Elevated PCSK 9 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 ( PCSK 9) 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 PCSK 9 levels. Methods and Results Fasting lipograms and PCSK 9 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). PCSK 9 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 PCSK 9 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 PCSK 9 and LDL ‐C (r=0.6769; P <0.0001); however, this was eliminated following statin therapy (r=0.2972; P =0.0625). Conclusions PCSK 9 levels are elevated in untreated FH patients, particularly in those with HoFH . High‐dose statin therapy further increases PCSK 9 levels. PCSK 9 inhibitors might be a beneficial therapy for FH patients, even in those with HoFH .