Proprotein Convertase Subtilisin/kexin Type 9 Inhibitor Therapy Research Articles

Challenges in the management of familial hypercholesterolemia: a case report

BackgroundFamilial hypercholesterolemia (FH) is a serious genetic condition that results in abnormally high levels of low-density lipoprotein cholesterol (LDL-C) in the bloodstream, significantly increasing the risk of early onset of cardiovascular disease. The heterozygous form of FH (HeFH) is widespread, affecting around 1 in 500 people worldwide.Case reportIn this clinical report, we present the case of a patient who suffers from HeFH due to a mutation in the LDL receptor (LDLR) gene. A woman exhibited intolerance to statin therapy and did not attain adequate reduction in low-density lipoprotein cholesterol (LDL-C) levels on ezetimibe monotherapy. Genetic testing confirmed the presence of a pathogenic variant for FH with the deletion of exons 7–14. The administration of alirocumab (a dose of 150 mg sc) as the primary therapy did not exhibit the desired therapeutic outcome. Consequently, the patient was given inclisiran therapy (a dose of 284 mg sc), which significantly reduced LDL cholesterol levels after 3 months of treatment and during the 1-year follow-up.ConclusionInclisiran therapy has shown promising results for individuals with HeFH who experience statin intolerance. This therapy works by using a small interfering RNA (siRNA) to target the mRNA of proprotein convertase subtilisin/kexin type 9 (PCSK9), which leads to a significant reduction of LDL-C levels. This approach can be an alternative for patients without significant reductions in LDL-C levels with PCSK9 inhibitor therapy. For HeFH patients with limited treatment options due to statin intolerance and genetic mutations, inclisiran can represent a promising therapeutic option.

PCSK9 inhibitor added to high-intensity statin therapy to prevent cardiovascular events in patients with acute coronary syndrome after percutaneous coronary intervention: a randomized, double- blind, placebo-controlled, multicenter SHAWN study

BackgroundIt is currently uncertain whether the combination of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor and high-intensity statin treatment can effectively reduce cardiovascular events in patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) for culprit lesions. MethodsThis study protocol describes a double-blind, randomized, placebo-controlled, multicenter study aiming to investigate the efficacy and safety of combining a PCSK9 inhibitor with high-intensity statin therapy in patients with ACS following PCI. A total of 1,212 patients with ACS and multiple lesions will be enrolled and randomly assigned to receive either PCSK9 inhibitor plus high-intensity statin therapy or high-intensity statin monotherapy. The randomization process will be stratified by sites, diabetes, initial presentation and use of stable (≥4 weeks) statin treatment at presentation. PCSK 9 inhibitor or its placebo is injected within 4 hours after PCI for the culprit lesion. The primary endpoint is the composite of cardiovascular death, myocardial infarction, stroke, re-hospitalization due to ACS or heart failure, or any ischemia-driven coronary revascularization at 1-year follow-up between 2 groups. Safety endpoints mean PCSK 9 inhibitor and statin intolerance. ConclusionThe SHAWN study has been specifically designed to evaluate the effectiveness and safety of adding a PCSK9 inhibitor to high-intensity statin therapy in patients who have experienced ACS following PCI. The primary objective of this study is to generate new evidence regarding the potential benefits of combining a PCSK9 inhibitor with high-intensity statin treatment in reducing cardiovascular events among these patients.

LONG–TERM FOLLOW–UP IN PATIENTS ON PCSK9 INHIBITOR THERAPY: COMBINING FAST TRACK STRATEGY AND OUTPATIENT MANAGEMENT

Abstract Background Dyslipidemia is a significant risk factor for cardiovascular diseases, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as an effective treatment option. This study aims to investigate the lipid profile in the long–term follow–up of dyslipidemic patients receiving PCSK9 inhibitor therapy in an entirely outpatient setting. Methods We enrolled 381 patients from our dyslipidemia outpatient clinic. Study population included both patients with a first dyslipidemia visit and those discharged from a cardiology unit with fast fast–track protocol. Patients were followed up at 6 (n = 252), 12 (n = 191), and 36 months (n = 77) to assess the effects of PCSK9 inhibitor therapy on lipid profile. Results At the 6–month follow–up, the total cholesterol levels decreased significantly (223.1±35.2 mg/dL vs 129.6±31.9 mg/dL p < 0.001) as LDL cholesterol levels (148±45 vs 72.6±46 mg/dL p < 0.001). The 12–month follow–up maintained similar levels of lowering (total cholesterol 123.6±39 mg/dL LDL 67.5±41 mg/dL p < 0.001) as well as the 36–month follow–up (total cholesterol 138.1±43 mg/dL LDL 71.6±44 mg/dL p < 0.001). No significant reductions in triglycerides and HDL levels were observed during follow–up. Conclusion The study highlights the feasibility and effectiveness of the long–term management of dyslipidemic patients with PCSK9 hypercholesterolemia in an entirely outpatient setting, including patients referred through the fast–track protocol.

