PCSK9 Inhibitor Treatment Research Articles

Association between PCSK9 inhibitor with cause-specific morality amongst cancer survivors

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor has emerged as a novel pharmacotherapy for dyslipidemia and been shown to be effective in reducing the risks of atherosclerotic cardiovascular diseases. PCSK9 is aberrantly expressed in a broad spectrum of cancers and has been demonstrated to contribute to cancer prognosis. However, no prior study has investigated the associations between PCSK9 inhibitors (PCSK9i) with cardiovascular and cancer mortality amongst cancer survivors. Purpose This study investigated the effects of PCSK9i on cause-specific mortality amongst cancer survivors. Methods This retrospective study used data from the Tianjin Coronary Artery Disease Cohort, which included medical data from 71 secondary or tertiary hospitals in Tianjin, China. Adult patients with coronary artery disease (CAD) diagnosed with incident cancer between 2017 and 2023 were enrolled in this study. Propensity score matching with a 1:3 ratio for PCSK9i users versus non-users was performed. The primary outcomes included all-cause mortality, cardiovascular mortality, and cancer mortality. Multivariable Cox regression was used to test associations between PCSK9i with outcomes, adjusting for age, gender, cardiovascular and non-cardiovascular comorbidities, lipid-lowing agents and other medication use, lipid level, as well as cancer characteristics. Multivariable competing risk analysis was used as sensitivity analysis. Results A total of 62,341 incident cancer patients were identified. After matching, 424 PCSK9i users and 1,272 non-users were included in this study. During a median follow-up of 1,009 days, 315 patients died, among which 98 died due to cardiovascular cause, 146 died due to cancer cause. Compared to non-users, cancer patients treated with PCSK9i presented with significantly lower risk of all-cause mortality (hazard ratio [HR], 0.33; 95% confidence interval [CI] 0.23-0.47; p <0.001), after adjusting for potential confounders. In addition, PCSK9i therapy was associated with a 63% lower risk of cardiovascular mortality (HR, 0.37; 95%CI 0.20-0.69; p=0.002) and a 75% lower risk of cancer-related mortality (HR, 0.25; 95%CI 0.14-0.45; p<0.001), in relation to non-PCSK9i group. Sensitivity analysis using multivariable competing risk model also suggested a significant association between PCSK9i treatment with reduced risk of cardiovascular mortality (HR, 0.41; 95%CI 0.22-0.76; p=0.005) and cancer mortality (HR, 0.26; 95%CI 0.15-0.48; p<0.001) among cancer survivors. Conclusion The use of PCSK9i was associated lower risks of all-cause, cardiovascular-related, and cancer-related mortality amongst cancer survivors. These findings potentially indicate benefits of PCSK9i beyond adverse cardiovascular events related to atherosclerosis.

Unraveling immune checkpoint inhibitors effects on atherosclerosis: mechanisms and preventive approaches

Abstract Background Immune checkpoint inhibitors (ICIs) represent a novel and rapidly evolving field in cancer treatment. Despite increasing reports of accelerated atherosclerosis and ICI-related atherosclerotic cardiovascular (CV) events in clinical studies and case reports, there is a notable lack of data concerning the underlying mechanisms, appropriate monitoring, and potential interventions. Objectives To explore the role of ICIs in triggering and/or accelerating the atherosclerotic process, with a specific focus on the involvement of CD8+ T-cells. Additionally, we aimed to evaluate and compare the potential beneficial effects of statins and Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors on atherosclerosis under ICIs treatment. Methods Thirty 8-week-old C57BL mice were divided into six groups as follows: (1) Control, normal diet; (2) Control, atherogenic diet; (3) Atherogenic diet + anti PD-1; (4) Atherogenic diet + statins + anti-PD1; (5) Atherogenic diet + PCSK9-i + anti PD-1; (6) Atherogenic diet + PCSK9 inhibitors. At 16 weeks, the carotid arteries and heart were removed for histological examination, and serum was withdrawn for blood work and further analysis. Results Anti-PD1 treatment resulted in extensive lymphocytic infiltration of the carotid intima, primarily constituted of CD8+ T cells. This infiltration was significantly attenuated when statins or PCSK-9 inhibitors were used in conjunction with anti-PD1 treatment. Serum analysis for CD4+ and CD8+ T cells by ELISA revealed no difference in CD4+ abundance between the groups. However, plasma CD8+ T cells were significantly increased with anti-PD1 treatment, and furthermore, when PCSK9 inhibitors were used in combination; but not when statins were used. Conclusion The induction of CD8+ T cell infiltration in the arterial carotid walls by anti-PD-1 was prevented with the use of either statins or PCSK9 inhibitors. In the plasma, while statins reduced the hyper-expression of CD8+ T cells observed under PD-1 treatment, PCSK9 inhibitors enhanced this expression. This may provide a first indication of the potential benefit of PCSK9 inhibitor treatment for both preventing arterial inflammation and enhancing the desired anti-tumor immune response under ICIs treatment. Figure legend: 1A. A cross-section of the carotid artery after 16 weeks of treatment, stained with H&E. Magnification is X100. 1B. A cross-section of the carotid artery after 16 weeks of treatment, stained with anti-CD8 Ab. Magnification is X100. 1C. quantitative CD8+ T cells staining in the carotid arteries. 1D. quantitative results of ELISA for plasma CD8+ T cells.

