Inhibiting PCSK9 in Dyslipidemia Patients with Diabetes

News about proprotein convertase subtilisin/kexin type 9 (PCSK9) has largely involved its role in the body’s ability to regulate low-density lipoprotein (LDL) cholesterol. Cardiologists welcomed the development of injectable drugs called PCSK9 inhibitors, which reduce LDL cholesterol up to 60%.

Attention is now turning to the potential for PCSK9 inhibitors to treat patients with type 1 diabetes (T1D), who lack the ability to produce insulin. Miao, et al, explored the role of insulin in the regulation of PCSK9 in a 2015 paper,¹ and concluded that while insulin could be a trigger for PCSK9, it did not act alone. But understanding insulin’s role in regulating PCSK9 was important to gain insight into whether the use of PCSK9 inhibitors made sense in patients with T1D, who suffer much higher rates of cardiovascular disease, in part due to dyslipidemia.

In a study published Tuesday in Diabetes Care, researchers funded by the National Institutes of Health and JDRF looked into levels of PCSK9 in younger patients with T1D. While the enzyme is known to be elevated in patients with obesity and type 2 diabetes (T2D), “it is not known whether PCSK9 levels are also changed in individuals with T1D.”²

Researchers led by Amy E. Levenson, MD, of Boston’s Children’s Hospital measured PCSK9 levels in 176 youth with T1D (mean age 15.2 years), with 74 controls (mean age 15.4 years). Their hypothesis proved fruitful: the young patients had higher systolic and diastolic blood pressure measures, as well as elevated levels of apolipoprotein B, which can appear even in patients whose T1D is well-controlled.

While youth with T1D had normal levels of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, their serum PCSK9 concentrations were much higher than youth in the control group. Females in the control group and in the T1D group had higher PCSK9 levels than males, respectively. PCSK9 levels for control group males were 187 ± 67 ng/mL; control group females, 215 ± 83 ng/mL; T1D males, 253 ± 98 ng/mL; and T1D females, 299 ± 106 ng/mL. Researchers also noted that for youth with T1D, PCSK9 was significantly correlated with glycated hemoglobin (A1C).

The authors noted 3 findings:

• PCSK9 levels are higher in those with T1D than those without diabetes; insulin increases PCSK9 expression, and levels in T1D adults track insulin doses.
• For those with T1D, PCSK9 levels are correlated with A1C, which has been seen in other studies and consistent with the level of dyslipidemia seen in T1D patients with poor glycemic control.
• PCSK9 levels are higher in females, consistent with earlier studies. However, the authors tested the assumption that this is related to sex steroids and did not find differences in the females who were prepubescent or in early puberty.

“Future work will be necessary to understand the contribution of PCSK9 to the dyslipidemia and increased CVD risk associated with T1D, particularly in females,” the authors concluded.

A symposium on the inhibition of PCSK9 in dyslipidemia patients with diabetes is scheduled for Sunday, June 11, 2017, at the 77^th Scientific Sessions of the American Diabetes Association, taking place in San Diego, California.

References

1. Miao J, Manthena PV, Haas ME, et al. The role of insulin in the regulation of PCSK9. Arterioscler Throm Vasc Biol. 2015; 35(7):1589-1596.

2. Levenson AE, Wadwa RP, Shah AS, et al. PCSK9 is increased in youth with type 1 diabetes [published online June 6, 2017]. Diabetes Care. 2017; https://doi.org/10.2337/dc16-2563.