Evolocumab Treatment in Pediatric Patients With Homozygous Familial Hypercholesterolemia: Pooled Data From Three Open-Label Studies.

Pediatric patients with homozygous familial hypercholesterolemia (HoFH) have an increased risk of atherosclerotic cardiovascular disease and difficulty meeting low-density lipoprotein cholesterol (LDL-C) goals. In this post hoc analysis, we evaluated pooled safety and efficacy data from 3 studies in pediatric patients with HoFH treated with the PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibody inhibitor evolocumab. Patients with HoFH aged 10 to 17 years received treatment with open-label evolocumab 420 mg subcutaneously monthly or biweekly in the TAUSSIG, RAMAN, or HAUSER-OLE clinical studies. All patients received background statins with or without ezetimibe. Study duration ranged from 12 to 260 weeks. The primary end point was treatment-emergent adverse events per 100 patient-years. Efficacy end points were changes from baseline to week 12 in lipids and PCSK9. Of the 39 patients in the pooled analysis, 69.2% were males, median age was 13.0 years, and 79.5% (31/39) had genotyped HoFH with LDLR pathogenic variants. Overall, median exposure to evolocumab was 18.2 (Q1, Q3: 3.0, 18.5) months. Treatment-emergent adverse events with an exposure-adjusted patient incidence rate of ≥5% were upper respiratory tract infection (6.6%), influenza (5.2%), and acne (5.0%) per 100 patient-years. Exposure-adjusted patient incidence of serious treatment-emergent adverse events was 13.3% per 100 patient-years. Excluding 4 patients receiving lipoprotein apheresis, week 12 median percentage change from baseline in LDL-C was -2.9% (Q1, Q3: -21.7, 1.5); however, 42.9% (15/35) of patients achieved ≥15% reduction in LDL-C from baseline. Residual LDLR (LDL receptor) activity was not associated with a reduction in LDL-C. In this pooled data analysis from 3 studies in pediatric patients with HoFH, evolocumab was well tolerated, with no new safety signals reported. These safety findings are consistent with findings from previous studies of evolocumab. Patients showed marked variability in LDL-C reduction. Results from this pooled analysis support guidelines suggesting a trial of PCSK9 inhibitor therapy regardless of estimated residual LDLR function. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01624142, NCT03403374, and NCT02624869.

Expression of pro- and anti-inflammatory cytokines during anti-proprotein convertase subtilisin/kexin type 9 therapy in patients with statin-resistant familial hypercholesterolemia.

Some clinical dyslipidemia cases do not respond to statins, known as statin-resistant familial hypercholesterolemia (SR-FH), in which patients are under a high cardiovascular risk despite statin therapy. Therefore, novel therapeutic alternatives are required. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) reduce cholesterol levels and cardiovascular disease risk, particularly in patients with SR-FH, where PCSK9i may differentially affect pro- and anti-inflammatory mediators depending on the clinical setting. To evaluate the effect of PCSK9i treatment on pro- and anti-inflammatory cytokines in patients with SR-FH. Before-after comparison, quasi-experimental, single-center study in patients with SR-FH. Blood samples were processed to obtain complete blood counts of glycated hemoglobin and serum lipid levels. Flow cytometry was performed to characterize baseline circulating M1- and M2-macrophages and monocytes. Multiplexing of plasma samples was used to compare plasma fraktaline, interleukins (ILs), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF)-alpha. The endpoints were lower serum lipid levels and pro-inflammatory mediator modification. Twenty patients with SR-FH, aged 58 years and most of them males, were included, with a mean body-mass index of 26.4 and showing ischemic heart disease and similar values of baseline M1- and M2-macrophages and monocytes. Six-month iPSCK-9 therapy considerably reduced LDLc, increased anti-inflammatory cytokine (IL-4), and modified pro-inflammatory cytokine (TNF-alpha and MCP-1) levels. No notable effects were observed for the other markers. PCSK9i therapy exerted subclinical anti-inflammatory and anti-atherogenic effects, indicating potential benefits for clinical outcomes.

