PCSK9 Inhibitors Research Articles

Triglyceride-glucose index and hsCRP-to-albumin ratio as predictors of major adverse cardiovascular events in STEMI patients with hypertension.

This study aimed to evaluate the association between the triglyceride-glucose (TyG) index and high-sensitivity C-reactive protein-to-albumin ratio (hsCAR) and the prognosis of patients with STEMI and hypertension. A total of 699 patients diagnosed with STEMI and hypertension were included in this study database. Compared to the low TyG index group (< 7.8), the high TyG index group (≥ 7.8) was associated with an increased risk of MACE (HR 2.09, 95% CI = 1.58-2.77; P < 0.001). Similarly, a higher hsCAR (≥ 0.15) was linked to an increased risk of MACE (HR 1.46, 95% CI = 1.12-1.90; P = 0.005). Subsequently, we categorized the population into four groups based on the defined cutoff points. Compared to the low TyG-low hsCAR subgroup, the other three subgroups demonstrated an elevated risk of MACE. Among patients treated with PCSK9 and SGLT2 inhibitors, the combined effect of the TyG index and hsCAR on MACE was attenuated. Finally, The combined TyG index and hsCAR model exhibited optimal performance (AUC = 0.71, 95% CI = 0.67-0.75; P < 0.001). This study demonstrates that the TyG index and hsCAR provide strong combined predictive power. The synergistic utilization offers a comprehensive approach to cardiovascular risk assessment.

PCSK9 and its relationship with HMGB1, TLR4, and TNFα in non-statin and statin-treated coronary artery disease patients.

Despite statin use in coronary artery disease (CAD), significant risk remains, potentially due to increased proprotein convertase subtilisin/kexin-type 9 (PCSK9) production, which raises LDL-C levels and induces inflammation. The exact relationship between PCSK9, inflammatory markers like TNFα, TLR4, CRP, and HMGB1, and monocyte subsets is poorly understood. This study aimed to explore these relationships in non-statin and statin-taking CAD patients. This case-control study included 91 controls and 91 stable CAD patients, divided into no-statin (NS, n = 25), low-dose statin (LDS, n = 25), and high-dose statin (HDS, n = 41) groups. Serum levels of LDL-C, CRP, PCSK9, TLR4, HMGB1, and TNFα were measured. Monocyte subsets were classified using flow cytometry into classical monocytes (CM), intermediate monocytes (IM), and non-classical monocytes (NCM). CAD patients showed elevated PCSK9, LDL-C, and inflammatory markers compared to controls. Statin groups (LDS, HDS) had lower LDL-C and inflammatory markers but higher PCSK9 than the NS group, with the HDS group showing the lowest LDL-C and inflammatory markers but the highest PCSK9. In the NS group, PCSK9 positively correlated with inflammatory markers (HMGB1, TNFα, TLR4, CRP) and monocyte subsets (IM%, NCM%). In the total statin group (LDS + HDS), PCSK9 negatively correlated with HMGB1, TLR4, and NCM%, for each, respectively, and positively with CM%. Multivariable linear regression showed significant associations between PCSK9 and HMGB1, NCM%, and IM% in the NS group, and HMGB1, NCM%, and TLR4 in the total statin group. In conclusion, we recommend combining PCSK9 inhibitors with statins in high-risk CAD patients. This may enhance statin efficacy, reduce LDL-C, and inhibit the TLR4/NF-кB inflammatory pathway, decreasing atherosclerotic inflammation.

Cycloartane-type triterpenoids from Combretum quadrangulare Kurz with PCSK9 secretion inhibitory activities.

Nine previously undescribed (1-9) and seven known (10-16) cycloartane-type triterpenoids were isolated and characterized from Combretum quadrangulare Kurz using physicochemical and spectroscopic methods. The absolute configurations of these compounds were determined through modified Mosher's method and quantum chemical calculation of electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra. Their inhibitory activities against PCSK9 secretion were assessed, and a plausible structure-activity relationship was delineated. Compounds 2, 14, and 15 exhibited notable inhibitory effects on PCSK9 mRNA and protein levels, and significant PCSK9 mRNA inhibition was observed when co-treated with atorvastatin. Compound 15 showed the most potent activity, markedly enhancing LDL uptake compared to the negative control. In vivo pharmacokinetic studies confirmed that compound 15 exhibited higher distribution in the liver than plasma, where PCSK9 is predominantly synthesized. These findings emphasize the potential significance of the cycloartane-type triterpenoid scaffold in discovering PCSK9 inhibitors.

