PCSK9 Inhibitors in Clinical Practice: Experience of a Specialized Lipid Center

Aim. To characterize patients receiving PCSK9 inhibitors, and assess the efficiency of their treatment in a specialized lipid center.Material and methods. A retrospective analysis of the medical records of patients who visited the Lipid clinic of the National Medical Research Center for Therapy and Preventive Medicine (Moscow, Russia), receiving PCSK9 inhibitor and having lipid profile in dynamics, was carried out (n=77). Cardiovascular risk (CVR) and low-density lipoprotein cholesterol (LDL-C) target levels were evaluated in accordance with the Russian guidelines for the diagnostics and correction of dyslipidemias 2020.Results. Of 77 patients taking PCSK9 inhibitors (44.2% males, the median of age 56 [47; 66] years), the majority (64.0%) had a probable or definite familial hypercholesterolemia (FH). The proportion of other lipid metabolism disorders, pure hypercholesterolemia and combined hyperlipidemia was 21% and 15%. More than half of the patients (68.8%) had a very high CVR, mainly due to the presence of coronary heart disease (84.9%). The proportion of patients receiving PCSK9 inhibitors as monotherapy was 7.8%, in combination with high-intensity statin therapy – 33.8%, as part of triple lipid-lowering therapy (high-intensity statin, ezetimibe, PCSK9 inhibitors) – 50.6%. Addition of PCSK9 inhibitors to combined lipid-lowering therapy enabled to reduce the LDL-C level to 1.02 [0.62; 1.39] mmol/l with its total decrease from the baseline by 87.3%. While taking PCSK9 inhibitors, LDL-C <1.8 mmol/l and <1.4 mmol/l achieved at 78.3% and 57.7% FH patients with high and very high CVR, respectively. Among patients with other hyperlipidemias, 74.1% of patients with very high CVR was achieved the target LDL-C level <1.4 mmol/l.Conclusion: In a specialized lipid center, PCSK9 inhibitors are prescribed to patients with high or very high CVR, most of whom are FH patients. The effectiveness of the use of PCSK9 inhibitors in real-world practice is comparable to the results of clinical trials.

PCSK9 as a Target for Development of a New Generation of Hypolipidemic Drugs

PCSK9 has now become an important target to create new classes of lipid-lowering drugs. The prevention of its interaction with LDL receptors allows an increase in the number of these receptors on the surface of the cell membrane of hepatocytes, which leads to an increase in the uptake of cholesterol-rich atherogenic LDL from the bloodstream. The PCSK9 antagonists described in this review belong to different classes of compounds, may have a low molecular weight or belong to macromolecular structures, and also demonstrate different mechanisms of action. The mechanisms of action include preventing the effective binding of PCSK9 to LDLR, stimulating the degradation of PCSK9, and even blocking its transcription or transport to the plasma membrane/cell surface. Although several types of antihyperlipidemic drugs have been introduced on the market and are actively used in clinical practice, they are not without disadvantages, such as well-known side effects (statins) or high costs (monoclonal antibodies). Thus, there is still a need for effective cholesterol-lowering drugs with minimal side effects, preferably orally bioavailable. Low-molecular-weight PCSK9 inhibitors could be a worthy alternative for this purpose.

Inclisirán as an alternative treatment for Hypercholesterolemia

Hypercholesterolemia (CH) is defined as the elevation of serum cholesterol levels, especially low-density lipoprotein (LDL) cholesterol, which is considered to be one of the most relevant risk factors for triggering cardiovascular disease, for This is vitally important to start treatment, there are several highly useful pharmacological groups for lipid-lowering therapy, among them we highlight the PCSK9 inhibitors, among the molecules that are part of this group we find inclisirán, this being a structure that promises a lot in regarding the management of hypercholesterolemia.

The Role of Lipid-Lowering Treatment in the Secondary Prevention of Ischemic Stroke

Dyslipidemia is a major modifiable risk factor for ischemic stroke. Treatment with statins reduces the incidence of recurrent ischemic stroke and also reduces coronary events in patients with a history of ischemic stroke. Therefore, statins represent an important component of secondary prevention of ischemic stroke. In patients who do not achieve low-density lipoprotein cholesterol (LDL-C) targets despite treatment with the maximal tolerated dose of a potent statin, ezetimibe should be added to their lipid-lowering treatment and also appears to reduce the risk of cardiovascular events. Selected patients who do not achieve LDL-C targets despite statin/ezetimibe combination are candidates for receiving proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Finally, it appears that adding icosapent ethyl might also reduce cardiovascular morbidity in patients who have achieved LDL-C targets but have persistently elevated triglyceride levels.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors Induced Neurocognitive Disorder: A Pharmacovigilance Study by Analyzing the Data from the U.S. FDA Adverse Event Reporting System

PurposeThe neurocognitive disorder is a rare adverse event associated with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors in the randomized controlled trail (RCTs), there was limited evidence to prove their relation. This study aimed to assessing their association by detecting adverse signal in the FDA Adverse Event Reporting System (FAERS).MethodsThe disproportionality analysis was conducted to detect the potential adverse signal between neurocognitive disorders and PCSK9 inhibitors. The adverse event reports from the first quarter of 2004 to the second quarter of 2020 were extracted from the FAERS database.ResultsThere were 81,272 adverse reports correlated with the usage of the PCSK9 inhibitors, of which 152 reports corresponded with our inclusion criteria. Among them, there were 106 and 46 neurocognitive disorder reports related to the usage of Evolocumab and Alirocumab, respectively. The total ROR value presented negative disproportionality, however, Alirocumab has generated a positive signal with a higher ROR value in comparison with Evolocumab. Moreover, there were 61.19% of adverse reports were submitted by healthcare professionals. As for the outcome events, 7.79% of patients had initial or prolonged hospitalization and 3.90% suffered a disability.ConclusionThe pharmacovigilance research helps to find out more about PCSK9 inhibitor-related neurocognitive disorders. Although the positive signal was identified in Alirocumab in this study, it still required further research to prove the association between neurocognitive disorder and PCSK9 inhibitors. In addition, the tenable mechanism should be explored, which can improve the insight of this neotype lipid-lowering medicine.