Expected eligibility for PCSK9i therapy in secondary prevention, ESC/EAS guidelines vs Irish reimbursement criteria in post PCI patients

Abstract Introduction Reimbursement of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in Ireland is determined by the national center for pharmacoeconomics (NCPE) managed access protocol. To be eligible for a PCSK9i, patients must have had a myocardial infarction or CABG, LDL of >3.5mmol/L, be treated with a high dose statin and ezetimibe. In contrast, the 2019 ESC/EAS dyslipidemias guidelines recommend that patients at ‘very high risk’ with an LDL-C of >1.4mmol/L on a maximally tolerated dose of a statin and ezetimibe, be considered for PCSK9i. In this study, we aimed to define the proportion of patients who are potentially suitable for a PCSK9i at follow-up outpatient post-percutaneous coronary intervention (PCI). Method We retrospectively analysed data on patients who had PCI in University Hospital Limerick (UHL) between January 2016 to December 2019, with follow-up complete lipid profiles at baseline and at 6 - 8 weeks during outpatient review. We sought to compare the potential PCSK9i eligible population in our cohort based on guideline recommendations vs Irish reimbursement criteria. We performed a hierarchal analysis of patients on high dose statin therapy with an LDL-C >1.4mmol/L at follow-up, who could potentially be eligible for a PCSK9i based on expected LDL-C. Expected LDL-C in these patients was calculated based on a 25% reduction in LDL-C with the addition of ezetimibe. Results Our analysis includes 1817 patients, with baseline characteristics; mean age 63.65years, 78.26% male, 40.01% smokers, 20.09% Diabetes Mellitus. 844 (46.45%) patients had a history of MI making them eligible for a PCSK9i based on NCPE clinical criteria. 12 patients (0.66%) in this group were on a high dose statin, and would have an expected LDL-C of >3.5mmol/L with the addition of ezetimibe, therefore making them eligible for a PCSK9i as per NCPE MAP criteria. In contrast to the NCPE MAP criteria all 1817 patients were deemed eligible for a PCSK9i based on ESC/EAS clinical criteria of "very high risk". 1275 patients (70.17%) had an LDL-C level >1.4mmol/L, 6 - 8 weeks post PCI despite high dose statin therapy. Only a minority of patients in this cohort were on ezetimibe, 57/1817 (3.14%). The addition of ezetimibe to patients with an LDL-C >1.4mmol/L, would result in 784 (43.14%) potentially being eligible for a PCSK9i based on current ESC guidelines, results are summarized in figure 1. Discussion Our data highlights the discrepancy between current ESC/EAS guidelines and reimbursement criteria for PCSK9i in Ireland. Based on expected attainable LDL-C minimal patients with coronary artery disease are eligible for reimbursement of a PCSK9i in Ireland for secondary prevention. Our findings also highlight that the majority of patients with established coronary disease do not meet their LDL-C goal at early follow-up. The addition of ezetimibe, would still result in over 40% of our cohort still having a significant lipid burden.

FRI570 Repatha Induced Thyroid Storm

Abstract Disclosure: L.R. Sepulveda-Garcia: None. L.N. Madera Marin: None. L. El Musa Penna: None. W. Medina-Torres: None. M.A. Ortiz-Rivera: None. A. Rosado-Burgos: None. M. Alvarado: None. M. Ramirez: None. L.A. Gonzalez-Rodriguez: None. Introduction: Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are an effective medical therapy for lowering plasma LDL-cholesterol and enhancing the LDL-cholesterol ability of statins. In 2020, a case of transient hyperthyroidism secondary to evolocumab was reported. We present a case of impending thyroid storm after a patient received evolocumab. Patient description: 60 y/o female patient with medical history remarkable for hyperlipidemia, anti-TPO positive non-toxic multinodular goiter, hypertension, fibromyalgia, and coronary artery disease who presented with heat intolerance, palpitations, tremors, and insomnia after second dose of evolocumab. At physical exam found with tachycardia, hypertension, anxious mood, tremors, leg pitting edema +1 bilateral, and deep tendon reflexes +3 in lower extremities, although no palpable or painful goiter. Laboratories compatible with hyperthyroidism [TSH < 0.008 uIU/mL (0.3 – 3.0 uIU/mL), Free T4 4.29 ng/dL (0.89 – 1.76 ng/dL), Total T4 20.03 ug/dL (4.5-12 ug/dL)] and clinically with severe thyrotoxicosis. Patient was sent to ED for further evaluation and management. Case outcomes: Upon admission patient presented with a tonic-clonic seizure with short post ictal state. Burch-Wartofsky scale Point Scale 35, consistent with impending thyroid storm. Thyrotoxicosis management given requiring high doses of PTU, hydrocortisone and propranolol, including the need to add cholestyramine to the regime. By day 9 of therapy, patient was transitioned to methimazole 30mg daily with discontinuation of hydrocortisone and cholestyramine. Upon discharge, 2 weeks later, thyroid function tests had normalized to a FT4 of 1.39 ng/dL and a Total T4 of 9.6 ug/dL. Case discussion: A case of transient hyperthyroidism with PCSK9 inhibitor was previously reported requiring only symptomatic treatment. In this case a patient presented with severe thyrotoxicosis after she received her second dose of evolocumab. PCSK9 inhibitor therapy immunological influence on thyroid remains unknown. This case shows the importance of thyroid function test follow up in patients on PCSK9 inhibitor therapy and the possibility of immunological influence on the thyroid. Presentation: Friday, June 16, 2023

