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

Raal F, Panz V, Immelman A,  Pilcher G
J Am Heart Assoc. 2013;2:e000028 doi: 10.1161/JAHA.112.000028)

Background

Familial hypercholesterolemia (FH)  is often caused by a mutation in the LDL-receptor (LDLR)[1]. Being receptor negative (<2% residual LDLR activity) gives a worse prognosis than being receptor-defective (2-25%) residual activity)[2].
Some patients with FH have been found to carry mutations in the proprotein convertase subtilisin kexin type 9 (PCSK9) gene [3,4]. PCSK9 is a protease which binds to hepatic LDLR. It directs LDLR to the lysosomes for degradation, thereby preventing the normal recycling of LDLR to the cell surface, and reducing LDL-C clearance. Thus PCSK9 levels tend to correlate with plasma LDL-C [5,6]. Loss-of-function mutations in PCSK9 have been associated with lower LDLR degradation and low LDL-C [7], whereas gain-of-function mutations cause elevated LDL-C and higher CV risk [3].
Statins lower LDL-C levels by inhibiting the rate-limiting step in hepatic cholesterol synthesis and upregulating LDLR. However, statins also  upregulate PCSK9 expression [8].
This study aimed to investigate PCSK9 levels in untreated homozygous (HoFH) and heterozygous FH (HeFH) patients, and to determine the effect of high-dose statin treatment on the relationship between PCSK9 and LDL-C levels. Early morning fasting lipograms and PCSK9 levels were measured. A subset of patients was treated with either 80 mg atorvastating or 40 mg rosuvastatin daily, for at least 4 weeks after which blood tests were repeated.

Main results

• PCSK9 levels are elevated in untreated HoFH (279 +/- 27 ng/ml) and untreated HeFH (202 +/- 14 ng/ml) as opposed to control individuals (132 +/- 10 ng/ml, P<0.01 for both comparisons).
• After high-dose statin treatment, PCSK9 had increased with 37% in HeFH (P<0.01), but not statistically significantly increased in HoFH (21%). PCSK9 increased after statin treatment in 18/20 HeFH patients, and in 10/20 HoFH patients.
• PCSK9 levels correlated positively with total cholesterol levels (r=0.6745, P<0.0001) and LDL-C (r=0.7282, P<0.0001), but correlations were lost after statin treatment (total cholesterol: r=0.2922, P=0.0672, LDL-C: r+0.2972, P=0.0625).

Conclusion

PCSK9 levels were particularly elevated in untreated HoFH but also in HeFH, and levels correlated with total cholesterol and LDL-C, although these correlations disappeared after statin treatment, upon which LDL-C levels lowered  and PCSK9 increased. PCSK9 increased in 50% of HoFH patients, whereas its levels rose more consistently in HeFH. Elevation of PCSK9 levels might blunt the efficacy of statins by further diminishing LDLR levels. This might explain why doubling statin dose only gives modest further reduction of LDL-C. The current results support the view that PCSK9 inhibitors in combination with statins, can reduce LDL-C levels further in patients with FH, even when LDLR are defective.

References

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3.Abifadel M, Varret M, Rab s JP, Allard D, Ouguerram K, De Villiers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derr_e A, Vill_eger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J,Prat A, Krempf M, Junien C, Seidah NG, Boileu C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;134:154–156.
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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.