Statin treatment further increases already elevated PCSK9 levels in FH patients
Abstract
Literature -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 GJ 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
1. Leigh SE, Foster AH, Whittall RA, Hubbart CS, Humphries SE. Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. Ann Hum Genet. 2008;72:485–498.2.Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: current perceptions on diagnosis and treatment. Atherosclerosis. 2012;223:262–268.
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.
4. Maxwell KN, Breslow JL. Proprotein convertase subtilisin kexin 9: the third locus implicated in autosomal dominant hypercholesterolemia. Curr Opin Lipidol. 2005;16:167–172.
5. Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem Sci. 2007;32:71–77.
6. Alborn WE, Cao G, Careskey HE, Qain YW, Subramaniam DR, Davies J, Conner EM, Konrad RJ. Serum proprotein convertase subtilisin kexin type 9 is correlated directly with serum LDL cholesterol. Clin Chem. 2007;53:1814–1819.
7. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med.2006;354:1264–1272.
8. Jeong HJ, Lee HS, Kim KS, Kim YK, Yoon D, Park SW. Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J Lipid Res. 2008;49:399–409.
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.