Major cardiovascular events increase in long-term proprotein convertase subtilisin/kexin type 9 inhibitors therapy: the Tuscany cost-effective study.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) represent a breakthrough in the treatment of hypercholesterolemia. The aim of this study was to perform a multicentre prospective analysis on the effects of PCSK9i since their distribution in Italy. During the study period (July 2017 to February 2022) 246 patients (mean age 61 ± 11 years, male 73%) who were evolocumab (142/246) or alirocumab (104/246) new users were enrolled in the CERTI (Costo Efficacia Regione Toscana Inibitori PCSK9) study. Lipid value, adverse events (AEs), major cardiovascular events (MACEs) and intima-media thickness were analysed. PCSK9i therapy allowed a significant improvement in patients' lipid profile [total cholesterol -35%, P < 0.001; triglycerides -9%, P < 0.05; low-density lipoprotein (LDL) cholesterol -51%, P < 0.001; Lp(a) levels -4%, P < 0.05], maintained during the follow-up. No significant variations in intima-media thickness were observed. In the subgroup of patients with more than 1 year of PCSK9i therapy (165/246 patients) we highlighted: a 66% reduction in MACEs compared with the year before recruitment; a progressive increase in MACEs during the follow-up (MACEs event/rate at first year 0.08 vs. MACEs event/rate at year 5: 0.47); a patients cluster with late MACEs older, with higher prevalence of hypertension, smoking habit and peripheral vascular disease. During the follow-up, we recorded AEs in 31% of patients, which mainly resulted in reduction/discontinuation of lipid-lowering therapy for 50 patients or in discontinuation/shift of PCSK9i (respectively 8 and 6 cases). Our data agree with the large evidence on the effectiveness/tolerability of PCSK9i therapy; however, although PCSK9i represents a good cholesterol-lowering therapeutic option, our study shows a progressive increase in MACEs during the late follow-up that deserve further research.

PCSK9 Inhibitor Therapy as an Alternative for Statin Intolerance

Scientific relevance. The main cause of cardiovascular pathologies is atherosclerosis, which is secondary to lipid metabolism disorders, in particular, the accumulation of low-density lipoprotein (LDL) cholesterol. Dyslipidaemia treatment with the largest evidence base predominantly includes statins in combination therapy, but their use is limited by into lerance in some patients. Alternatively, the treatment may include proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.Aim. The study aimed to analyse the applicability of PCSK9 inhibitors in patients with statin intolerance.Discussion. According to the literature analysis, the most common presentation of statin intolerance is statin-associated muscle symptoms. The pathogenesis of statin-associated adverse events is mainly mediated by HMGCoA reductase inhibition, treatment effects on cellular and subcellular processes and skeletal muscles, and patients’ genetic makeup. The mechanism of action of PCSK9 inhibitors is entirely different and involves binding and inactivation of the PCSK9 protein, which lowers blood LDL cholesterol levels. PCSK9 inhibitors have been associated with some adverse drug reactions, most notably immunogenicity; however, PCSK9 inhibitors effectively reduce LDL levels even if patients develop antibodies.Conclusions. Therefore, PCSK9 inhibitors are a safe, well-tolerated, and effec tive therapeutic strategy for hyperlipidaemia in patients with statin intolerance.