Abstract 4136741: Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and Lipid Reduction: A Network Meta-Analysis

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors offer additional lipid reduction beyond that achieved with statins. However, the optimal PCSK9 therapy for lowering lipid levels in patients with hypercholesterolemia and/or hyperlipidemia on background statin therapy remains unclear. Methods: PubMed and EMBASE databases were searched for RCTs assessing tafolecimab, evolocumab or alirocumab vs. placebo (administrated Q2W or Q4W, 12-week treatment) in patients with hypercholesterolemia and/or hyperlipidemia on medium-intensity statin up to March 28, 2024. The outcomes of interest were the percentage change in low-density lipoprotein cholesterol (LDL-C) or lipoprotein(a) from baseline to the 12th week. A frequentist random-effect network meta-analysis was applied to calculate MD and 95% CI using Stata 16.0 software. Results: A total of 4960 patients [PCSK9 inhibitors (n=3230), placebo (n=1730)] across 13 RCTs were included. At week 12, tafolecimab, evolocumab and alirocumab (either Q2W or Q4W) all induced significant reductions in LDL-C levels compared to placebo ( Figure ). The efficacy of evolocumab Q2W was significantly higher compared with alirocumab Q2W (MD=-18.67%, 95% Cl [-29.59%, -7.74%]), while similar LDL-C reduction was observed in tafolecimab Q2W vs. alirocumab Q2W and evolocumab Q2W vs. tafolecimab Q2W. Furthermore, tafolecimab Q4W and evolocumab Q4W were more effective in lowering LDL-C levels compared to alirocumab Q4W (tafolecimab vs. alirocumab: MD=-23.66%, 95% Cl [-32.58%, -14.74%]; evolocumab vs. alirocumab: MD=-25.84%, 95% Cl [-34.21%, -17.46%]), while there was no difference between evolocumab Q4W and tafolecimab Q4W. Lastly, the ranking of the effects for reducing lipoprotein(a) levels was as follows: tafolecimab &gt; evolocumab&gt; alirocumab (either Q2W or Q4W). Conclusions: In patients with hypercholesterolemia and/or hyperlipidemia treated with medium-intensity statins, tafolecimab and evolocumab (either Q2W or Q4W) might be preferred choices for lowering LDL-C. Additionally, tafolecimab (either Q2W or Q4W) appears to be the most effective agent for reducing lipoprotein(a) levels.

Abstract 4119868: Statin and PCSK9 Inhibitor Utilization and Spending in Medicaid between 2018 to 2022: A National Analysis

Introduction: Low-income working-aged adults in the Medicaid program have a high burden of cardiovascular risk factors and disease, but often face barriers accessing necessary therapies. Little is known about contemporary patterns of utilization and spending on lipid-lowering therapies in Medicaid programs. Goal: To evaluate national trends in utilization and spending on statins and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in Medicaid. Methods: We performed a serial cross-sectional study using the Medicaid Spending by Drug Database, which contains national-level Medicaid spending data for medications partially or fully reimbursed by Medicaid for the approximately 84 million beneficiaries. We evaluated annual trends in utilization (prescription fills) and total spending for statins and PCSK9i from 2018 to 2022, both overall and by individual drug formulation. Spending was adjusted for inflation and reported in 2022 US dollars. Results: Medicaid beneficiaries filled 20.4 million statin prescriptions in 2018 compared to 20.3 million in 2022, representing a 0.4% decrease. However, Medicaid spending on statins decreased by 7.1%, from $246.2 million to $226.8 million over the same period. Prescription fills for generic Rosuvastatin increased the most (0.79 million to 2.6 million, +224.2%), while fills for brand-name Crestor decreased the most (0.065 million to 0.003 million, -95.2%). Medicaid beneficiaries filled 121,737 prescriptions for PCSK9 inhibitors in 2022 compared to 7,617 in 2018 (+1498%), coinciding with a 640% increase in total spending ($8.9 million to $65.7 million). Repatha Sureclick was the most filled PCSK9i in Medicaid with 80,503 fills in 2022, representing $43.9 million in total Medicaid spending. Conclusions: Despite almost no change in statin utilization between 2018 and 2022, Medicaid spending on statins fell by approximately $20 million, driven by a shift from brand-name to generic formulations. In contrast, spending on PCSK9 inhibitors increased by $57 million as these medications became more widely used. Understanding these trends is critical as Medicaid programs work to ensure access to effective cardiovascular therapies while also identifying opportunities for cost efficiencies nationwide.