A register-based cohort study on the effectiveness and Safety of anti-PCSK9 treatment in persons with hyperlipidemia.

Dyslipidemia is a known risk factor for cardiovascular disease. While statins are the primary treatment, some individuals require additional lipid-lowering therapies, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Alirocumab and evolocumab have shown efficacy in reducing low-density lipoprotein cholesterol (LDL-C) levels and reduce the risk of major cardiovascular events (MACE) but have not been directly compared in clinical trials. This study aims to assess the effects of PCSK9 inhibitors on LDL-C levels and evaluate the impact of a mandated switch from alirocumab to evolocumab. Taking advantage of the mandated switch in PCSK9 treatment in Denmark, we conducted a register-based cohort study of 907 individuals with dyslipidemia treated with PCSK9 inhibitors in the Capital Region of Denmark from 2016 to 2022. We analyzed LDL-C levels, treatment retention, and MACE, adjusting for variables such as age, sex, dose, and concurrent lipid-lowering medications. We show that PCSK9 inhibitors treatment resulted in a 49% reduction in LDL-C levels. Following a mandated switch from alirocumab to evolocumab, no significant difference was observed in LDL-C levels or adverse clinical outcomes, including MACE. Treatment discontinuation was most likely within the first 100 days, and no significant difference in discontinuation rates was found between the two drugs. Our study demonstrates that both alirocumab and evolocumab are effective in significantly reducing LDL-C levels in individuals with dyslipidemia. The mandated switch from alirocumab to evolocumab did not result in significant changes in LDL-C or clinical outcomes, suggesting that these treatments can be used interchangeably. These findings support the clinical equivalence of the two PCSK9 inhibitors and may guide therapeutic decisions in lipid management.

3-year clinical outcomes of patients with very high cardiovascular risk eligible for PCSK9 inhibitor treatment

3-year clinical outcomes of patients with very high cardiovascular risk eligible for PCSK9 inhibitor treatment

PCSK9 inhibitors in real life-Cardiometabolic risk management in dyslipidemic patients in Vienna.

Proprotein convertase subtilisin kexin type9 (PCSK9) inhibitors have emerged as important therapeutic options for patients unable to achieve the low-density lipoprotein cholesterol (LDL‑C) target or to tolerate alternative lipid-lowering agents. The aim of this study was to investigate the efficacy of PCSK9 inhibitor treatment in tertiary routine care, by determining the percentage of patients reaching individual LDL‑C target levels 1 year after treatment initiation. Patients routinely started on PCSK9 inhibitors at our lipid clinic between 2017 and 2020 were retrospectively analyzed. Attainment of the LDL‑C target, utilization of follow-ups, cardiovascular events and effects on laboratory parameters were investigated. In this study 347 patients were included, with the majority managed in secondary prevention (94.5%). The LDL‑C target was achieved by 44.9% after ca. 14months, with differences between statin users and non-users (51.0% vs. 22.7%; p < 0.001). The median LDL‑C decreased from 126.00 mg/dL at baseline to 48 mg/dL (-61.6%; -77.00 mg/dL; p < 0.001) after ~2months and to 60 mg/dL (-52.9%; -59.00 mg/dL; p < 0.001) after ~14months. Median lipoprotein(a) levels decreased significantly from 184.0 nmol/L to 165.5 nmol/L (-25.9%; -25.5 nmol/L; p = 0.001) after ~2months, whereas no effects on creatine kinase, amylase and lipase were detectable. Of the patients 15% utilized 4follow-ups. The PCSK9 inhibitor intolerance occurred in 3.5% of patients. With the effect of LDL-lowering remaining constant over 14months, PCSK9 inhibitor treatment showed effective and sustainable LDL‑C lowering in amajority of patients in secondary prevention, bringing them closer to the recommended LDL‑C goal, particularly those under concomitant statin medication. Treatment with PCSK9 inhibitors appears to be well-tolerated, confirming data from clinical trials in real life.

