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

Abstract

BackgroundProprotein 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 ResultsFasting 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).ConclusionsPCSK9 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.

Insights Into PCSK9, Low-Density Lipoprotein Receptor, and Low-Density Lipoprotein Cholesterol Metabolism

“…This is further supported by their studies where infused hPCSK9 resulted in reduced clearance rates, reduced intracellular PCSK9 accumulation, and increases in serum PCSK9 levels that were directly related to LDLR activity: fastest and lowest in wild type, slower and moderately elevated in LDLR +/− , and slowest and highest in LDLR −/− mice. These finding are consistent with the recent report by Raal et al 5 of serum PCSK9 levels in untreated patients with the equivalent clinical syndromes of homozygous (Ho) and heterozygous (He) familial hypercholesterolemia (FH) compared with a control group with normal lipid levels.…”

“…The most recent human studies show that PCSK9 levels are elevated ≈2-fold in untreated subjects with HeFH and 2-to 3-fold in those with HoFH compared with 3-and 6-fold increases in LDL-C, respectively. 5 The defective LDLR function seen in human subjects with He-or HoFH…”

Effect of the Proprotein Convertase Subtilisin/Kexin 9 Monoclonal Antibody, AMG 145, in Homozygous Familial Hypercholesterolemia

“…In terms of relevancy for all HoFH patients, it is important to note that in 2 large studies 9,21 of >200 HoFH patients, 70% to 75% had mutations consistent with defective LDL receptor function, with ≈15% receptor negative and the remainder unknown. If the response seen in this trial is confirmed, AMG 145 may offer an additional therapeutic option for a large number of these patients.…”

Šeiminė Hipercholesterolemija

“…PCSK9 -fermentas, atsakingas už MTL receptorių degradaciją. Žinomos tiek "gain-offunction" PCSK9 geno mutacijos, kurios nulemia paspartėjusią MTL receptorių degradaciją bei padidėjusią MTL-C koncentraciją kraujyje, tiek "loss of function" mutacijos, sukeliančios hipocholesterolemiją [17]. Tyrimų duomenimis, ŠH dažniausiai nulemia MTL receptoriaus mutacijos (52-76 proc.…”