PCSK9 Inhibitors Research Articles

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 <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<.0001). PCSK9 inhibitor use was also associated with 8% lower odds of heart failure (odds radio, .63; 95% CI, 0.47-0.85; p<.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 <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.

PCSK9 inhibitors and coronary atherosclerotic plaque modification: a meta-analysis

Abstract Introduction Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as a promising class of medications, primarily recognized for their potent cholesterol-lowering effects. Beyond their established role in reducing low-density lipoprotein cholesterol levels, recent studies suggest a potential impact of PCSK9 inhibitors on the modification of coronary atherosclerotic plaques. Purpose The purpose of this meta-analysis is to comprehensively synthesize data from relevant clinical studies and trials that have investigated the effects of PCSK9 inhibitors on coronary atherosclerotic plaque characteristics. Methods We performed a literature search for studies assessing the evolution of coronary atherosclerotic plaques after treatment with a PCSK9 inhibitor compared to a control group. We excluded reviews, editorials, case reports/case series, and studies that did not use PCSK9 inhibitors or did not have a control group for comparison. The main outcomes of interest were the changes in percent atheroma volume (PAV), total atheroma volume (TAV), minimal fibrous cap thickness (FCT), lipid arch, as well as the number of patients with improved PAV at follow-up. Effect sizes are presented as standardized mean difference (SMD) or risk ratio (RR) with their corresponding 95% confidence intervals (CIs) and were pooled based on a random-effects model. Publication bias was assessed by funnel plot inspection and egger’s regression test. Results The literature search yielded 189 results. After application of the exclusion criteria, a total of 8 studies were selected for data extraction and inclusion in the meta-analysis. Concerning the intravascular ultrasound findings PCSK9 inhibitors induced greater reductions in PAV (SMD -2.70, 95% CI -5.24 to -0.15, p=0.04) (Figure 1) and TAV (SMD -2.46, 95% CI -4.68 to -0.23, p=0.03) (Figure 2), with a greater proportion of patients exhibiting an improvement in PAV (RR 1.30, 95% CI 1.20 to 1.41, p<0.01). Moving to optical coherence tomography parameters, patients treated with PCSK9 inhibitors had an increase in minimal FCT (SMD 2.09, 95% CI 0.12 to 4.07, p=0.04) and a lower lipid arch (SMD -0.64, 95% CI -0.97 to -0.32, p<0.01). Funnel plot inspection and egger’s regression test did not indicate the presence of publication bias. Conclusion This meta-analysis suggests that PCSK9 inhibitors use is associated with a favorable coronary atherosclerotic plaque remodeling.Figure 1Figure 2

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.

The impact of discontinuing proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors on clinical outcomes

Abstract Background/Introduction Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors have demonstrated efficacy in lowering low-density lipoprotein cholesterol (LDL-C) levels and reducing the risk of cardiovascular events. Despite these advantages, some patients are unable to continue the use of PCSK9 inhibitors due to financial or other reasons. Limited clinical studies have been conducted to investigate the clinical outcomes of patients discontinuing PCSK9 inhibitors for various reasons. Purpose This study aims to specifically investigate patients who were unable to continue PCSK9 inhibitors, with a particular focus on those discontinuing due to financial or other reasons. The primary objective is to assess the impact of discontinuation on major adverse cardiovascular events (MACE). Methods This study focused on 205 Japanese patients who received PCSK9 inhibitors between July 2016 and December 2023. The clinical outcomes of patients who continued or discontinued PCSK9 inhibitors were comprehensively compared. The primary endpoint was major adverse cardiovascular events (MACE), encompassing cardiovascular death, coronary revascularization, target lesion revascularization (TLR), and fatal or non-fatal myocardial infarction (MI). Results Among 205 patients (median age: 69 years; interquartile range [IQR]: 60-76 years 68% male), the median follow-up was 413 days (IQR, 49-1148 days). At one year, the median LDL-C was 43mg/dL, and 158 patients (77%) achieved LDL-C <70 mg/dL. During the follow-up, 64% (131 patients) continued PCSK9 inhibitors, while 36% (74 patients) discontinued. Of the discontinuation group, 30% (22 patients) cited financial problems, 24% (18 patients) clinical stability, and 12% (9 patients) patient preference. Multivariate Cox regression analysis revealed that the group discontinuing PCSK9 inhibitors had a higher incidence of MACE than the group that continued (hazard ratio: 1.84; 95% confidence interval: 1.02 to 3.55; p=0.05). Conclusions This study suggests an increased risk of MACE when PCSK9 inhibitors are discontinued for financial or other reasons. This insight is vital for healthcare management and decision-making among medical practitioners.PCSK9: continuation vs discontinuation