A UK multicentre audit of the management of patients with primary hypercholesterolaemia or mixed dyslipidaemia with bempedoic acid against published lipid-lowering treatment targets.

Bempedoic acid, an adenosine triphosphate citrate lyase inhibitor, was introduced to UK practice via a pre-reimbursement access scheme for adults with primary hypercholesterolaemia or mixed dyslipidaemia who are at high risk of cardiovascular disease, in whom statins are either not tolerated or contraindicated, who have not achieved target cholesterol, despite being on ezetimibe therapy, and do not qualify for PCSK9 inhibitor treatment. This retrospective multicentre audit aimed to evaluate the achievement of lipid-lowering targets with bempedoic acid in UK patients based on recommendations in the Joint British Societies (JBS) guidelines for the prevention of cardiovascular disease. Pseudo-anonymized medical record data for 221 adults treated with bempedoic acid as part of the UK scheme were entered into a bespoke data collection tool at four UK hospitals. Patient demographics, clinical characteristics, treatment pathways and lipid assessment results (against JBS lipid-lowering targets) were collected against pre-specified criteria. Overall, 54% (99/184) of patients achieved the JBS2 audit standard (total cholesterol (TC) <5 mmol/L and low-density lipoprotein cholesterol (LDL-C) <3 mmol/L or ≥25% reduction in TC and ≥30% reduction in LDL-C) at 12 weeks post-initiation. At week 12, the mean absolute change in LDL-C was -1.0 mmol/L; the mean percentage reduction from baseline was 22.0%. Additionally, 52% (96/185) of patients had an LDL-C of <3 mmol/L and 10% (18/185) an LDL-C of <1.8 mmol/L at 12 weeks (as per JBS3). This audit highlights the role of bempedoic acid as part of combination therapy for a population with previously limited treatment options.

Early Use of PCSK9 Inhibitors in the Prognosis of Patients with Acute Coronary Syndrome by Protecting Vascular Endothelial Function.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) has a protective effect on acute coronary syndrome (ACS). However, most studies have shown that this protective effect is based on a decrease in low-density lipoprotein cholesterol, while other mechanisms remain limited. This study aimed to determine whether PCSK9i can improve the prognosis of ACS patients by protecting endothelial function. A total of 113 ACS patients were enrolled and randomly assigned to PCSK9i group (PCSK9i combined with statins) and control group (statins only). Blood lipids and endothelial function indicators were measured and analyzed 6 weeks before and after treatment. The effect of PCSK9i on the expression and secretion of endothelial function indicators in vascular endothelial cells were studied by cell experiments. After 6 weeks of treatment, endothelial function indicators such as nitric oxide (NO), thrombomodulin, intercellular cell adhesion molecule-1, endothelin-1, and flow-mediated vasodilation were significantly improved in PCSK9i group compared with control group. Only the changes of NO and von Willebrand factor were associated with blood lipid levels, whereas the changes of other endothelial function indicators were not significantly associated with blood lipid levels. PCSK9i reduced the incidence of major adverse cardiovascular events in patients with ACS compared to those in the control group. In cell experiments, PCSK9i treatment significantly ameliorated LPS induced endothelial injury in HUVECs. PCSK9i can protect vascular endothelial function partly independently of its lipid-lowering effect and ameliorate the prognosis of patients with ACS within 6 weeks. This mechanism may involve heat shock transcription factor 1/heat shock proteins -related signaling pathways. Early use of PCSK9i in patients with ACS should be strongly considered in clinical practice.

