Letter by Koh Regarding Article, "Pleiotropic Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors?"

PCSK9 inhibition is an effective therapy to reduce LDL cholesterol (LDL-C) and cardiovascular events. A recent study shows that one or two doses of inclisiran, a long-acting synthetic small-interfering RNA (siRNA) that selectively targets hepatic PCSK9, causes a sustained reduction of plasma LDL-C for up to 6 months. Pending further studies of safety and efficacy, this may represent an important addition to the armamentarium for inhibiting PCSK9.

Elevated low-density lipoprotein cholesterol (LDLC) levels in the plasma is the most important causative factor of atherosclerosis and associated ischemic cardiovascular diseases. The LDL receptor (LDLR) is the preferential pathway through which LDLs are cleared from the circulation. LDLs bound to the LDLR are internalized into clathrin-coated pits and subsequently undergo lysosomal degradation, whereas the LDLR is recycled back to the plasma membrane. See accompanying article on page 1333 Familial hypercholesterolemia (FH) is an autosomal dominant disorder associated with elevated LDL levels and premature coronary heart disease. FH is caused primarily by mutations of the LDLR or of apolipoprotein B100 (apoB100), the protein component of LDL that interacts with the LDLR. In 2003, “gain of function” mutations on a newly identified gene, proprotein convertase subtilisin/kexin type 9 ( PCSK9), were associated with FH. In 2005, a causative association was established between “loss of function” mutations in PCSK9 and low LDLC levels in 2% of the African-American population. The coronary heart disease risk in these individuals was reduced by 88%. As a result of these landmark studies (reviewed in Reference 1), PCSK9 became the subject of intensive research to discover the underlying mechanisms. PCSK9 is a serine protease mainly expressed in the liver and the intestine. It acts by reducing the amount of LDLR in hepatocytes. This was demonstrated in vitro and in mouse models …

Development of Novel DNA-Encoded PCSK9 Monoclonal Antibodies as Lipid-Lowering Therapeutics.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that regulates the expression of LDL receptor (LDLR) protein. Gain-of-function mutations in PCSK9 cause hypercholesterolemia, and loss-of-function mutations result in lower plasma LDL-cholesterol. Here, we investigate the kinetics and metabolism of circulating PCSK9 relative to tissue levels of LDLRs. The administration of recombinant human PCSK9 (32 microg) to mice by a single injection reduced hepatic LDLRs by approximately 90% within 60 min, and the receptor levels returned to normal within 6 h. The half-life of the PCSK9 was estimated to be approximately 5 min. Continuous infusion of PCSK9 (32 microg/h) into wild-type mice caused a approximately 90% reduction in hepatic LDLRs within 2 h and no associated change in the level of LDLR in the adrenals. Parallel studies were performed using a catalytically inactive form of PCSK9, PCSK9(S386A), and similar results were obtained. Infusion of PCSK9(D374Y), a gain-of-function mutation, resulted in accelerated clearance of the mutant PCSK9 and a greater reduction in hepatic LDLRs. Combined, these data suggest that exogenously administrated PCSK9 in plasma preferentially reduces LDLR protein levels in liver at concentrations found in human plasma and that PCSK9's action on the LDLR is not dependent on catalytic activity in vivo.

price tag raises concerns about affordability.

