients.
"LDL-apoB100 FCR is an important modulator of circulating PCSK9 levels since it explained 46% of PCSK9 variance," they say.
However, no such association was found in diabetic patients.
Multivariate analysis revealed that, among the nondiabetics, both PCSK9 and fasting glycemia were associated with LDL-apoB100 FCR whereas other potential confounders, including LDL cholesterol, were not. Plasma PCSK9 and fasting glycemia explained 37% and 13% of LDL-apoB100 FCR variance, respectively.
Further analysis revealed that HbA1c was associated with LDL-apoB100 FCR whereas age, duration of diabetes, triglycerides, and LDL cholesterol were not.
"Altogether these results strongly suggest that circulating PCSK9 is a better marker of LDL catabolism than plasma LDL cholesterol concentration," say the authors.
The researchers further separated the diabetes patients into two groups, a "controlled" diabetes group (HbA1c ≤7%) and an "uncontrolled" group (HbA1c >7%).
"Interestingly, the negative correlation between plasma PCSK9 and LDL-apoB FCR, noted in the non-diabetic population, is observed at a borderline significance in well controlled Type 2 diabetic patients, whereas this correlation is totally lost in Type 2 diabetic patients with uncontrolled diabetes," write Verges and team.
"Thus the absence of a significant correlation between plasma PCSK9 and LDL-apoB FCR in the whole diabetic population was due to the 'uncontrolled' diabetes subgroup," they explain.
The team says the data indicate that PCSK9 and hyperglycemia independently influence LDL catabolism and that in the case of uncontrolled Type 2 diabetes, the influence of diabetes on LDL catabolism may have overwhelmed the influence of PCSK9 on LDL FCR.
"In Type 2 diabetes, glycemic control is an important factor modifying the relationship between PCSK9 and LDL catabolism, which should be taken into account when analyzing the effect of the future PCSK9 inhibitors in this specific population," they conclude.
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By Sally Robertson