Comparative efficacy of colchicine and intensive LDL-C lowering in patients with ASCVD receiving statins: a network meta-analysis of randomised controlled trials

Abstract Background Adding intensive low-density lipoprotein cholesterol (LDL-C) lowering treatments or colchicine to statins resulted in additional cardiovascular benefits. However, the relative efficacy and priority of these agents are unclear. Purpose We aimed to compare the effects of these supplementary agents on cardiovascular outcomes in patients with atherosclerotic cardiovascular diseases (ASCVD) receiving statins. Methods We performed a systematic review and frequentist network meta-analysis on randomized controlled trials. The primary efficacy endpoint was the main adverse cardiovascular event (MACE), and the secondary efficacy endpoints were myocardial infarct, stroke, coronary revascularization, cardiovascular death and all-cause mortality. The safety endpoints were treatment discontinuation and non-cardiovascular death. Colchicine was used as reference treatment. Random-effects model was used in case of high heterogeneity, the fixed-effects model was preferred otherwise. We ranked the comparative effects of all drugs with surface under the cumulative ranking (SUCRA) probabilities. Results 17 trials totaling 85823 participants treated with colchicine, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, Niemann-Pick C1-like 1 protein (NPC1L1) inhibitor and ATP citrate lyase (ACL) inhibitor were included. Compared with colchicine, NPC1L1 inhibitor was associated with increased risk of MACE (risk ratio [RR]: 1.39, 1.21-1.59), stroke (RR: 1.81, 1.09-3.00) and coronary revascularization (RR: 1.36, 1.11-1.68), and PCSK9 inhibitor was associated with increased risk of MACE (RR: 1.27, 1.10-1.46). However, NPC1L1 inhibitor (RR: 0.68, 0.48-0.96) and PCSK9 inhibitor (RR: 0.64, 0.44-0.93) were associated with reduced risk of non-cardiovascular death in comparison to colchicine. PCSK9 inhibitors had a lower risk of MACE (RR: 0.91, 95% CI: 0.85-0.98) and coronary revascularization (RR: 0.89, 95% CI: 0.81-0.97) compared with NPC1L1 inhibitor. Although no regimen prolonged survival, colchicine had the lowest rank at non-cardiovascular death and the worse performance on all-cause mortality. Conclusions In patients with ASCVD receiving statins, inflammation-inhibiting with colchicine seems to be superior to intensive LDL-C lowering therapy with PCSK9 inhibitor or NPC1L1 inhibitor in cardiovascular prevention. However, using colchicine as an alternative to intensive lipid-lowering therapy may need to be weighed against the greater cardiovascular benefits and the potential harms of higher non-cardiovascular death. Given the worse performance of colchicine on survival based on current evidence, colchicine may be more appropriate for patients who have been treated with intensive LDL-C-lowering agents but still have recurrent cardiovascular events.Forest plots of included agentsRadar plot of treatments based on SUCRA

Strike early-strike strong lipid-lowering strategy with PCSK9i in ACS patients. Real-world evidence from AT-TARGET-IT registry