HomeCirculationVol. 138, No. 12Letter by Koh Regarding Article, “PCSK9 Variants, Low-Density Lipoprotein Cholesterol, and Neurocognitive Impairment: Reasons for Geographic and Racial Differences in Stroke Study (REGARDS)” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Koh Regarding Article, “PCSK9 Variants, Low-Density Lipoprotein Cholesterol, and Neurocognitive Impairment: Reasons for Geographic and Racial Differences in Stroke Study (REGARDS)” Kwang Kon Koh, MD, PhD Kwang Kon KohKwang Kon Koh Department of Cardiovascular Medicine, Heart Center, Gachon University, Gil Medical Center, Incheon, Korea. Gachon Cardiovascular Research Institute, Incheon, Korea. Search for more papers by this author Originally published17 Sep 2018https://doi.org/10.1161/CIRCULATIONAHA.118.035495Circulation. 2018;138:1283–1284To the Editor:Mefford et al1 report that that lifelong exposure to low PCSK9 (proprotein convertase subtilisin/kexin type-9) levels and cumulative exposure to lower levels of low-density lipoprotein cholesterol are not associated with neurocognitive effects in blacks.Recent studies showed that low-density lipoprotein (LDL)-cholesterol levels <25 mg/dL or <15 mg/dL on a PCSK9 inhibitor, alirocumab, were not associated with an increase in overall treatment-emergent adverse event rates or neurocognitive events, although cataract incidence increased 3 times in the group achieving LDL-cholesterol levels <25 mg/dL.2 However, the follow-up period is not enough to be safe. Although evolocumab was not correlated with reduced cognitive function over a median of 19 months,3 more prolonged exposure to extremely low LDL-cholesterol levels could cause neurocognitive dysfunction, cataract, and new-onset diabetes mellitus, because it would impair cellular function, although these studies reported no incidence of diabetes mellitus.Statins are important for preventing adverse cardiovascular events in patients with both a high risk and a low risk of vascular disease by reducing the levels of LDL-cholesterol. However, statins dose-dependently increase adverse effects and increase the risk of type 2 diabetes mellitus.4 This was previously hypothesized to be attributable to off-target effects, but recent studies have demonstrated that it was attributable to on-target effects.4 Like statins, PCSK9 inhibitors may increase adverse effects and increase the risk of type 2 diabetes mellitus. In the mendelian randomization study, data from cohort studies, randomized controlled trials, case control studies, and genetic consortia were used to estimate associations of PCSK9 genetic variants with LDL-cholesterol, fasting blood glucose, hemoglobin A1c, fasting insulin, etc, and risk of type 2 diabetes mellitus by using a standardized analysis plan, meta-analyses, and weighted gene-centric scores. Combined analyses of 4 independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL-cholesterol showed associations with increased fasting glucose (0.09 mmol/L; 95% CI, 0.02–0.15), bodyweight (1.03 kg; 0.24–1.82), waist-to-hip ratio (0.006; 0.003–0.010), and an odds ratio for type 2 diabetes mellitus of 1.29 (1.11–1.50). PCSK9 variants associated with lower LDL-cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes mellitus.5 In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.4,5Sources of FundingThis work was supported by a grant of the Korean Society of CardioMetabolic Syndrome.DisclosuresNone.Footnoteshttps://www.ahajournals.org/journal/circ

Coronary artery disease (CAD), the most common type of heart disease, is the leading reason for mortality in both developing and developed countries. Increased cholesterol and fatty deposits (called plaques) may cause hardening or narrowing of the arteries which supply blood to heart muscles. Triglycerides, low density lipoproteins (LDL), high density lipoproteins (HDL) are different types of cholesterols found in the blood and LDL is the main target for lipid modifying therapy, with the aim of improving long term CAD prognosis. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is one of the candidate genes with expression of PCSK9 protein and PCSK9 inhibitors are coming up as newer lipid lowering therapy. This narrative review highlights the journey of drug development from recognition of PCSK9 gene to the recent approvals of PCSK9 targeting LDL lowering pharmacotherapy. A bibliographic survey was made with titles PCSK9, PCSK9 inhibitors and coronary artery disease in different search engines from year 2000 to 2019 and filtered with review, preclinical and clinical studies. Retrieved articles were revisited and it was observed that PCSK9 is expressed mainly in hepatocytes and to some extent in mesenchymal cells of kidney, intestinal ileum, colon epithelia and in telencephalon neurons of embryonic brain. In hepatocytes, loss-of function mutations of PCSK9 leads to higher levels of LDL receptors. These receptors make LDL receptor-LDL cholesterol complex, which is directed to the lysosome for degradation of LDL in hepatocytes and lowers LDL cholesterol levels, ultimately resulting in protection from CAD. Gain-of-function mutations hamper LDL degradation. PCSK9 research has proposed an exciting new area for cholesterol management and CAD risk reduction. Different PCSK9 inhibitors with different therapeutic targets for CAD are evolving day by day from bench to bedside. This review could be valuable for helping researchers acquire a deeper insight for PCSK9 and its Inhibitors.

