pcsk9 inhibitor
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2021 ◽  
Author(s):  
Fang Yuan Li ◽  
Pucong Ye ◽  
Yu Hao ◽  
Juan Du ◽  
Hang Zhang ◽  
...  

Abstract Background: Homozygous/compound heterozygous familial hypercholesterolemia (HoFH/cHeFH) is characterized by extremely elevated low-density lipoprotein-cholesterol (LDL-C) levels that have been reported to contribute to a long-term chronic systemic inflammation. The aims of this study are to describe the inflammatory profile of HoFH/cHeFH patients and explore the effect of PCSK9 inhibitor (PCSK9i) on a series of inflammatory biomarkers, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-HDL ratio (MHR), monocyte-lymphocyte ratio (MLR) and mean platelet volume-lymphocyte ratio (MPVLR). Methods: In this prospective cohort study, 21 definitive HoFH/cHeFH on high-intensity statins plus ezetimibe were placed on subcutaneous injections of PCSK9i 450mg every 4 weeks (Q4W). The biochemical parameters and inflammatory profile were analyzed at the day before PCSK9i therapy, 3 months and 6 months after PCSK9i therapy.Results: We found that HoFH/cHeFH on maximum tolerated statin dose plus ezetimibe displayed an elevated lipid and disturbed blood biomarker profile. After 3 months of add-on PCSK9i therapy, a significant reduction of LDL-C was observed. Meanwhile, percentage and count of neutrophils, monocyte counts, MPV, as well as two inflammatory biomarkers, NLR and MLR were reduced. However, at 6-month PCSK9i treatment, NLR and MLR returned to pre-PCSK9i treatment levels.Conclusions: PCSK9i induces a transient decrease in NLR and MLR in HoFH/cHeFH patients. Our results add evidence in evaluating the effects of PCSK9i on systemic inflammation.


2021 ◽  
Author(s):  
Dan Zhao ◽  
Xue-qin Zhang ◽  
Wen-jing Guo ◽  
Zhi-hui Cui ◽  
Yi-cheng Wang ◽  
...  

Abstract Ovarian failure in postmenopausal female leads E2 to dramatic decrease which is an important reason of menopausal dyslipidemia. PCSK9 as a secretory lipid metabolic regulator plays a critical role in the cholesterol metabolism by negatively regulating LDLR in hepatocytes. Clinical data showed PCSK9 was elevated and positively correlated with LDL-C in the blood of postmenopausal women. However, the relationship between E2 and PCSK9 and the role of PCSK9 in postmenopausal dyslipidemia are still unclear. In this research, 10-week-old ovariectomized mice were fed for 4 weeks with normal diet or high-fat diet, then tested the lipid metabolism profiles and PCSK9 in the blood and the expression of LDLR and PCSK9 in the liver. On this basis, PCSK9-/- ovariectomized mice were used to further verify the effect of PCSK9 in dyslipidemia of ovariectomized mice. Finally, the ovariectomized mice with high-fat diet were subcutaneous injected respectively with E2 or PCSK9 inhibitor alone or both together for 2 weeks and were tested as previous experiment. The results showed PCSK9, TC and LDL-c all increased in the blood of in WT ovariectomized mice and their PCSK9 is positively correlated with LDL-c, while there were on obvious lipid metabolism disorder in the PCSK9−/− ovariectomized mice. PCSK9 inhibitor increased the LDLR on the liver and ameliorated the dyslipidemia in WT ovariectomized mice. It suggests that PCSK9 plays an important role in the dyslipidemia of ovariectomized mice, which provides a new strategy for clinical diagnosis and treatment of the dyslipidemia in post-menopause.


2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
M Naegele ◽  
Y Raemy ◽  
J Barthelmes ◽  
L Kreysing ◽  
T Haider ◽  
...  

Abstract Background Hypercholesterolemia is associated with endothelial dysfunction. While good evidence exists for the beneficial endothelial effects of first-line lipid-lowering drugs (statins), less is known on the new class of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. This is particularly true for the differential effects on micro- and macrovascular endothelial function and arterial stiffness. Purpose The goal of this study was to study the change in retinal microvascular dysfunction, brachial artery endothelial function and arterial stiffness in high-risk cardiovascular risk patients before and after initiation of PCSK9 inhibitor therapy with alirocumab or evolocumab. Methods In this prospective observational study, cardiovascular high-risk patients with a clinical indication for PCSK9 inhibitors were included for the measurement of retinal microvascular function (flicker light-induced dilatation of retinal arterioles and venules, FIDart and FIDven respectively; retinal arteriovenous ratio, AVR), brachial artery flow-mediated dilatation (FMD) and arterial stiffness (pulse wave velocity, PWV; augmentation index, AI). Measurements were performed at baseline, after 3 months and after 12 months of PCSK9 inhibitor therapy. The primary endpoint was the change in FIDart after 12 months of therapy compared to baseline. Results We recruited 48 patients (mean age 57±11 years, 27% female, 81% coronary artery disease) which began treatment with alirocumab or evolocumab in our lipid outpatient clinic. 6 patients were excluded from the analysis (n=3 stopped due to side effects, n=1 stopped due to new metastatic cancer, n=1 moved abroad, n=1 no retinal vessel analysis possible). LDL cholesterol was reduced from 3.8±1.2 to 1.5±0.8 and 1.8±0.9 mmol/L at 3 and 12 months respectively (all p<0.001). There was no significant change in systolic blood pressure during therapy. The primary endpoint FIDart was significantly increased after 12 months of PCSK9 inhibitor therapy compared to baseline (3.4±2.3 vs. 2.6±1.6%, p=0.01). Among the secondary endpoints, augmentation index improved at 12 months vs. baseline (21±12 vs. 24±9%, p=0.03). No significant change was seen for FIDven, AVR, FMD and PWV after 3 and 12 months of therapy. Conclusion In cardiovascular high-risk patients, PCSK9 inhibition is associated with an improvement of retinal microvascular function and augmentation index after one year of therapy. No effects were seen for macrovascular parameters such as FMD or PWV in our cohort. FUNDunding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): University Hospital Zurich, AGLA Grant (sponsored by Amgen)


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