Chronic PCSK9 inhibitor therapy leads to sustained improvements in endothelial function, arterial stiffness, and microvascular function.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) effectively decrease low-density lipoprotein cholesterol (LDL-C) and reduce cardiovascular events in patients at very high cardiovascular risk. Recent short-term studies suggest a partially LDL-C independent beneficial effect of PCSK9 inhibitor (PCSK9i) therapy on endothelial function and arterial stiffness, whereas it is unknown if this effect persists and what the effect is on microcirculation. To investigate the effects of PCSK9i therapy on vascular parameters beyond its lipid lowering effect. In this prospective trial, 32 patients at very high cardiovascular risk and indication for PCSK9i therapy were included. Measurements were performed at baseline and after 6 months of PCSK9i treatment. Endothelial function was assessed as flow-mediated dilation (FMD). Arterial stiffness was measured as pulse wave velocity (PWV) and aortic augmentation index (AIx). Peripheral tissue oxygenation (StO2) as a marker of microvascular function was assessed at the distal extremities using near-infrared spectroscopy camera. Six months of PCSK9i therapy decreased LDL-C levels from 141 ± 54 to 60 ± 30 mg/dl (-56 ± 21 %, p < 0.001), FMD significantly increased from 5.4 ± 1.7 % to 6.4 ± 1.9 % (+19 ± 10 %, p < 0.001), PWV decreased in male patients significantly from 8.9 ± 2.1 to 7.9 ± 1.5 m/s (-12 ± 9 %, p = 0.025). AIx decreased from 27.1 ± 10.4 % to 23.0 ± 9.7 % (-16 ± 14 %, p < 0.001), StO2 significantly increased from 67 ± 12 % to 71 ± 11 % (+7 ± 6 %, p = 0.012). Brachial and aortic blood pressure showed no significant changes after six months. There was no correlation between LDL-C reduction and changes in vascular parameters. Chronic PCSK9i therapy is associated with sustained improvements in endothelial function, arterial stiffness, and microvascular function independent from lipid lowering.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and the Risk of Fracture: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Osteoporosis and hyperlipidemia are closely correlated and statins might be associated with a decreased risk of fracture. We aimed to investigate the association between proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) therapy and the risk of fracture. The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to October 22, 2022. Randomized clinical trials (RCTs) that addressed to fracture events of participants using alirocumab, evolocumab, bococizumab or inclisiran, with a follow-up of ≥ 24weeks were included. Meta-analyses were conducted to calculate the odds ratio (OR) with 95% confidence intervals (CIs) for major osteoporotic fracture, hip fracture, osteoporotic non-vertebral fracture, and total fracture. 30 trials assessing PCSK9i among 95, 911 adults were included. There were no significant associations between PCSK9i therapy and the risk of major osteoporotic fracture [OR 1.08 (95% Cl 0.87-1.34), p = 0.49], hip fracture [OR 1.05 (95% Cl 0.73-1.53), p = 0.79], osteoporotic non-vertebral fracture [OR 1.03 (95% Cl 0.80-1.32), p = 0.83], and total fracture [OR 1.03 (95% Cl 0.88-1.19), p = 0.74] over a period of 6-64months. No significant associations were detected in any of the sensitivity analyses and subgroup analyses stratified by the type of PCSK9i, follow-up duration, age, sex, sample size, and patient profile. Pooled results of our meta-analysis showed that exposure to PCSK9i was not associated with reduced risks of fracture in the short term.

555 ADHERENCE AND PERSISTENCE OF PCSK9 INHIBITORS IN CLINICAL PRACTICE: THE REAL-WORLD ITALIAN EXPERIENCE (AT-TARGET-IT STUDY)

Abstract Introduction Hypercholesterolemia is a major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). Proprotein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9i) are recommended in patients with documented ASCVD or Familial Hypercholesterolaemia (FH), not achieving LDL-C target while treated with maximally tolerated dose of lipid-lowering therapy (LLTs). In this conext, single country real-life data, reporting use of PCSK9i in clinical practice are needed. Purpose AT-TARGET-IT is an observational, retrospective, IV phase registry, involving 10 Italian sites, designed to study adherence and persistence of PCSK9i (either Evolocumab or Alirocumab) in patients with ASCVD or FH. Methods All clinical and demographic characteristics were recorded at the time of first prescription and at the latest observation preceding inclusion in the study. Adherence was calculated as Medical Possession Ratio (MPR), defined as the ratio between the drug units dispensed during the treatment period and the duration of the treatment period itself. Persistence was defined as therapeutic continuity from the start of treatment upon enrollment and was assessed at the time points of 6, 12 and 18 months from prescription. Results 798 patients were enrolled. In the overall population, mean age was 62 years (±7.8) and the majority were male (66%). Patients were followed for a median time of 19.33 months. 760 patients (95.2%) showed high adherence to therapy, 13 (1.6%) partial adherence, and 25 (3.1%) no adherence. At 6 month 99.7% of patients enrolled in the study remained on therapy; there were 519 and 423 patients in the study with a follow up of at least 12 and 18 months respectively. Persistence in these groups was 98.1% and 97.5%, respectively. Overall, 28 patients (3.5%) discontinued therapy. No differences in adherence and persistence were found between patients on Alirocumab or Evolocumab. Conclusion The AT-TARGET-IT registry study demonstrated that, in a large single-country real-world population, PCSK9i therapy is extremely successful in routine clinical practice, very high adherence and persistence.

Impact of PCSK9 Inhibition on Proinflammatory Cytokines and Matrix Metalloproteinases Release in Patients with Mixed Hyperlipidemia and Vulnerable Atherosclerotic Plaque.

Atherosclerosis is a disorder in which, in addition to high cholesterol levels, several plasma factors play a significant role in its development. Among these cytokines and molecules are interleukin 6 (IL-6), interleukin 18 (IL-18), tumor necrosis factor α (TNF-α), metalloproteinase 2 (MMP-2), and metalloproteinase 9 (MMP-9), all of which may contribute to the stabilization of atherosclerotic plaque. The purpose of this study was to determine the effect of advanced lipid-lowering therapy on the levels of these determinants by utilizing proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors in patients with verified high-risk atherosclerotic plaque. Methods: The study involved patients with dyslipidemia who had the presence of unstable atherosclerotic plaque verified by ultrasonography and who were eligible to begin alirocumab treatment. The levels of IL-6, IL, 18, TNF-α, and MMPs were determined in this group before and after three months of therapy. After treatment, a statistically significant decrease in concentrations of Il-18, Il-6, TNF-α (p < 0.001) and MMP-2 (p < 0.05) was observed. Additionally, we observed that the concentrations of these markers were significantly higher in the group of patients prior to initiating therapy than in the control group. Our study’s results suggest that PCSK-9 inhibitor therapy significantly reduces the concentration of factors influencing the stability of atherosclerotic plaque, which may explain their essential importance in reducing cardiovascular risk in patients receiving this treatment.