Despite the availability of effective drug therapies that reduce low-density lipoprotein (LDL)-cholesterol (LDL-C), cardiovascular disease (CVD) remains an important cause of mortality and morbidity. Therefore, additional LDL-C reduction may be warranted, especially for patients who are unresponsive to, or unable to take, existing LDL-C-reducing therapies. By inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, monoclonal antibodies (PCSK9 inhibitors) may further reduce LDL-C, potentially reducing CVD risk as well. Primary To quantify short-term (24 weeks), medium-term (one year), and long-term (five years) effects of PCSK9 inhibitors on lipid parameters and on the incidence of CVD. Secondary To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of type 2 diabetes, cognitive function, and cancer. Additionally, to determine if specific patient subgroups were more or less likely to benefit from the use of PCSK9 inhibitors. We identified studies by systematically searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and Web of Science. We also searched Clinicaltrials.gov and the International Clinical Trials Registry Platform and screened the reference lists of included studies. We identified the studies included in this review through electronic literature searches conducted up to May 2016, and added three large trials published in March 2017. All parallel-group and factorial randomised controlled trials (RCTs) with a follow-up time of at least 24 weeks were eligible. Two review authors independently reviewed and extracted data. When data were available, we calculated pooled effect estimates. We included 20 studies with data on 67,237 participants (median age 61 years; range 52 to 64 years). Twelve trials randomised participants to alirocumab, three trials to bococizumab, one to RG7652, and four to evolocumab. Owing to the small number of trials using agents other than alirocumab, we did not differentiate between types of PCSK9 inhibitors used. We compared PCSK9 inhibitors with placebo (thirteen RCTs), ezetimibe (two RCTs) or ezetimibe and statins (five RCTs).Compared with placebo, PCSK9 inhibitors decreased LDL-C by 53.86% (95% confidence interval (CI) 58.64 to 49.08; eight studies; 4782 participants; GRADE: moderate) at 24 weeks; compared with ezetimibe, PCSK9 inhibitors decreased LDL-C by 30.20% (95% CI 34.18 to 26.23; two studies; 823 participants; GRADE: moderate), and compared with ezetimibe and statins, PCSK9 inhibitors decreased LDL-C by 39.20% (95% CI 56.15 to 22.26; five studies; 5376 participants; GRADE: moderate).Compared with placebo, PCSK9 inhibitors decreased the risk of CVD events, with a risk difference (RD) of 0.91% (odds ratio (OR) of 0.86, 95% CI 0.80 to 0.92; eight studies; 59,294 participants; GRADE: moderate). Compared with ezetimibe and statins, PCSK9 inhibitors appeared to have a stronger protective effect on CVD risk, although with considerable uncertainty (RD 1.06%, OR 0.45, 95% CI 0.27 to 0.75; three studies; 4770 participants; GRADE: very low). No data were available for the ezetimibe only comparison. Compared with placebo, PCSK9 probably had little or no effect on mortality (RD 0.03%, OR 1.02, 95% CI 0.91 to 1.14; 12 studies; 60,684 participants; GRADE: moderate). Compared with placebo, PCSK9 inhibitors increased the risk of any adverse events (RD 1.54%, OR 1.08, 95% CI 1.04 to 1.12; 13 studies; 54,204 participants; GRADE: low). Similar effects were observed for the comparison of ezetimibe and statins: RD 3.70%, OR 1.18, 95% CI 1.05 to 1.34; four studies; 5376 participants; GRADE: low. Clinical event data were unavailable for the ezetimibe only comparison. Over short-term to medium-term follow-up, PCSK9 inhibitors reduced LDL-C. Studies with medium-term follow-up time (longest median follow-up recorded was 26 months) reported that PCSK9 inhibitors (compared with placebo) decreased CVD risk but may have increased the risk of any adverse events (driven by SPIRE-1 and -2 trials). Available evidence suggests that PCSK9 inhibitor use probably leads to little or no difference in mortality. Evidence on relative efficacy and safety when PCSK9 inhibitors were compared with active treatments was of low to very low quality (GRADE); follow-up times were short and events were few. Large trials with longer follow-up are needed to evaluate PCSK9 inhibitors versus active treatments as well as placebo. Owing to the predominant inclusion of high-risk patients in these studies, applicability of results to primary prevention is limited. Finally, estimated risk differences indicate that PCSK9 inhibitors only modestly change absolute risks (often to less than 1%).