Abstract 4131737: Atherosclerotic Cardiovascular Disease Risk Management in a Primary Care Residency Clinic

The 2018 AHA/ACC Multisociety Guideline on the Management of Blood Cholesterol recommends to target an LDL-C &lt;70mg/dL in very high risk ASCVD patients. If the patient is on maximally tolerated statin therapy and LDL-C remained &gt;70mg/dL, addition of ezetimibe was recommended. If LDL continued to be elevated, the addition of PCSK9 inhibitor was discussed. In 2019, the European Atherosclerosis Society recommended lowering the target LDL-C goal to &lt;55mg/dL in patients with very high ASCVD risk. This is based on prior studies demonstrating dose-dependent reduction in ASCVD with LDL-C reduction. The purpose of this study is to identify individuals at very high ASCVD risk and determine if they are on optimal medical therapy to achieve LDL &lt;55mg/dL with the intention to improve atheroscloertic cardiovascular risk management in primary care residency clinics. A review of electronic medical records from a primary care residency clinic was performed. Patients with hyperlipidemia and prior ASCVD event were identified. Additional data including lipid panel and current medical management were collected. Patients were stratified into very high risk and not very high risk groups according to AHA classification and analyzed. A total of 1,727 patients were found to have hyperlipidemia and a prior ASCVD event. The not very high risk group had an average age of 51 years with 54% (n=40) females and 45.9% (n=34) males. The very high risk group contained 95.7% (n=1,653) patients. The average age in the very high risk group was 68 years with 53.2% (n=879) of patients being female and 46.8% (n=774) being males. Of those patients, 73.6% (n=1,216) had an LDL ≥ 55 mg/dL. In these patients, 563 were on high intensity statin, 163 on moderate intensity statin and 15 on low intensity statin. There were 475 patients not on any statin. Of those on statin therapy, 66 were on ezetimibe alone and 10 were on both ezetimibe and PCSK9 inhibitors. Over 95% of patients with a prior ASCVD event were identified as being very high risk. Our data demonstrates that 3 in 4 patients were not on optimal medical therapy based on a stricter LDL goal. There was poor escalation of medical therapy as not all patients were on high intensity statin and only 10% of patients were on ezetimibe while even fewer patients were on additional PCSK9 inhibitor therapy. This study highlights the importance of risk stratification and vigilance in optimizing medical therapy.

Abstract 4140167: Lipid Management among US Veterans with Prevalent Atherosclerotic Cardiovascular Disease (ASCVD) * Veteran Affairs Lipid Optimization Reimagined Quality Improvement Program (VALOR-QI)

