Lipoprotein Apheresis and Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors in Patients With Heterozygous Familial Hypercholesterolemia: A One Center Study

2020 ◽  
Vol 26 (1) ◽  
pp. 51-58
Author(s):  
Vana Kolovou ◽  
Niki Katsiki ◽  
Stamatis Makrygiannis ◽  
Sophie Mavrogieni ◽  
Nikoletta Karampetsou ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Proprotein Convertase ◽  
Low Density Lipoprotein Cholesterol ◽  
Lipoprotein Apheresis ◽  
Heterozygous Familial Hypercholesterolemia ◽  
Previously Treated

Aim: We evaluated the lipid-lowering (LL) effect of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in patients with heterozygous familial hypercholesterolemia (HeFH) treated with LL-drugs and lipoprotein apheresis (LA). Patients and Methods: The PCSK9i treatment (evolocumab 420 mg/4 weeks, alirocumab 150 mg/2 weeks, or alirocumab 75 mg/2 weeks: 9, 6, and 2 patients, respectively) was initiated in patients with HeFH (n = 17; aged 35-69 years, 10 men, previously treated with statins + ezetimibe ± colesevelam and LA sessions for 2-12 years). A lipid profile was obtained before and immediately after the LA session and before, 1 and 2 months after switching to PCSK9i treatment. The duration of PCSK9i therapy ranged from 3 to 18 months. Results: Median total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) levels before LA were 268, 198, 46, and 126 mg/dL, respectively, and decreased (at the end of the LA session) to 117, 50, 40, and 51 mg/dL, respectively ( P < .001 for TC and P = .001 for all other comparisons). The median time-averaged LDL-C levels following LA were 155 (121, 176; median [25th, 75th percentile]) mg/dL. Median TC, LDL-C, and TG levels before PCSK9i therapy were 269, 190, and 127 mg/dL and decreased to 152, 100, and 95 mg/dL, respectively ( P = .002, P < .002, and P < .03, respectively). Steady LDL-C levels with PCSK9i treatment were significantly lower compared with time-averaged LDL-C levels following LA (median value: 100 vs 155 mg/dL; P = .008). With PCSK9i, from 13 patients with CHD, 6 (46.1%) patients achieved LDL-C <70 mg/dL, and 2 patients (15.4%) achieved LDL-C <100 mg/dL. Lipoprotein apheresis was discontinued in all patients except for 2 who continued once monthly. Conclusions: PCSK9i can reduce LDL-C more consistently over time compared with a transient decrease following LA in HeFH patients. PCSK9i therapy may reduce the frequency of LA. Larger trials are required to establish the clinical implications of PCSK9i in patients previously on LA.

scholarly journals Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town

2020 ◽  
Author(s):  
Roeland Huijgen ◽  
Dirk J. Blom ◽  
Merel L. Hartgers ◽  
Kévin Chemello ◽  
Asier Benito-Vicente ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Proprotein Convertase ◽  
Low Density Lipoprotein Cholesterol ◽  
Cascade Screening ◽  
Gain Of Function

Objective: Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor ( LDLR ) mutations account for >90% of cases, apolipoprotein B ( APOB ) mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 ( PCSK9 ) gain of function mutations are rare (<1% of cases). We aimed to evaluate the functional impact of several novel PCSK9 variants in a cohort of patients with FH by genetic cascade screening and in vitro functionality assays. Approach and Results: Patients with clinically diagnosed FH underwent genetic analysis of LDLR , and if negative, sequential testing of APOB and PCSK9 . We analyzed cosegregation of hypercholesterolemia with novel PCSK9 variants. Gain of function status was determined by in silico analyses and validated by in vitro functionality assays. Among 1055 persons with clinical FH, we identified nonsynonymous PCSK9 variants in 27 (2.6%) patients and 7 of these carried one of the 4 previously reported gain of function variants. In the remaining 20 patients with FH, we identified 7 novel PCSK9 variants. The G516V variant (c.1547G>T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL; P< 0.001). In vitro studies demonstrated the pathogenicity of the G516V variant. Conclusions: In our study, 1.14% of cases with clinical FH were clearly attributable to pathogenic variants in PCSK9 . Pathogenicity is established beyond doubt for the G516V variant.