In-hospital initiation of a PCSK9 inhibitor in patients with acute coronary syndrome: A systematic review and meta-analysis of randomized controlled trials.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to be effective and safe in patients with stable angina and previous myocardial infarction. However, evidence for initiating their use in patients hospitalized with acute coronary syndrome (ACS) is limited. This systematic review and meta-analysis was performed to provide more clinical evidence. PubMed, Embase, OVID, Cochrane Library and ClinicalTrials.gov were systematically searched for eligible randomized controlled trials up to March 20, 2023. The risk ratios, standardized mean differences and 95% confidence intervals were calculated for primary and secondary outcomes. The bias risk of the included studies was assessed using the Cochrane RoB 2 criteria. About 8 randomized controlled trials involving 1255 inpatients with ACS were included. PCSK9 inhibitor treatment significantly reduced low-density lipoprotein cholesterol (LDL-C) (SMD -1.28, 95% CI -1.76 to -0.8, P = .001), triglycerides (TG) (SMD -0.93, 95% CI -1.82 to -0.05, P = .03), total cholesterol (SMD -1.36, 95% CI -2.01 to -0.71, P = .001), and apolipoprotein B (Apo B) (SMD -0.81, 95% CI -1.09 to -0.52, P = .001) within approximately 1 month. PCSK9 inhibitor treatment significantly reduced the total atheroma volume (TAV) (SMD -0.33, 95% CI -0.59 to -0.07, P = .012). It also significantly increased minimum fibrous cap thickness (FCT) (SMD 0.41, 95% CI 0.22-0.59, P = .001) in long-term follow-up (>6 months). PCSK9 inhibitor treatment significantly reduced the risk of readmission for unstable angina (RR 0.32, 95% CI 0.12-0.91, P = .032) in short-term follow-up (<6 months). There were no significant differences in all-cause mortality, cardiovascular death, myocardial infarction, ischemic stroke, coronary revascularization or heart failure. Only nasopharyngitis (RR 1.71, 95% CI 1.01-2.91, P = .047) adverse events were significantly observed in the PCSK9 inhibitor group. Application of a PCSK9 inhibitor in hospitalized patients with ACS reduced lipid profiles and plaque burdens and was well tolerated with few adverse events.

The benefits of PCSK9 inhibitors in patients with acute coronary syndrome: a systematic review and meta-analysis

Abstract Background Proprotein convertase subtilisin/kexin 9 (PSCK9) inhibitors have been beneficial for many patients with hyperlipidemia. The objective of this study was to investigate the benefit of PSCK9 inhibitors in patients with acute coronary syndrome (ACS). Methods We systematically searched PubMed, EMBASE, and Cochrane Clinical Trials (published before January 2023; no language restriction) to compare the treatment of patients with ACS using PCSK9 inhibitors and placebo. The primary end points were major adverse cardiovascular events, nonfatal myocardial infarction, cardiogenic death, stroke, hospitalization for recurrent ACS, and coronary revascularization. Fixed- or random-effects models were used to assess the aggregated data. Results Of the 1686 identified studies, 5 were eligible and included in our analysis (of a total of 38,005 participants, 18,609 cases were placed in the PCSK9 inhibitor treatment group and 19,396 cases in the placebo group). Compared with the placebo group, PCSK9 inhibitors significantly reduced the major adverse cardiovascular events (odds ratio [OR]: 0.83; 95% confidence interval [CI]: 0.77–0.88; P &lt; 0.00001) for patients following ACS. The incidence of nonfatal myocardial infarction (relative risk: 0.80; 95% CI: 0.74–0.87; P &lt; 0.00001), cardiovascular death (OR: 0.96; 95% CI: 0.83–1.10; P = 0.56), stroke (OR: 0.74; 95% CI: 0.63–0.88; P = 0.0007), hospitalization for recurrent ACS (OR: 0.57; 95% CI: 0.40–0.83; P = 0.003), or coronary revascularization (OR: 0.82; 95% CI: 0.76–0.88; P &lt; 0.00001) all demonstrated a significant decrease in the comparison between the 2 groups. Conclusion This meta-analysis demonstrated that treatment with PCSK9 inhibitors in patients with ACS reduced the probability of multiple cardiovascular events and improved patient prognosis.

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.

Clinical characteristics associated with elevated levels of lipoprotein(a) in patients with vascular risk.