ASCVD is the most prevalent form of cardiovascular disease and the main cause of morbidity and mortality for Veterans in the VA healthcare system. Management of cholesterol is one of the most effective approaches for reducing CV disease, however, over two-thirds of Veterans with ASCVD are not optimally managed. Veterans with ASCVD are at high risk for recurrent CV events and can benefit greatly from more effective management of their low-density lipoprotein (LDL-C) cholesterol. The reasons for the current undertreatment of dyslipidemia in Veterans with ASCVD are multifaceted, including factors such as low disease awareness among the patients, patient’s preference, statin intolerance, and poor adherence to medications. Purpose: VALOR-QI is a collaborative effort between the U.S. Department of Veterans Affairs (VA) and the American Heart Association (AHA) with the goal of positively impacting Veterans’ cardiovascular health. Method: This project targets at risk veterans over 18 years of age, with ASCVD and LDL-C ≥70 mg/dl or non-HDL-C ≥100 mg/dl identified across 50 VA medical centers nationwide. As part of the program, VA sites work with an AHA QI Consultant to develop and deploy a local quality improvement plan to help overcome site specific barriers preventing Veterans from achieving optimal cholesterol levels. Health coaches at these centers aid in lipid optimization through patient counseling, medication adherence support, appointment reminders, and referrals to a nutritionist or clinical pharmacist as required. The plan’s effectiveness will be assessed by tracking LDL-C goal achievement rates, LDL-C changes with therapy use, and veteran demographics. Our primary endpoints are for over 30% of veterans to reach the LDL-C target and a significant drop (around 10%) from baseline in veterans with ASCVD and LDL-C not at target. Best practices are shared among sites using the PDSA implementation science model. Results: As of May 2024, 182 patients at the Hines VA are engaged in the project. Among them, 84.8% are on lipid-lowering therapy, 83.1% are on statins (with 57.9% on a high intensity dose), and 11.3% are on dual therapy with a statin plus an additional medication (PCSK9 inhibitor or ezetimibe). So far, 59.5% of enrolled patients reached their LDL-C cholesterol target of &lt;70 mg/dl. Conclusion: Lipid lowering strategies with collaboration of patients, network providers, dieticians and health coaches improved lipid control in veterans with ASCVD.

PCSK9 inhibitor with cause-specific mortality amongst cancer survivors: a chance to kill two birds with one stone.

PCSK9 inhibitor with cause-specific mortality amongst cancer survivors: a chance to kill two birds with one stone.

Abstract 4140140: Cardiology Follow-Up as a Determinant of LDL-C Management Success in Secondary Cardiovascular Prevention

Managing low-density lipoprotein (LDL) cholesterol is crucial for secondary cardiovascular prevention. Despite ACC/AHA recommendations for maintaining LDL below 70 mg/dL, achieving this target remains suboptimal. This study investigates the impact of consistent cardiologist involvement on LDL cholesterol management. Methods: We conducted a multicenter, cross-sectional cohort study within the Steward Healthcare System in Massachusetts, analyzing data from 10,211 patients hospitalized from January 2019 to March 2024. This study offers a detailed snapshot of data across the study period, capturing both recent and long-standing cases identified through ICD codes for conditions like NSTEMI, CAD, STEMI, or CABG, specifically as markers for secondary cardiovascular prevention. We utilized the most recent LDL cholesterol measurements for our analysis and compared the distribution of lipid-lowering medications across groups. Notably, follow-ups with cardiologists outside our network were not tracked, potentially omitting relevant data. Statistical analysis employed the Chi-square test for categorical variables and binary logistic regression to adjust for confounders. Results: showed that patients with regular cardiology visits more often achieved LDL levels below 70 mg/dL (57.45% vs. 46.67%; OR 1.54, 95% CI: 1.42-1.68; P&lt;0.0001). These patients also had lower mean LDL levels (68.72 ± 27.02) compared to those without cardiology follow-up (75.82 ± 30.27; P&lt;0.0001). Higher usage of PCSK9 inhibitors and non-statin medications was noted among the visiting group, with an adjusted OR of 1.43 (95% CI: 1.29-1.59; P&lt;0.0001). Conclusion: Our study shows that cardiologist involvement significantly enhances cholesterol management in CAD patients, as evidenced by a higher proportion achieving optimal LDL levels and more aggressive use of lipid-lowering medications. Despite these benefits, some patients discontinue their follow-ups with cardiologists after coronary events, shifting cholesterol management to primary care providers (PCPs). This transition often results in less aggressive treatment strategies, evidenced by elevated LDL levels in patients lacking recent cardiology care. To sustain effective cholesterol management and stringent LDL targets, long-term follow-up with a cardiologist is crucial. Furthermore, equipping PCPs with the necessary tools and protocols to adopt more aggressive treatment approaches could bridge the care gap when specialist visits are infrequent.