scholarly journals The consequences of PCSK9 inhibition in selected tissues

2021 ◽  
Vol 75 ◽  
pp. 385-397
Author(s):  
Mateusz Maligłówka ◽  
Łukasz Bułdak ◽  
Bogusław Okopień ◽  
Aleksandra Bołdys
Keyword(s):  
Bacterial Infections ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Lipid Lowering ◽  
Low Density ◽  
Proprotein Convertase ◽  
Low Density Lipoprotein Cholesterol ◽  
Pcsk9 Inhibition

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of nine members of the proprotein convertase family. These serine proteases play a pivotal role in the post-translational modification of proteins and the activation of hormones, enzymes, transcription factors and growth factors. As a result, they participate in many physiological processes like embryogenesis, activity of central nervous system and lipid metabolism. Scientific studies show that the family of convertases is also involved in the pathogenesis of viral and bacterial infections, osteoporosis, hyperglycaemia, cardiovascular diseases, neurodegenerative disorders and cancer. The inhibition of PCSK9 by two currently approved for use monoclonal antibodies (alirocumab, evolocumab) slows down the degradation of low-density lipoprotein cholesterol receptors (LDLRs). This leads to increased density of LDLRs on the surface of hepatocytes, resulting in decreased level of low-density lipoprotein cholesterol (LDL-C) in the bloodstream, which is connected with the reduction of cardiovascular risk. PCSK9 inhibitors (PCSK9i) were created for the patients who could not achieve appropriate level of LDL-C using current statin and ezetimibe therapy. It seems that high therapeutic efficacy of PCSK9i will make them more common in the clinical use. The pleiotropic effects of previously mentioned lipid-lowering therapies were the reasons for literature review of possible positive and negative effects of PCSK9 inhibition beyond cholesterol metabolism.

scholarly journals From lipoprotein apheresis to proprotein convertase subtilisin/kexin type 9 inhibitors: Impact on low-density lipoprotein cholesterol and C-reactive protein levels in cardiovascular disease patients

2018 ◽  
Vol 25 (17) ◽  
pp. 1843-1851 ◽  
Author(s):  
Maria G Zenti ◽  
Anna Altomari ◽  
Maria G Lupo ◽  
Margherita Botta ◽  
Enzo Bonora ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Low Density ◽  
Proprotein Convertase ◽  
C Reactive Protein ◽  
Low Density Lipoprotein Cholesterol ◽  
Lipoprotein Apheresis ◽  
Reactive Protein ◽  
Cholesterol Levels

In this observational study, we compared the effect of lipoprotein apheresis and evolocumab or alirocumab on levels of lipoprotein cholesterol, triglycerides and inflammatory markers (C reactive protein and interleukin 6) in cardiovascular patients ( n = 9). Patients were monitored during the last year of lipoprotein apheresis followed by six months of treatment with proprotein convertase subtilisin/kexin type 9 inhibitors. The biochemical parameters were determined pre- and post- every apheresis procedure for 12 months and then after one, three and six months of treatment with evolocumab (140 mg every two weeks [Q2W]) or alirocumab (75 mg or 150 mg every two weeks [Q2W]). Lipoprotein apheresis significantly reduced low-density lipoprotein cholesterol levels from 138 ± 32 mg/dl to 46 ± 16 mg/dl ( p < 0.001), with an inter-apheresis level of 114 ± 26 mg/dl. Lipoprotein(a) was also reduced from a median of 42 mg/dl to 17 mg/dl ( p < 0.01). Upon anti-proprotein convertase subtilisin/kexin type 9 therapy, low-density lipoprotein cholesterol levels were similar to post-apheresis (59 ± 25, 41 ± 22 and 42 ± 21mg/dl at one, three and six months, respectively) as well as those of lipoprotein(a) (18 mg/dl). However, an opposite effect was observed on high-density lipoprotein cholesterol levels: –16.0% from pre- to post-apheresis and +34.0% between pre-apheresis and proprotein convertase subtilisin/kexin type 9 inhibitors. Apheresis significantly reduced high-sensitivity C-reactive protein levels (1.5 ± 1.2 mg/l pre-apheresis to 0.6 ± 0.6 mg/l post-apheresis), while no changes were found upon proprotein convertase subtilisin/kexin type 9 mAbs administration. In conclusion, our study demonstrated that, by switching from lipoprotein apheresis to anti-proprotein convertase subtilisin/kexin type 9 therapies, patients reached similar low-density lipoprotein cholesterol and lipoprotein(a) levels, increased those of high-density lipoprotein cholesterol, and showed no changes on high-sensitivity C-reactive protein.

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