PCSK9 Plasma Levels Are Associated with Mechanical Vascular Impairment in Familial Hypercholesterolemia Subjects without a History of Atherosclerotic Cardiovascular Disease: Results of Six-Month Add-On PCSK9 Inhibitor Therapy.

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a key regulator of low-density lipoprotein (LDL) metabolism involved in the degradation of the low-density lipoprotein receptor (LDLR) through complex mechanisms. The PCSK9 plasma levels change according to lipid lowering therapy (LLT). Few data exist regarding the role of PCSK9 in vascular damage. We aimed to evaluate the impact of PCSK9 plasma levels on pulse wave velocity (PWV) and the effect of PCSK9 inhibitors (PCSK9-i) on circulating PCSK9 and PWV in a cohort of heterozygous familial hypercholesterolemia (HeFH) subjects. In a previous step, HeFH patients were enrolled and LLT was prescribed according to guidelines. Biochemical analyses and PWV assessment were performed at baseline (T0), after 6 months of high-efficacy statin plus ezetimibe (T1) and after 6 months of PCSK9-i (T2). The PCSK9 levels were evaluated in 26 selected HeFH subjects at the three time points and 26 healthy subjects served as controls for the reference value for PCSK9 plasma levels. The PWV values decreased at each time point in HeFH subjects after LLT starting (8.61 ± 2.4 m/s, −8.7%; p < 0.001 vs. baseline at T1, and 7.9 ± 2.1 m/s, −9.3%; p < 0.001 vs. both T1 and baseline) and it was correlated to PCSK9 (r = 0.411, p = 0.03). The PCSK9 levels increased on statin/EZE therapy (+42.8% at T1) while it decreased after PCSK9-i was started (−34.4% at T2). We noted a significant relationship between PCSK9 levels and PWV changes at T1 and T2. In conclusion, PCSK9 levels were associated with baseline PWV values in HeFH subjects; moreover, we found that PCSK9 level variations seemed to be correlated with PWV changes on LLT. A longer observation time and wider sample size are needed to assess the potential role of PCSK9 plasma levels on the vascular function and remodelling, and to clarify the effects of PCSK9-i in these pathways.

Exploring rates of PCSK9 inhibitor persistence and reasons for treatment non-persistence in an integrated specialty pharmacy model

Nearly 40% of patients do not continue proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) therapy after 6 months, despite their ability to lower low-density lipoprotein cholesterol (LDL-C) and risk of cardiovascular events. Limited work has assessed persistence to PCSK9i therapy in an integrated specialty pharmacy model. To assess rates of persistence to PCSK9i therapy and report reasons for non-persistence in patients serviced within an integrated specialty pharmacy. We conducted a single-center, retrospective review of patients prescribed a PCSK9i at an academic health system between September 2015 and August 2018. Persistence was calculated as a binary measure (yes/no) of whether the patient was still receiving PCSK9i therapy at 3-, 12-, and 24-months; frequency distributions described reasons for non-persistence and descriptive statistics described the change in LDL-C from baseline to 24 months. 477 patients met inclusion criteria, 53% were male with median age of 63 years [IQR 56-70]. Median LDL-C at baseline was 157mg/dL and 86% had an atherosclerotic cardiovascular disease indication. Persistence at 3-, 12-, and 24-months was 94%, 80%, and 68%, respectively. Of the 262 patients persistent on PCSK9i therapy at 24 months with LDL-C values available, median LDL-C was 65 mg/dL. The most common reasons for non-persistence at 24 months included medication adverse effects (54%) and loss to follow-up (17%). High rates of persistence to PCSK9i were seen in patients receiving care within an integrated specialty pharmacy model compared with rates in previous studies, suggesting specialty pharmacists may play a role in mitigating many common reasons for PCSK9i non-persistence.

Effectiveness and safety of PCSK9 inhibitor therapy in patients with familial hypercholesterolemia within a therapeutic program in Poland: Preliminary multicenter data.