Therapeutic Challenges Derived from the Interaction Among Apolipoprotein E, Cholesterol, and Amyloid in Alzheimer’s Disease

The isoform E4 of the Apolipoprotein E (ApoE) represents one of the strongest genetic risk factors for late-onset Alzheimer’s disease (AD). ApoE has key roles in cholesterol transport and amyloid-β (Aβ) metabolism, which are both central to AD pathogenesis. The E4 isoform has been implicated in reduced cholesterol homeostasis, increased Aβ aggregation, and heightened tau phosphorylation, contributing to amyloid plaques and neurodegeneration. This manuscript examines the complex interactions among ApoE isoforms, cholesterol metabolism, and amyloid pathology. Moreover, the therapeutic challenges associated with lipid-lowering agents (e.g., statins, PCSK9 inhibitors), anti-amyloid immunotherapies, and anticoagulants are described, focusing on ApoE4 carriers. Decision-making challenges are discussed by analyzing the pros and cons of these therapies.

Pharmacogenomics of Lipid-Lowering Therapies in Obese Individuals with Dyslipidemia

Dyslipidemia is a key contributor to cardiovascular diseases, especially in obese individuals, where lipid metabolism is frequently impaired. Lipid-lowering therapies, such as statins, fibrates, and PCSK9 inhibitors, are commonly prescribed to manage dyslipidemia, but their efficacy and adverse effect profiles vary significantly across individuals. Pharmacogenomics, the study of how genetic variations influence drug response, has emerged as a powerful tool in predicting these inter-individual differences and optimizing treatment regimens. In obese individuals, genetic polymorphisms in genes involved in lipid metabolism, such as SLCO1B1, CYP3A4, APOE, and LDLR, have been linked to variable responses to lipid-lowering drugs. This review explores the impact of pharmacogenomics on lipid-lowering therapies in obese individuals with dyslipidemia, emphasizing the potential of personalized medicine in improving therapeutic outcomes. By understanding genetic influences on drug efficacy and safety, clinicians can tailor treatments to individual patients, thereby reducing adverse effects and improving lipid control. We also highlight current challenges in translating pharmacogenomic findings into clinical practice and discuss the future directions of this emerging field. Keywords: Pharmacogenomics, Lipid-Lowering Therapies, Dyslipidemia, Obesity, Statins, Fibrates, PCSK9 Inhibitors

Gene-Based Targeting for Treatment of Hypercholesterolemia and Prevention of Atherosclerotic Cardiovascular Disease

Familial hypercholesterolemia, characterized by high levels of LDL cholesterol is a monogenic metabolic disorder linked to atherosclerotic cardiovascular disease. Several genetic mutations in genes such as LDLR and PSK9 are thought to cause familial hypercholesterolemia. This ultimately causes dysfunction of the LDLR pathway, increasing circulating LDL levels. Current treatment revolves around decreasing LDL cholesterol levels in the blood. Statins are the current gold standard while sterol absorption inhibitors (ezetimibe) and PCSK9 inhibitors (evolocumab) are either used as primary treatment in individuals with statin intolerance, or supplementary treatment otherwise. However, CRISPR-Cas9 offers an upstream therapeutic intervention, inducing mutations in pathogenic genes (such as LDLR) to upregulate or downregulate gene expression and subsequently reduce LDL cholesterol levels. This technology thus has great potential as a two-fold treatment option, offering an effective solution for familial hypercholesterolemia, while simultaneously diminishing the risk of atherosclerotic cardiovascular disease. A limitation to current research exists in the sole analysis of monogenic factors in genetic screening, thus polygenic, multifactorial analyses are required to assess more holistic treatment plans. Furthermore, there exist current limitations to CRISPR-Cas9 including ethical limitations and social considerations revolving around the perpetuation of social inequities through technology necessitating future research on global health policies.

2024 Recommendations on the Optimal Use of Lipid-Lowering Therapy in Established Atherosclerotic Cardiovascular Disease and Following Acute Coronary Syndromes: A Position Paper of the International Lipid Expert Panel (ILEP).