Lipoprotein(a) (Lp(a)) is increasingly used in the evaluation of patients with vascular risk due to its association with cardiovascular events. The purpose of this study was to identify the clinical characteristics of patients with elevated levels of Lp(a) attended in an outpatient vascular risk unit. An observational, retrospective study was conducted to assess the clinical characteristics of patients with elevated levels of Lp(a) (≥50 mg/dL), as compared to patients with normal values (<50 mg/dL). The sample was composed of 878 patients identified as having a high vascular risk due to a diagnosis of vascular disease, attended in a vascular risk unit between 2021 and 2022. The highest levels of Lp(a) were independently associated with a higher probability of having a history of peripheral arterial disease (p=0.024), polygenic familial hypercholesterolemia (PH, p=0.030) and combined familial hypercholesterolemia (CFH, p=0.015); and using PCSK9 inhibitor treatment (p=0.029) and combination therapy with statins and ezetimibe (p=0.018). In contrast, there were no significant differences in relation to familial history of early cardiovascular disease (p=0.143) or personal history of cardiovascular disease (p=0.063), which contrasts with other series. Elevated levels of Lp(a) were associated with a history of peripheral arterial disease, diagnosis of FHP and CFH, and need for more intense lipid-lowering treatments.

Efficacy of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Treatment for Repeated In-stent Restenosis in a Coronary Artery.

A 57-year-old woman experienced chest pain. A coronary angiogram revealed middle left anterior descending artery stenosis. Despite receiving adequate anti-hyperlipidemia treatment and undergoing percutaneous coronary intervention (PCI), she experienced angina and required PCI six more times for in-stent restenosis. As she had high lipoprotein (a) (LP-[a]) levels at the seventh PCI procedure, proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) was administered, and a reduction in the LP-(a) and low-density lipoprotein cholesterol (LDL-C) values was observed. She experienced no recurrence of angina for five years with PCSK9i treatment. PCSK9i can reduce not only LDL-C but also LP-(a) levels, resulting in cardiac event risk reduction.

Abstract 16485: Treatment With PCSK9 Inhibitors Influence miRNAs Expression and Changes of Arterial Wall Properties

Background and aim: MicroRNAs (miRNAs) are involved in the synthesis of proprotein convertase subtilisin-kexin type 9(PCSK9), which is one of regulators of low-density lipoprotein cholesterol (LDL-C) metabolism. There is no data on whether changes in the expression of miRNAs involved in PCSK9 metabolism, could be related to arterial wall properties changes. The aim was to verify whether PCSK9 inhibitors (PCSK9i) treatment and the changes in the expression of miRNAs are associated with arterial wall properties in post-myocardial infarction (MI) patients with insufficiently regulated LDL-C levels and increased Lp(a) levels. Methods: Seventy-six participants after MI were enrolled and randomized to a placebo group or PCSK9i group. The treatment group received subcutaneous alirocumab 150 mg or evolokumab 140 mg, every 2 weeks. Blood for biochemical and genetic analysis was taken and ultrasound measurements of flow-mediated dilation of brachial artery (FMD), carotid intima-media thickness (c-IMT) and pulse wave velocity (PWV) were performed. All measurements were measured initially and after 6 months of treatment. Results: FMD improved from 10.9±6.3 to 14.4±5.7% in the PCSK9i group and 10.8±6.8 to 11.2±4.6% in the placebo group (p&lt;0.001, p=0.584). PWV changed from 5.8±1.4 to 5.5±1.6 m/s (p=0.024) in the PCSK9i group and in the placebo group from 5.6±1.5 to 5.5±1.1 m/s (p=0.879), with better improvement in the treated group (p=0.007). c-IMT decreased in the PCSK9i group (from 0.65±0.10 to 0.63±0.10 mm; p=0.017), with no change in the placebo group (from 0.64±0.09 to 0.63±0.09 mm; p=0.482). The expression of miR-191-5p and miR-483-5p increased in the PCSK9i group (p=0.028, p=0.020; respectively). The expression of miR-191-5p significantly decreased in the placebo group (p&lt; 0.001). A decrease in c-IMT was associated with a decrease in the expression of miR-224-5p (r=0.303; p=0.019), miR-337-3p (r=0.329; p=0.010) and miR-483-5p (r=0.367; p=0.004). Conclusions: Our results suggest that changes in selected miRNAs were associated with changes in the morphological properties of the arterial vessel wall. We have shown that the increase in miR-483-5p expression can be a good indicator of the regression of morphological atherosclerotic changes.

