Elevated PCSK9 Levels in Untreated Patients With Heterozygous or Homozygous Familial Hypercholesterolemia and the Response to High-Dose Statin Therapy

Background-Proprotein convertase subtilisin kexin type 9 (PCSK9) is an enzyme that impairs low-density lipoprotein cholesterol (LDL-C) clearance from the plasma by promoting LDL receptor degradation. Patients with familial hypercholesterolemia (FH) have reduced or absent LDL receptors and should therefore have elevated PCSK9 levels. Methods and Results-Fasting lipograms and PCSK9 levels were measured 51 homozygous FH (HoFH), 20 heterozygous FH (HeFH), and 20 normocholesterolemic control subjects. Levels were repeated following high-dose statin therapy. LDL-C levels were significantly higher in untreated HoFH (13.4 +/- 0.7 mmol/L) and HeFH patients (7.0 +/- 0.2 mmol/L) compared with controls (2.6 +/- 0.1 mmol/L) (P<0.01). Statin therapy decreased LDL-C levels from 13.4 +/- 0.7 to 11.1 +/- 0.7 mmol/L in HoFH and from 7.0 +/- 0.2 to 3.6 +/- 0.2 mmol/L in HeFH patients (P<0.01). PCSK9 levels were higher in untreated HoFH (279 +/- 27 ng/mL) and HeFH (202 +/- 14 ng/mL) than in controls (132 +/- 10 ng/mL) (both P<0.01). High-dose statin therapy increased PCSK9 levels from 279 +/- 27 to 338 +/- 50 ng/mL in HoFH, and significantly so in the HeFH patients from 202 +/- 14 to 278 +/- 20 ng/mL (P<0.01). Linear regression analysis showed a correlation between PCSK9 and LDL-C (r=0.6769; P<0.0001); however, this was eliminated following statin therapy (r=0.2972; P=0.0625). Conclusions-PCSK9 levels are elevated in untreated FH patients, particularly in those with HoFH. High-dose statin therapy further increases PCSK9 levels. PCSK9 inhibitors might be a beneficial therapy for FH patients, even in those with HoFH.