BackgroundIn Poland, treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has become available free of charge in a therapeutic program. Assessed herein, is the efficacy and safety of alirocumab and evolocumab in patients with heterozygous familial hypercholesterolemia (FH).MethodsData of 55 adult FH patients who participated in the program were analyzed upon meeting the criteria established by the Ministry of Health (low density lipoprotein cholesterol [LDL-C] above 160 mg/dL on max. tolerated statin dose and ezetimib). The efficacy of PCSK9 inhibitors in reducing LDL-C with drug administration every 2 weeks was assessed after 3 months and 1 year of therapy. A safety profile evaluation was performed at each visit. 48 patients completed the 3-month and 21 for the 1-year observation periods (34 patients treated with alirokumab and 14 with evolocumab).ResultsThe mean concentration of direct-measured LDL-C decreased from the initial level of 215.1 ± 74.5 mg/dL to 75.3 ± 64.1 mg/dL, i.e., by 65 ± 14% following 3 months of treatment. This effect was stable in 1-year observation (77.7 ± 72.8 mg/dL). Adverse effects were flu-like symptoms (13.0%), injection site reactions (11.1%), fatigue (5.6%) and musculoskeletal symptoms (5.6%). Seven patients failed to complete the 3-month treatment period due to side effects or non-compliance, and 1 patient failed to complete the 1-year treatment due to myalgia.ConclusionsThis study confirmed high effectiveness of PCSK9 inhibitors in reducing LDL-C levels in patients with FH. Due to restrictive inclusion criteria with LDL-C threshold level > 160 mg/dL (> 4.1 mmol/L) required for participation in the therapeutic program, a relatively small number of FH patients were eligible for treatment.

Case Series: Patients with Hypo-Responsiveness to PCSK9 Inhibitor Therapy

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> Proprotein convertase subtilisin/Kexin type 9 inhibitors (PCSK9i) [alirocumab, evolocumab] are fully human monoclonal antibodies that bind to plasma PCSK9 and prevent LDL receptor degradation. They reduce LDL-C by 50-70% and improve cardiovascular morbidity and mortality by 50% (Gouni-Berthold I.,2017). They are indicated as an adjunct to diet and maximally tolerated statin in individuals with familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional LDL-C lowering. Evolocumab reduced LDL-C by 30% or greater in 99.8% patients, and alirocumab reduced LDL-C by atleast 15% in 98.9% patients (Qamar et al.,2019, Bays et al.,2018). About 87-98% achieve LDL-C goal with PCSK9i (Gouni-Berthold I.,2017). Hence, majority of patients on PCSK9i are expected to have a substantial and consistent LDL-C reduction. But, hypo-responsiveness to PCSK9i (less than 30% LDL-C reduction from baseline at all time points, i.e., beyond two standard deviations of mean for expected LDL-C reduction [Qamar et al.,2019]) are encountered more commonly in the clinical setting than expected. <h3>Objective/Purpose</h3> Assess factors contributing to hypo-responsiveness to PCSK9i. <h3>Methods</h3> A case series of five patients with hypo-responsiveness to PCSK9i reported in table 1. <h3>Results</h3> Unusual response to PCSK9i occur 3-fold higher in real-world than reported in clinical trials (Warden et al.,2020). Maximal PCSK9i LDL-C reduction occurs in 14-days (Chaudhary et al.,2017). In clinical trials, LDL-C was obtained at the end of dosing interval. Evolocumab reduces LDL-C by 85% at midpoint and by 60% at end of dosing interval (Qamar et al.,2019). Less than 15% LDL-C reduction in ODYSSEY trials was reported due to poor adherence to PCSK9i or concurrent lipid-lowering therapy (Bays et al.,2018). All our patients were adherent to treatment and had accurate injection techniques. Our patients have unique genetics and co-morbidities, which might have contributed to interindividual variation and hypo-responsiveness to PCSK9i. Elevated Lp(a) co-measured with LDL-C can contribute to suboptimal response as PCSK9i can lower Lp(a) by 15-30% only (Ruscica et al.,2020). PCSK9 and Lp(a) levels increase in nephrotic syndrome (Pavlakou et al.,2017, Hopewell et al.,2018). Disorders with very low LDL receptor activity can influence response to PCSK9i. There is a potential for immunogenicity, but anti-drug antibodies impact on clinical response to PCSK9i is unknown. There is no evidence of insufficient PCSK9 blockade, difference with switching PCSK9i, or changing injection site. <h3>Conclusions</h3> Careful medication reconciliation and injection technique assessment are the initial steps in evaluating hypo-responsiveness to PCSK9i. Understanding possible etiologies for hypo-responsiveness to PCSK9i might help advance lipid-lowering pharmacology.

Effectiveness and safety of proprotein convertase subtilisin/kexin type 9 inhibitors in patients with familial hypercholesterolemia. Our experience in implementing the drug program of the Polish National Health Fund.