Abstract Background/Introduction No data are available on early initiation of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in patients with acute coronary syndrome (ACS) in real-world. Purpose This study investigates the effects of PCSK9i started at time of ACS hospitalization on lipid control and major CV events in real-world. Methods The lipid control outcome was the percentage of patients reaching the LDL-C target of < 55 mg/dL at first lipid control. The clinical outcome was the incidence of composite major CV events (all cause death, non-fatal MI, non-fatal stroke, and ischemia-driven revascularization) during follow-up in relation to quartiles of LDL-C at first lipid control. Results We included 771 patients with ACS from AT-TARGET-IT registry, receiving PCSK9i prescription during hospitalization or at discharge. Median LDL-C was 137 mg/dL and decreased to 43 mg/dL at first lipid control. 527 (68.3%) patients achieved LDL-C target at the first lipid control at a median time of 37 days from hospitalization; of them, 404 (76.8%) were discharged on statin plus ezetimibe background therapy. Event curves through a median follow-up of 11 months across quartiles of LDL-C showed a stepwise lower risk of 4P-MACE, 3P-MACE, all-cause mortality, and ischemia-driven revascularization in lower quartile of LDL-C values at first lipid control (<23 mg/dL) and in patients reaching LDL-C <55 mg/dL. Conclusions Intensive and early lipid-lowering therapy using PCSK9i in patients with ACS (strike early strike strong strategy) is safe and effective in clinical practice and associated with a reduction of residual CV risk.

Effects of lipid-lowering therapies on lipoprotein(a) levels in patients with dyslipidemia: a systematic review and network meta-analysis of 64 randomised controlled trials

Abstract Background Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular disease. However, there has yet to be a drug approved specifically for lowering Lp(a). There is paucity of studies evaluating the use of current lipid-lowering agents, and their effects, if any, on Lp(a). Purpose We aimed to identify and compare the effects of lipid-lowering therapies on Lp(a) levels, cardiovascular and safety outcomes, in patients with dyslipidemia. Methods A systematic search was performed across four databases (PubMed, Embase, Scopus, Cochrane) for randomised controlled trials (RCTs) published from inception to 3 January 2023. The percentage change of serum Lp(a) levels, cardiovascular and safety outcomes were compared among statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin), fibrates, ezetimibe, niacin, PCSK9 inhibitors (alirocumab, evolocumab, bococizumab) and inclisiran, in patients with primary dyslipidemia. Frequentist network meta-analysis was performed to compare the treatment effects among different drug classes, stratified by use of background statin therapy. Results A total of 64 RCTs were included, comprising 55,256 patients. In patients on background statin therapy, PCSK9 inhibitors significantly lowered Lp(a) levels, compared with placebo (mean difference [MD] -26.8, 95% confidence intervals [95%CI] -30.8 to -22.7), ezetimibe (MD -21.6, 95%CI -31.4 to -11.8), fibrates (MD -19.4, 95%CI -37.4 to -1.5), and niacin (MD -13.8, 95%CI -25.6 to -2.1). PCSK9 inhibitors were associated with lower risk of major adverse cardiovascular events and similar risk of treatment-related adverse events than placebo. Comparing the PCSK9 inhibitors, evolocumab achieved greater Lp(a)-lowering than alirocumab in patients on background statin therapy (MD -11.4, 95%CI -18.6 to -4.1), including those with heterozygous familial hypercholesterolemia. Niacin also achieved 12.9% (95%CI 1.8 to 24.0) reduction in Lp(a) compared with placebo, but had a higher risk of treatment-related adverse effects than fibrates. Statin monotherapy did not affect Lp(a) levels, regardless of type or intensity of statin therapy. Ezetimibe and fibrate had no effect on Lp(a) levels. Conclusions PCSK9 inhibitors produced the greatest effect on Lp(a) levels, compared with other lipid-lowering therapies. Further studies into PCSK9 inhibitors are necessary to characterise their efficacy and safety specifically for Lp(a)-lowering, and elucidate the impact of Lp(a) reduction on cardiovascular risk.% change in Lp(a) levels

Clinical reality and challenges with familial hypercholesterolemia patients management. 2024 results from the Regional Center for Rare Diseases (RCRD) Registry in Poland