Atherosclerotic cardiovascular disease (ASCVD) and consequent acute coronary syndromes (ACS) are substantial contributors to morbidity and mortality across Europe. Fortunately, as much as two thirds of this disease's burden is modifiable, in particular by lipid-lowering therapy (LLT). Current guidelines are based on the sound premise that, with respect to low-density lipoprotein cholesterol (LDL-C), "lower is better for longer", and recent data have strongly emphasised the need for also "the earlier the better". In addition to statins, which have been available for several decades, ezetimibe, bempedoic acid (also as fixed dose combinations), and modulators of proprotein convertase subtilisin/kexin type 9 (PCSK9 inhibitors and inclisiran) are additionally very effective approaches to LLT, especially for those at very high and extremely high cardiovascular risk. In real life, however, clinical practice goals are still not met in a substantial proportion of patients (even in 70%). However, with the options we have available, we should render lipid disorders a rare disease. In April 2021, the International Lipid Expert Panel (ILEP) published its first position paper on the optimal use of LLT in post-ACS patients, which complemented the existing guidelines on the management of lipids in patients following ACS, which defined a group of "extremely high-risk" individuals and outlined scenarios where upfront combination therapy should be considered to improve access and adherence to LLT and, consequently, the therapy's effectiveness. These updated recommendations build on the previous work, considering developments in the evidential underpinning of combination LLT, ongoing education on the role of lipid disorder therapy, and changes in the availability of lipid-lowering drugs. Our aim is to provide a guide to address this unmet clinical need, to provide clear practical advice, whilst acknowledging the need for patient-centred care, and accounting for often large differences in the availability of LLTs between countries.

Genetic associations of metabolic factors and therapeutic drug targets with polycystic ovary syndrome

IntroductionPolycystic ovary syndrome (PCOS) is frequently accompanied with metabolic dysfunctions, yet the causal relationships between metabolic factors and PCOS remain to be conclusively established and etiology-based therapies are lacking. ObjectivesTo comprehensively identify the metabolic causal factors and potential drug targets for PCOS. MethodsThis genetic association study was conducted using bidirectional two-sample Mendelian Randomization (MR), multivariable MR (MVMR) and drug-target MR. Considering metabolic sexual dimorphism, female-specific genome-wide association studies (GWASs) for metabolic factors were obtained. To ensure the robustness of the findings, an additional independent PCOS GWAS dataset was utilized for replication. ResultsThe PCOS cohort included 10,074 PCOS cases (mean age 28 to 45 years) and 103,164 controls (mean age 27 to 60 years) of European ancestry. All participants were female. Employing two-sample MR analysis, we found that genetically proxied body mass index (BMI) (OR = 3.40 [95 % CI, 2.65–4.36]), triglyceride (TG) (OR = 1.54 [95 % CI, 1.17–2.04]), low-density lipoprotein cholesterol (LDL-c) (OR = 1.37 [95 % CI, 1.07–1.76]), and type 2 diabetes (T2D) (OR = 1.24 [95 % CI, 1.09–1.41]) were significantly associated with an increased risk of PCOS, whereas genetically predicted high-density lipoprotein cholesterol (HDL-c) (OR = 0.61 [95 % CI, 0.47–0.80]) decreased the odds of PCOS. Stepwise MVMR established a hierarchy of interactions among these metabolic factors, identifying BMI and HDL-c as the most prominent causal factors. Notably, drug-target MR analysis identified incretin-based therapeutics, PCSK9 inhibitors, LPL gene therapy, sulfonylureas, and thiazolidinediones as potential therapeutics for PCOS. All these findings were validated in an independent dataset. ConclusionThis study offered insights into the roles of obesity, diabetes, and dyslipidemia in PCOS etiology and therapeutics, underscoring the necessity for managing metabolic health in women and paving the way for tailored therapeutic strategies for PCOS based on its metabolic underpinnings.

PCSK9 inhibitors in the management of atherosclerotic cardiovascular disease: Current clinical trials and future directions

PCSK9 inhibitors in the management of atherosclerotic cardiovascular disease: Current clinical trials and future directions

Berberine: A Multi-Target Natural PCSK9 Inhibitor with the Potential to Treat Diabetes, Alzheimer's, Cancer and Cardiovascular Disease.