IntroductionHeterozygous familial hypercholesterolemia (FH) is characterized by an elevated plasma low-density lipoprotein cholesterol (LDL-C) concentration despite intensive statin and ezetimibe therapy, which significantly increases the cardiovascular risk.AimThe study evaluated the efficacy and safety of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, in reducing lipids in patients with FH.Material and methodsThis was a single-center analysis of 22 patients diagnosed with FH treated with the PCSK9 inhibitors under the drug program of the National Health Fund. The follow-up interviews and laboratory tests were performed at baseline (22 patients), 3 months (22 patients) and 15 months (9 patients) after the first dose of PCSK9 inhibitors.ResultsThe mean (SD) baseline level of the total LDL-C fraction was 4.7 ±1.6 mmol/l in the whole group of patients and was significantly reduced after 3 and 15 months of PCSK9 inhibitors therapy to 1.7 ±1.6 and 1.6 ±1.1 mmol/l, respectively. The average percentage of reduction in LDL-C level was 64.9 ±23.7% after 3 months and 66.9 ±18.4% after 15 months. In comparison with baseline, a significant reduction in total cholesterol was observed at both time points (p <0.0002). There were no adverse cardiovascular events or significant growth in the level of alanine transaminase, creatinine, and creatine kinase throughout the study.ConclusionsPatients with FH treated with PCSK9 inhibitors achieved a significant reduction of LDL-C and total cholesterol with the safety of this treatment in follow-up.

Association between causative mutations and response to PCSK9 inhibitor therapy in subjects with familial hypercholesterolemia: A single center real-world study

Background and aimsFamilial hypercholesterolemia (FH) is an autosomal dominant disease that leads to cardiovascular (CV) disease. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-I) demonstrated efficacy in low-density lipoprotein cholesterol (LDL-C) reduction and in prevention of CV events. The aim of our study is to evaluate the relationship between LDL receptor (LDLR) mutations and response to PCSK9-I therapy. Methods and resultsWe evaluated total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) in consecutive patients with FH before PCSK9-I treatment and after 12 (T12w) and 36 (T36w) weeks of treatment. We evaluated LDL-C target achievement according to different mutations in LDLR. Eighty FH subjects (mean age:54 ± 13.3 years), 39 heterozygous (He) with defective LDLR gene mutations, 30 He with null mutations and 11 compound-He or homozygous (Ho) were recruited. At baseline, 69 subjects were under maximal lipid lowering therapy (MLLT) and 11 subjects had statin-intolerance. From baseline to T36w we observed an overall 51% reduction in LDL-C. We found no difference in LDL-C changes between subjects with He-defective mutation and He-null mutations both at T12w (p = 1.00) and T36w (p = 0.538). At T36w, LDL-C target was achieved in 59% of He-defective mutations subjects and in 36% of He-null mutations subgroup (p = 0.069), whereas none of compound-He/Ho-FH achieved LDL-C target. ConclusionsAfter 36 weeks there were no differences in response to PCSK9-I therapy between different groups of He-FH subjects. Response to PCSK9-I was significantly lower in carriers of compound-He/Ho mutations.Registration number for clinical trials: NCT04313270 extension.

LDL cholesterol target achievement in heterozygous familial hypercholesterolemia patients according to 2019 ESC/EAS lipid guidelines: Implications for newer lipid-lowering treatments

BackgroundThe 2019 European guidelines (ESC/EAS) for the treatment of dyslipidaemias recommend more aggressive targets for low-density lipoprotein cholesterol (LDL-C) in patients with familial hypercholesterolemia (FH). Current lipid-lowering treatment is often inadequate to achieve these targets. MethodsData from the HELLAS-FH registry were analysed to assess achievement of LDL-C targets in adults with FH based on the 2019 ESC/EAS guidelines. In patients who had not achieved LDL-C target, the maximally reduced LDL-C value was calculated after theoretical switch to rosuvastatin/ezetimibe 40/10 mg/day. The percentage of patients who remained candidates for proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) was then calculated. ResultsPatients (n = 1694, mean age 50.8 ± 14.7 years) had LDL-C levels 242 ± 71 mg/dL (6.3 ± 1.8 mmol/L) at diagnosis. Most treated patients were receiving statins (97.5%) and about half were on additional ezetimibe (47.5%). Based on the 2019 ESC/EAS guidelines the percentage of patients achieving LDL-C goals was only 2.7%. Following theoretical up titration to rosuvastatin/ezetimibe 40/10 mg, LDL-C target achievement rate would increase to 5.9%. In this scenario, most patients (55.9%) would be eligible for PCSK9i treatment. Following theoretical administration of a PCSK9i, LDL-C target achievement rate would rise to 57.6%. However, 42.4% of patients would still be eligible for further LDL-C lowering treatment. ConclusionsMost FH patients do not reach new LDL-C targets even if on maximum intensity statin/ezetimibe treatment. In this case, more than half of FH patients are candidates for PCSK9i therapy and a considerable proportion may still require additional LDL-C lowering.