Abstract Background HeFH is one of the most prevalent genetic diseases significantly increasing the risk of CVD events and mortality. Despite new achievements with earlier diagnosis and new effective drugs, most of heFH patients do not achieve LDL-C goal and are still on residual CVD risk. Purpose We aimed to present the most recent data from the regional FH registry in Poland to show the challenges and reality of everyday clinical management with FH patients. Methods The registry is conducted at the RCRD in the 2nd largest, supraregional hospital in Poland. The main inclusion criteria were being phenotypically or genetically diagnosed with FH. Nonadherence was investigated based on detailed interview, monitoring the treatment’s effects and purchasing prescribed medications. For this analysis we investigated only adult FH patients from the registry. Due to small number of cases (n=5), patients treated with inclisiran were not included in this analysis. Results We included 142 consecutive heFH patients at mean age 45,8±14,9 years (min/max 18-75 years; 60% women). Mean BMI was 29.6±5.52 kg/m2, mean baseline TC was 282.9±80 mg/dl (the highest observed was 600 mg/dl), LDL-C 204.2±72.5 mg/dL (the highest observed -762 mg/dl), TG - 151.1±123.4 mg/dl, Lp(a) 37.6±41.5 mg/dl and HDL-C - 52.3±14.2 mg/dl. Most patients were diagnosed with LDLR (72%) or APOB (24%) mutations. High intensity statin therapy was used in 74.3% of patents, ezetimibe (mostly as a part of combination LLT) in 47.2%, and PCSK9 inhibitors in all those that met the reimbursement criteria – 25.6% of FH patients. Non-adherence to statin therapy and ezetimibe in the follow up of 2 years was 27%. In patients treated with statin therapy and ezetimibe mean achieved LDL-C was 153.6±82.82 mg/dl and on triple therapy - 64.5±43.73 mg/dl. Mean achieved LDL-C in the investigated population was 87.9±55.5 mg/dl. LDL-C goal was achieved in 39% of patients – in those treated with triple therapy with PCSK9 inhibitors it was 57.14%, and in those on statins and ezetimibe only 27.1%. Combination therapy of statins and ezetimibe did not significantly change baseline Lp(a) level (p=0.109), but when PCSK9 inhibitors were introduced the mean Lp(a) reduction by 34.2% (p=0.049) was observed. Based on the multivariable regression analysis, the following factors played the most important role for FH patients to be on LDL-C target: DLCN total score (OR 1.21, 95%CI: 1.04-1.40; p=0.013), DLCN category (10.39, 1.43-75.29; p=0.021), ezetimibe use (4.78, 1.15-19.92; p=0.031), and PCSK9 inhibitors use (4.56; 1.40-14.86; p=0.012). Conclusions FH patients in Poland are diagnosed definitely too late (45 years) and most of them are still not on LDL-C goal. Double and especially triple therapy significantly, even 5 times, increase the chance of achieving LDL-C goal, therefore PCSK9 inhibitors should be available for all FH patients, without the limitations existing currently e.g., within B101 drug program in Poland.

Comparing PCSK9 inhibitor prescription rates within high-risk populations: diabetes mellitus, multi-territory vascular disease, multivessel and recurrent coronary artery disease

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are subsidised in Australia for treatment of hypercholesterolemia in particularly high-risk patients with atherosclerotic cardiovascular disease (ASCVD). These high-risk groups are defined as: diabetes mellitus (with age≥60, Aboriginal or Torres Strait Islander origin or microalbuminuria), recurrent ASCVD (≥2 events within 5 years), multivessel coronary disease (≥50% stenosis in ≥2 large vessels) and multi-territory vascular disease (concurrent cerebrovascular or peripheral vascular disease). Methods A retrospective observational analysis was conducted on high-risk patients with LDL>2.6 admitted to a quaternary hospital with ASCVD between 2020-2022. Australian Pharmaceutical Benefits Scheme (PBS) criteria was applied to assess and compare PCSK9 inhibitor eligibility and prescription rates within high-risk populations. Results In total, 477 ASCVD patients with LDL>2.6 were included. This was further categorised into: multivessel coronary disease (n=239, 50.1%), diabetes mellitus (n=60, 12.6%), recurrent ASCVD (n=55, 11.5%) and multi-territory vascular disease (n=32, 6.7%), p<0.001. When 2020 PBS criteria was applied, the number of eligible patients were 16/239 (6.7%), 5/60 (8.3%), 13/55 (23.6%) and 4/32 (12.5%) respectively, p=0.002. Of PBS eligible patients, the number prescribed PCSK9 inhibitors were: 7/16 (43.8%) for multi-vessel coronary disease, 1/5 (20%) for diabetes mellitus, 4/13 (30.8%) for recurrent ASCVD and 1/4 (25%) for multi-territory vascular disease patients (p=0.73). Conclusion Although there was a significantly higher prevalence and proportion of eligible multivessel coronary disease patients, prescribing rates for PCSK9 inhibitor therapy remain low amongst all high-risk eligible groups including diabetes mellitus, multi-territory vascular disease, multivessel and recurrent coronary artery disease.