Berberine is a natural product with a wide range of pharmacological effects. It has antimicrobial, anti-cancer, anti-inflammatory, anti-hyperlipidemic, neuroprotective, and cholesterollowering properties, among others. It has been used in traditional Chinese and Ayurvedic medicine for 3000 years and is generally well-tolerated with few side effects. Its main drawback is low oral bioavailability, which has hindered widespread clinical use. However, recent interest has surged with the emergence of evidence that berberine is effective in treating cancer, diabetes, Alzheimer's disease, and cardiovascular disease via multiple mechanisms. It enhances insulin sensitivity and secretion by pancreatic β-cells in Type 2 Diabetes Mellitus in addition to reducing pro-inflammatory cytokines such as IL-6, IL-1β, TLR4 and TNF-α. These cytokines are elevated in Alzheimer's disease, cardiovascular disease, and diabetes. Reductions in pro-inflammatory cytokine levels are associated with positive outcomes such as improved cognition, reduced cardiovascular events, and improved glucose metabolism and insulin sensitivity. Berberine is a natural PCSK9 inhibitor, which contributes to its hypolipidemic effects. It also increases low-density lipoprotein receptor expression, reduces intestinal cholesterol absorption, and promotes cholesterol excretion from the liver to the bile. This translates into a notable decrease in LDL cholesterol levels. High LDL cholesterol levels are associated with increased cardiovascular disease risk. Novel synthetic berberine derivatives are currently being developed that optimize LDL reduction, bioavailability, and other pharmacokinetic properties.

PCSK9 Inhibitors: The Evolving Future.

PCSK9 inhibitors are a novel class of medications that lower LDL cholesterol (LDL-C) by increasing LDL receptor activity, promoting clearance of LDL-C from the bloodstream. Over the years, PCSK9 inhibitors have been explored as adjunct therapies to statins or as monotherapy in high-risk cardiovascular patients. This review aims to provide an updated perspective on PCSK9 inhibitors, assessing their clinical efficacy, safety, and significance, especially in light of recent clinical trials. The review examines the role of PCSK9 in cholesterol regulation and summarizes the results of major cardiovascular trials, including FOURIER, SPIRE-1, SPIRE-2, and ODYSSEY Outcomes. It also discusses emerging treatments like small interfering RNA (siRNA) therapies and evaluates PCSK9 inhibitor effects on LDL-C and lipoprotein(a) levels. Clinical trials have shown PCSK9 inhibitors reduce LDL-C by up to 60%. In the FOURIER trial, evolocumab reduced LDL-C by 59% and major cardiovascular events by 15%-20%. The SPIRE-2 trial, despite early termination, showed a 21% risk reduction in the primary composite endpoint with bococizumab. The ODYSSEY Outcomes trial reported a 57% LDL-C reduction with alirocumab, alongside a 15% reduction in adverse events. Emerging treatments like Inclisiran offer long-term LDL-C control with fewer doses. PCSK9 inhibitors are generally well-tolerated, with the most common side effect being injection site reactions. PCSK9 inhibitors significantly lower LDL-C and reduce cardiovascular events, offering promising therapies for high-risk patients, including those with familial hypercholesterolemia (FH) and those who cannot tolerate statins. Future research will focus on optimizing these inhibitors, integrating complementary therapies, and exploring gene-editing technologies to improve patient outcomes.

High discontinuation rate of statins among PCSK9i users: a nationwide study from 2015-2023

