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. 2013 Apr 24;2(2):e000028.
doi: 10.1161/JAHA.112.000028.

Elevated PCSK9 levels in untreated patients with heterozygous or homozygous familial hypercholesterolemia and the response to high-dose statin therapy

Frederick Raal  1 , Vanessa Panz, Andrew Immelman, Gillian Pilcher
Affiliations

Elevated PCSK9 levels in untreated patients with heterozygous or homozygous familial hypercholesterolemia and the response to high-dose statin therapy

Frederick Raal et al. J Am Heart Assoc. .

Abstract

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.

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Figures

Figure 1.
Figure 1.
Ladder plots showing paired levels of proprotein convertase subtilisin kexin type 9 (PCSK9) before and after high‐dose statin therapy in patients with (a) heterozygous familial hypercholesterolemia (HeFH; n=20), mean±SEM (ng/mL)=202±14 vs 278±20 (P<0.01; paired t‐test) and (b) homozygous familial hypercholesterolemia (HoFH; n=20), mean±SEM (ng/mL)=279±27 vs 338±50 (P>0.05; paired t‐test).
Figure 2.
Figure 2.
Linear regression plot showing the correlation between PCSK9 and LDL‐cholesterol in the combined groups of untreated patients with heterozygous familial hypercholesterolemia (HeFH; n=20), homozygous familial hypercholesterolemia (HoFH; n=20) and control subjects (n=20) (r=0.6769; P<0.0001). PCSK9 indicates proprotein convertase subtilisin kexin type 9; LDL, low‐density lipoprotein.
See this image and copyright information in PMC

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