Efficacy of lipid lowering therapy beyond statins to prevent cardiovascular events

Abstract Background Lipid lowering therapy is a key cornerstone in secondary prevention of patients with coronary artery disease. However, only a minority of patients with statin therapy reach LDL thresholds as suggested by the ESC. Ezetimibe, bempedoic acic, and proprotein convertase subtilisin/kexin type 9 (PCSK-9) (synthase-) inhibitors allow for the reduction in LDL-cholesterol in addition to statin therapy. Purpose We aimed to perform a meta-analysis of existing trials, evaluating how lipid lowering therapy beyond statins impacts cardiovascular outcome. In specific, we evaluated the potential influence of duration of follow-up on the association with mortality endpoints. Methods We performed a systematic search using the Pubmed, Cochrane, SCOPUS, and Web of Science databases for studies, evaluating the impact of an intensified lipid lowering therapy via ezetimibe, bempedoic acid, Bococizumab, Alirocumab, Evolocumab, Inclisiran in addition to statin therapy compared to statin therapy alone. Manuscript and congress presentations, published until 1st of August 2023, were included. We made our search specific and sensitive using Medical Subject Headings terms and free text and considered studies published in English language. Search terms used were : "Bempedoic Acid" or "Bococizumab" or "Alirocumab" or "Evolocumab" or "Ezetimibe" or "Inclisiran" and "statin" and "cardiovascular events". Results A total of 123,785 patients from 15 randomized controlled trials (IMPROVE-IT, FOURIER, ODYSSEY Outcomes, ODYSSEY LONG TERM, EWTOPIA 75, PACMAN-AMI, RACING, SIPRE I, SPIRE II, OSLER-1 and OSLER-2, CLEAR HARMONY, CLEAR OUTCOMES, CLEAR SERENITY, CLEAR WISDOM) were included. Treatment with ezetimibe or a PCSK-9 inhibitor was associated with a 19% risk reduction in cardiovascular events (OR [95%CI]: 0.81 [0.75; 0.86]). Effect sizes were similar for myocardial infarction (0.81 [0.74; 0.89]) and even more pronounced for ischemic stroke (0.77 [0.70; 0.84]). In contrast, all-cause mortality was not improved by the intensified lipid lowering therapy (0.99 [0.93; 1.04]). Stratifying by follow-up duration of < vs. ≥ 3 years, no improvement in all-cause mortality was observed in both groups (<3 years: 1.04 [0.93; 1.17]; ≥3 years: 0.97 (0.88; 1.06). No relevant heterogeneity and inconsistency between groups was present in all analyses (detailed data not shown). Conclusion Intensified LDL-lowering therapy with ezetimibe, bempedoic acic or PCSK-9 inhibitors, in addition to statins, reduces the risk of myocardial infarction and stroke, however, does not impact overall mortality. A potential survival benefit was also not observed in studies with follow-up duration of ≥ 3 years.

Lower rate of ischemic events with PCSK9 inhibition in patients with atherosclerotic cardiovascular disease but without prior ischemic events