Lipid lowering therapy in primary and secondary prevention in Austria: are LDL-C goals achieved?

Summary Background Cardiovascular disease (CVD) is the most frequent cause of death in Austria. The European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines recommend intensive lipid lowering therapy (LLT) in patients at high or very high CV risk. Lipid management and achievement of low-density lipoprotein cholesterol (LDL-C) goals in Austria have not recently been assessed. Methods Subgroup analysis for Austria of a European 18 country, cross-sectional, observational study. Patients received LLT for primary (PP) or secondary prevention (SP). Data including LLT in the preceding 12 months and most recent LDL‑C were collected during a single visit between June 2017 and November 2018. Achievement of the risk-based 2016 and 2019 ESC/EAS LDL‑C goal while receiving stabilized LLT was assessed. Results A total of 293 patients were enrolled from 8 Austrian sites, of which 200 (PP = 104, SP = 96) received stabilized LLT at the LDL‑C measurement date. Overall, 58% (71% PP, 43% SP) and 38% (52% PP, 23% SP) achieved the risk-based 2016 and 2019 goals, respectively. Most patients received moderate-intensity statin monotherapy (46%), while 34% used high-intensity statin monotherapy. Combination therapy of moderate/high-intensity statin with ezetimibe (12%), or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors with statin ± ezetimibe (1%), was used infrequently. Conclusion The current Austrian routine lipid management using mainly moderate-intensity or high-intensity statin monotherapy is insufficient to attain ESC/EAS guideline goals, in particular the more stringent 2019 recommendations, a situation comparable to other participating European countries. In addition to switching to and optimizing doses of high-intensity statins, a combination with ezetimibe or PCSK9 inhibitors will be needed in many cases.

Exploring pleiotropic effects of lipid modifiers on coagulation and hemostasis with genetics

Background: Statins have long been suspected to have pleiotropic effects via thrombotic factors. Randomized controlled trials are too limited to be definitive. We examined the associations of genetically mimicking effects of statins, PCSK9 inhibitors and alternative lipid targets (in genes LDLR, APOC3, and LPL) on key indicators of coagulation system function, i.e., prothrombin time (PT) and activated partial thromboplastin time (aPTT). Methods: We assessed the effect of established genetic mimics of effects of lipid modifiers and alternative lipid treatment targets on PT (n=58,110) and aPTT (n=37,767), all transformed to z-scores, using Mendelian randomization taking advantage of Biobank Japan. Ischemic heart disease (IHD) was a control outcome. Results: Genetically mimicked effects of statins increased PT by 0.31 standard deviation (SD) per SD increase in LDL (95% confidence interval (CI) 0.10 to 0.51) based on rs12916 but did not affect aPTT. Genetically mimicking effects of targeting LDLR increased PT based on rs688 (0.33 SD per SD increase in TG, 95% CI 0.03 to 0.63) but did not affect aPTT. Genetically mimicking effects of PCSK9 inhibitors or targeting APOC3, or LPL had no effect on PT or aPTT. Genetically mimicking effects of statins, PCSK9 inhibitors and alternative lipid targets reduced risk of IHD in Biobank Japan. Conclusion: Statins, and possibly targeting LDLR, may also act via a coagulation cascade factor, likely specific to the extrinsic or common pathway. Further elucidation of the mechanistic pathway may facilitate development of new interventions and inform use of statins particularly in relation to use of other anticoagulants.

Association Between Circulating Proprotein Convertase Subtilisin/Kexin Type 9 Concentrations and Cardiovascular Events in Cardiovascular Disease: A Systemic Review and Meta-Analysis

Background: A large amount of evidence suggests that proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors have clinical benefits in patients with cardiovascular disease (CVD). However, whether PCSK9 concentrations predict future cardiovascular (CV) events remains unclear.Methods: We conducted a meta-analysis to investigate the ability of PCSK9 concentrations to predict future CV events in patients with established CVD. A comprehensive search of electronic databases was conducted in June 2021. We included relative risk (RR) estimates with 95% CI or events of interest.Results: Eleven cohort studies including 8,471 patients with CVD were enrolled. The pooled RR of CV events for the increase in the circulating baseline PCSK9 concentrations by 1 SD showed a positive association in a random-effect model (RR 1.226, 95% CI: 1.055–1.423, P = 0.008). Similarly, the risk of the total CV events increased by 52% in the patients in the highest tertile compared with those in the lowest tertile of circulating PCSK9 concentrations (RR 1.523, 95% CI: 1.098–2.112, P = 0.012). The association between PCSK9 and CV events was stronger in stable patients with CVD, patients treated with statins, and Asian patients.Conclusions: High PCSK9 concentrations are significantly related to the increased risk of future CV events. These results enrich the knowledge of PCSK9 function and suggest the further possible clinical role of PCSK9 inhibitors.