Abstract Background Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are recommended as additional lipid-lowering drug treatment for high-risk patients if the low-density lipoprotein cholesterol (LDL-C) targets are not achieved with statins and ezetimibe alone. Nationwide data from clinical practice on the use of PCSK9i are lacking. In 2015, PCSK9i became available in Norway with reimbursement restricted to patients with familial hypercholesterolemia (FH) and/or atherosclerotic cardiovascular disease (ASCVD) with LDL-C above certain levels. Purpose To investigate the use and adherence of lipid lowering drugs among a nationwide cohort of PCSK9i users, utlizing complete pharmacy dispensation data. Methods Information on all PCSK9i users ≤80 years with at least one year of follow-up after the first dispensation were extracted from the Norwegian Prescribed Drug Registry. We evaluated adherence to PCSK9i by calculating the proportion of days covered (PDC) during the initial year of PCSK9i therapy. Poor adherence was defined as PDC &amp;lt;80%, and discontinuation was defined as a gap in treatment ≥180 days during the follow-up period. We analyzed treatment patterns of statins and ezetimibe during the 1-year period before and after PCSK9i initiation by determining the proportion of patients with at least one dispensation of statin and/or ezetimibe treatment. Results A total of 2,997 PCSK9i users were identified. Median age at treatment initiation was 62 (IQR: 13) years and 43% were female. Non-adherence to PCSK9i was observed in 16% of the patients, and 18% discontinued treatment (Table). Non-adherence to PCSK9i was more prevalent in females, and in the lowest and highest age quartiles. No significant difference in non-adherence was found among patients with ASCVD compared to patients with FH. In the year preceding PCSK9i initiation, 74% of patients used statins (including combinations with ezetimibe), 11% used ezetimibe monotherapy, and 15% did not use any statin or ezetimibe treatment (Figure). During the year following PCSK9i initiation, 35% used statins (including combinations), 17% used ezetimibe monotherapy, and 48% did not use any statin or ezetimibe treatment. Among patients with ASCVD, 72% used statins prior to PCSK9i initiation, and 22% used statins after. Among patients with FH, 77% used statins prior to PCSK9i initiation, while 51% used statins after. Conclusion In this nationwide study of incident PCSK9i users, we observed a substantial decrease in usage of statins and ezetimibe following PCSK9i initiation. Further, almost 1 in 5 patients discontinued treatment with PCSK9i. There is a large potential for optimizing treatment and adherence to PCSK9i and conventional lipid-lowering drugs among Norwegian patients with ASCVD and familial hypercholesterolemia.Adherence and discontinuation to PCSK9iUse of statin and ezetimibe

PCSK9 inhibitors in HIV patients with dyslipidemia

Abstract Introduction Cardiovascular disease has become increasingly prevalent in the HIV (human immunodeficiency virus) population. Antiretroviral therapy and HIV itself independently increase the risk of dyslipidemia. While statins are currently the predominant therapy to treat dyslipidemia in HIV patients, drug-drug interactions and adverse drug events can limit their use. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a naturally occurring inhibitor of the LDL-receptor pathway. PCSK9 inhibitors offer an alternative in patients who cannot tolerate or need additional therapy in addition to statin for optimal dyslipidemia management. Purpose The purpose of this study is to compare major adverse cardiovascular events in HIV patients on a PCSK9 inhibitor (evolucumab, alirocumab, inclisiran) vs patients not on a PCSK9 inhibitor. Methods A retrospective cohort study was conducted using electronic medical records from a global federated health research network. The TriNetX network was searched on February 10, 2024, including records from 2020 to 2024. Patients were included based on a diagnosis of HIV status and concomitant dyslipidemia. Patients with HIV and dyslipidemia on a PCSK9 inhibitor were propensity-score matched for age, sex, race, and comorbidities with patients who were not on a PCSK9 inhibitor. The outcomes were mortality, myocardial infarction, heart failure and stroke. Results A total of 485 patients were included in the study. PCSK9 inhibitor use associated with 9% lower odds of all-cause mortality (odds radio, .29; 95% CI, 0.18-0.48; p&amp;lt;.0001). PCSK9 inhibitor use was also associated with 8% lower odds of heart failure (odds radio, .63; 95% CI, 0.47-0.85; p&amp;lt;.0023). No significant associations were noted for myocardial infarction (odds radio, .87; 95% CI, 0.63-1.21; p=0.406) or stroke (odds radio, .67; 95% CI, 0.45-1.01; p=0.052). Conclusion The role of dyslipidemia in HIV is challenging due the complex pathophysiology of HIV. There is an apparent increased risk of cardiovascular disease from the infection itself as well current antiretroviral therapies. While current guidelines recommend the use of statins as first line therapy for dyslipidemia in this population, the drug-drug interaction of statins with ARTs, as well as their side effects, limit their use at times. PCSK9 inhibitors are associated with lower odds of all-cause mortality and heart failure. No significant association was seen for myocardial infarction or stroke. They should be considered as an early intervention alongside statins in HIV patients with dyslipidemia. Further research should be done for the long term safety and tolerance of this therapy as well as cost-effectiveness and access to PCSK9 inhibitors in this population.

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 &amp;lt;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&amp;lt;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&amp;lt;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.