Effect of PCSK9 inhibitors on early neurological deterioration in patients with branch atheromatous disease

Objective: To investigate the effect of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors on the incidence of early neurological deterioration during the treatment of branch atheromatous disease (BAD). Methods: A retrospective analysis of 297 BAD patients admitted to the Department of Neurology in Zhengzhou People's Hospital from January 2020 to April 2023 was made. According to whether to use PCSK9 inhibitor treatment, they were divided into PCSK9 inhibitor group (81 cases) and control group (216 cases). Propensity score matching (PSM) method was used to eliminate the general situation difference between PCSK9 inhibitor group and control group. Seventy-two cases were successfully matched in each group. The early neurological deterioration (END) and low-density lipoprotein cholesterol (LDL-C) were compared. END was defined as the National Institutes of Health Stroke Scale (NIHSS) score increase≥2 points within 72 hours after stroke. Suspicious influencing factors leading to END were screened for multivariate logistic regression model analysis. Results: After PSM matching, among the 144 patients, 90 were male and 54 were female, aged (61.2±9.6) years. After matching, The hospital stay[M(Q1, Q3)] [9(7, 11)d vs 10(8, 13)d] in PCSK9 and NIHSS score at discharge [2(1, 3) vs 3(1, 4) points] were significantly different from those in the control group (all P<0.05). In addition, the incidence of END was reduced in the PCSK9 inhibitor group [12.5%(9/72) vs 31.9%(23/72),P<0.05]. Multivariate logistic regression analysis found that C-reactive protein (CRP)(OR=1.119,95%CI: 1.010-1.240, P<0.05) and PCSK9 inhibitor (OR=0.298, 95%CI: 0.117-0.755, P<0.05) were factors associated with the development of END. Conclusion: The use of PCSK9 inhibitors in the treatment of patients with BAD can reduce the incidence of END.

FRI091 Treatment Of Secondary Hyperlipidemia Due To Nephrotic Syndrome

Abstract Disclosure: J. Girard: None. H. Quadri: None. B. Jiang: None. B.K. Force: None. L. Abushamat: None. R.S. Aguirre: None. Introduction: Secondary Hyperlipidemia associated with nephrotic syndrome contributes to significant cardiovascular morbidity. The elevated atherogenic lipoprotein levels are caused by upregulation of HMG-CoA reductase and downregulation of lipoprotein lipase. More recently, studies in mice have linked PCSK9 and Inducible Degrader of the LDL Receptor (IDOL) as primary contributors to hypercholesterolemia in nephrotic syndrome due to the decrease in LDL receptor recycling (1). Treating nephrotic syndrome is the first-line treatment for the associated secondary hyperlipidemia. Since exposure time to atherogenic lipoproteins matters in the development of cardiovascular disease, statins, with or without ezetimibe, are utilized. PCSK9 inhibitors are initiated if LDL remains elevated despite these measures. This case report highlights a severe case of hypercholesterolemia associated with nephrotic syndrome and treatment response. Clinical Case: A 55-year-old male with no significant past medical history presented to the emergency department with shortness of breath and lower extremity edema. He denied a family and personal history of premature cardiovascular disease. Initial evaluation revealed a serum total cholesterol on 10x dilution of 833.9 (&amp;lt;/=200mg/dL), calculated LDL 718mg/dL (&amp;lt;100mg/dL), triglycerides 381mg/dL (&amp;lt;150mg/dL), HDL 39.3mg/dL (40-60mg/dL), Apo B &amp;gt;400mg/dL (&amp;lt;90mg/dL), and Lp(a) 17.5mg/dL (&amp;lt;75mg/dL). His serum albumin was &amp;lt;1.5g/dL (4.2-4.5g/dL), creatinine 2mg/dL (0.7-1.3mg/dL), and 24-hour calculated urinary protein level 10,294mg/24-hour (30-150mg/24-hour). A kidney biopsy revealed a mixed Type III and Type V Lupus Nephritis. The patient started lupus treatment along with atorvastatin 80mg qHS, fenofibrate 45mg daily, and ezetimibe 10mg daily. His LDL decreased to 418mg/dL (&amp;lt;100mg/dL) after 15 days. The patient continued to have undetectable albumin although kidney function improved after 2 months. We planned to initiate PCSK9 inhibitor treatment for further LDL reduction pending treatment of lupus, but patient died from septic shock prior to initiation. Conclusion: This case illustrates that extremely elevated LDL levels from nephrotic syndrome resulted in a nearly 60% reduction of LDL with statin and ezetimibe treatment. Statins, ezetimibe and PCSK9 inhibitor therapy should be considered stepwise when treating secondary hyperlipidemia from nephrotic syndrome. 1. LIU S, VAZIRI ND. ROLE OF PCSK9 AND IDOL IN THE PATHOGENESIS OF ACQUIRED LDL RECEPTOR DEFICIENCY AND HYPERCHOLESTEROLEMIA IN NEPHROTIC SYNDROME. NEPHROL DIAL TRANSPLANT. 2014 MAR;29(3):538-43. DOI: 10.1093/NDT/GFT439. EPUB 2013 OCT 28. PMID: 24166456 Presentation: Friday, June 16, 2023

