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.