Abstract Background Individuals with atherosclerotic cardiovascular disease (ASCVD) without prior ischemic events, such as myocardial infarction (MI), ischemic stroke (IS), or unstable angina (UA) hospitalization, are at very high risk for having an event. Purpose To estimate the impact of PCSK9 inhibitor (PCSK9i) therapy on ischemic events in this population. Methods Patients with ASCVD were initially selected from the Optum Research Database during Jan 2016 to Dec 2022. For selected patients the index (time zero for follow-up) was required to be in a period of ASCVD without prior ischemic events, however patients may have ischemic events after index. Determination of ASCVD and ischemic events was based on diagnosis and procedure codes. For the PCSK9i group, index was initiation of PCSK9i and information before index was examined to ascertain ASCVD and rule out prior ischemic events. For each patient in the PCSK9i group, up to 5 matching patients in the no-PCSK9i group were chosen based on propensity score (PS) distance, with maximum allowable PS distance of 0.1. Among all possible choices for index for the no-PCSK9i patient, the selected one minimized the PS-distance. The primary endpoint was defined as the composite of nonfatal MI, nonfatal IS, and all-cause death. In order to further reduce bias and ensure causally interpretable estimation, the G-computation methodology was employed by marginalizing the conditional treatment effect (as estimated by a Cox model) over the baseline characteristics. Two effects were estimated: intention-to-treat (ITT) where only the treatment assignment at index was considered as the intervention, and per-protocol (PP) where the effect of sustained treatment with PCSK9i over time was estimated. Results A total of 15,067 and 66,470 patients met the selection criteria for the PCSK9i and no-PCSK9i groups, respectively. Baseline characteristics were well-balanced at index. G-computation analysis resulted in estimated survival curves over time in the two groups for the ITT and PP scenarios (Figures 1 and 2). For the ITT scenario, the estimated 5-year event rate was 18.7% (95% confidence interval [CI]: 17.1%–20.1%) in the PCSK9i group and 28.4% (95% CI: 27.7%–29.1%) in the no-PCSK9i group. The implied relative risk reduction (RRR) and absolute risk reduction (ARR) were 34.3% (p<0.001) and 9.7% (p<0.001), respectively, in favor of the PCSK9i group. For the PP scenario, the estimated 5-year event rate was 10.7% (95% CI: 9.7%–11.7%) in the PCSK9i group and 28.8% (95% CI: 28.3%–29.5%) in the no-PCSK9i group. The implied RRR and ARR were 62.7% (p<0.001) and 18.1% (p<0.001), respectively, in favor of the PCSK9i group. Conclusions Initiation of PCSK9i in patients with ASCVD but without prior ischemic events is associated with significantly and substantially lower risk for ischemic events.Event Rates Intention-to-Treat ScenarioEvent Rates Per-Protocol Scenario

Efficacy of combination lipid lowering therapy in achieving low density lipoprotein cholesterol targets after one month of event in patients with acute coronary syndrome

Abstract Introduction Rapid reduction in low-density lipoprotein cholesterol (LDL-C) levels reduces the risk of recurrent events in patients with acute coronary syndrome (ACS) with benefits proportional to LDL-C reduction. Early use of combination lipid-lowering therapy (LLT) is therefore recommended. Proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i) combined with high-intensity statins (HIS) improve LDL-C goal attainment but are unaffordable for many patients in India and worldwide. Purpose We share our experience with the use of dual RE (rosuvastatin plus ezetimibe) and triple REB (rosuvastatin plus ezetimibe and bempedoic acid) combination LLT in patients admitted with ACS. Methods All ACS patients admitted to our institute over one year (January 2023 to December 2023) were considered in this retrospective analysis. Those with unavailable lipid profile reports, either at the time of ACS or at 1-month follow-up, were excluded. Clinical and laboratory details were obtained from hospital records. The primary objective was to assess the percentage change in LDL-C levels from index event to 4 weeks follow-up. Results A total of 299 patients were included, out of which 60 were on HIS alone, 71 were on RE, and 168 were on REB (Figure). The majority (99%) of patients in the REB group were statin naïve, compared to the other two groups. The baseline mean LDL-C levels at the time of the index event were 95.3+30.5, 103.2+39.6, and 115.6+32.9 mg/dl, respectively (p<0.001) (Table). The mean LDL-C levels at four weeks post-ACS reduced to 52.9+21.2, 45.9+20.5, and 43.7+15.4 mg/dl, respectively (p<0.01). The percentage reduction in LDL-C level was 44.4%, 55.5%, and 62.2%, respectively (p<0.001). REB enabled 70.8% and 95.2% of patients to achieve the Lipid Association of India, and American College of Cardiology recommended LDL-C targets of <50 mg/dl and <70 mg/dl within 4 weeks. These target levels were achieved in 67.6% and 88.7% of patients on the dual RE therapy and 50% and 81.6% of patients, respectively, on HIS alone. Conclusion Our study demonstrates the capacity to rapidly achieve LDL-C goals after ACS with triple REB therapy, an affordable regimen compared to costly PCSK9i therapy.Figure.Lipid lowering strategies usedComparison of study groups