Does Genotype Affect the Efficacy of PCSK9 Inhibitors in the Treatment of Familial Hypercholesterolemia?

This review discusses whether patients' genotype affects the efficacy of PCSK9 inhibitors in treating familial hypercholesterolemia and how this might influence clinical management. Currently, available evidence consistently demonstrates and is in good agreement that, in general, the LDL-C-lowering effect of PCSK9 inhibitors is similar across genotypes, except for compound heterozygous and homozygous familial hypercholesterolemia (FH). However, it remains to be seen whether the comparable therapeutic effect in lowering LDL-C level also leads to a comparable degree of cardiovascular risk reduction with different genotypes. Generally, the level of LDL-C reduction following PCSK9 inhibitor treatment is similar within different genotypes. Hence, genotype is a less reliable predictor for further LDL-C level reduction on PCSK9 inhibitor therapy, and attention should be given to other external influences, especially for heterozygous FH.

Analysis of steatosis biomarkers and inflammatory profile after adding on PCSK9 inhibitor treatment in familial hypercholesterolemia subjects with nonalcoholic fatty liver disease

Analysis of steatosis biomarkers and inflammatory profile after adding on PCSK9 inhibitor treatment in familial hypercholesterolemia subjects with nonalcoholic fatty liver disease

Management of patients with very high cardiovascular risk eligible for PCSK9 inhibitor treatment: 1-year outcomes of the PERI-DYS study

Management of patients with very high cardiovascular risk eligible for PCSK9 inhibitor treatment: 1-year outcomes of the PERI-DYS study

Consensus document on Lipoprotein(a) from the Italian Society for the Study of Atherosclerosis (SISA)

AimsIn view of the consolidating evidence on the causal role of Lp(a) in cardiovascular disease, the Italian Society for the Study of Atherosclerosis (SISA) has assembled a consensus on Lp(a) genetics and epidemiology, together with recommendations for its measurement and current and emerging therapeutic approaches to reduce its plasma levels. Data on the Italian population are also provided. Data synthesisLp(a) is constituted by one apo(a) molecule and a lipoprotein closely resembling to a low-density lipoprotein (LDL). Its similarity with an LDL, together with its ability to carry oxidized phospholipids are considered the two main features making Lp(a) harmful for cardiovascular health. Plasma Lp(a) concentrations vary over about 1000 folds in humans and are genetically determined, thus they are quite stable in any individual. Mendelian Randomization studies have suggested a causal role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis and observational studies indicate a linear direct correlation between cardiovascular disease and Lp(a) plasma levels. Lp(a) measurement is strongly recommended once in a patient's lifetime, particularly in FH subjects, but also as part of the initial lipid screening to assess cardiovascular risk. The apo(a) size polymorphism represents a challenge for Lp(a) measurement in plasma, but new strategies are overcoming these difficulties. A reduction of Lp(a) levels can be currently attained only by plasma apheresis and, moderately, with PCSK9 inhibitor treatment. ConclusionsAwaiting the approval of selective Lp(a)-lowering drugs, an intensive management of the other risk factors for individuals with elevated Lp(a) levels is strongly recommended.

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.