Joint statement from the European Atherosclerosis Society and European Society of Vascular Medicine focuses on patients with peripheral arterial disease

Atherosclerosis cardiovascular disease has become one of the main causes of death in China, and the dyslipidemia is an important factor in the occurrence and development of atherosclerosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted serine protease synthesized by the liver that binds to the low density lipoprotein (LDL) receptor promoting its degradation, is an important regulator of LDL metabolism. PCSK9 inhibitors can reduce intrahepatic lysosomal degradation of internalized LDL receptors, resulting in increased hepatic expression of LDL receptors and a reduced concentration of circulating LDL cholesterol. In recent years, the new drugs represented by PCSK9 inhibitors have attracted more and more attention and remarkable progress has been made. In this article, the current research advancesin PCSK9 inhibitors was reviewed. Key words: Athrosclerosis; PCSK9 inhibitors; Alirocumab; Evolocumab; Bococizumab; Inclisiran

Introduction and aim. Cardiovascular diseases are the main cause of mortality in the world. One of the alterable risk factors of ischaemic heart disease is dyslipidemia. Discovery and usage of a new group of drugs - PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors lead to a decrease of LDL-C (low-density lipoprotein cholesterol) levels in patients who are resistant to standard hypolipidemic therapy. The aim of this paper is to introduce PCSK9 inhibitors and describe their usage in medicine. Material and methods. A review of the available literature was performed by searching the PubMed and GoogleScholar databases using the following key words: PCSK9 inhibitors; alirocumab; evolocumab; inclisiran. Analysis of the literature. According to the European Society of Cardiology guidelines for dyslipidemias from year 2019, the main aim of dyslipidemia treatment is LDL-C reduction to target values depending on patient risk levels. It may be achieved in 2 ways, namely, by lifestyle modification or by pharmacological treatment with statins, fibrates and cholesterol absorption inhibitors. However, a therapy with PCSK9 inhibitors may be considered the most effective in certain groups of patients. Evolocumab and alirocumab are 2 representatives of those new drugs, which are allowed for use in 3 scenarios – in patients with familial hypercholesterolemia, in those with high risk of cardiovascular incident, and in those with statin intolerance. The major advantage of the aforementioned drugs is their safety. Since 2021 inclisiran (the first drug in siRNA class) is available for use as a new type of PCSK9 blocker. Conclusion. PCSK9 inhibitors can be life-saving for patients with a high risk of cardiovascular incidents associated with an elevated level of LDL-C. They reduce LDL-C more efficiently and have fewer side effects in comparison with the other hypolipidemic drugs. Therefore, PCSK9 inhibitors play a very important role in the lipid-lowering treatment.

HomeStrokeVol. 51, No. 11Correction to: PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibition and Stroke Prevention: Another Step Forward Free AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCorrectionPDF/EPUBCorrection to: PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibition and Stroke Prevention: Another Step Forward Originally published26 Oct 2020https://doi.org/10.1161/STR.0000000000000352Stroke. 2020;51:e348This article corrects the followingPCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibition and Stroke PreventionIn the article by Alberts and Thompson, “PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibition and Stroke Prevention: Another Step Forward,” which published online on April 21, 2020 (Stroke. doi: 10.1161/STROKEAHA.120.028567) a correction is needed.On page 1361, paragraph one, reads “…FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk; Improved Reduction of Outcomes: Vytorin Efficacy International Trial)….” It should read “FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk)….”Paragraph two reads “The current report focuses on reduction in stroke events seen in high-risk patients treated with PCSKi evolocumab….” It should read, “The current report focuses on reduction in stroke events seen in high-risk patients treated with the PCSKi evolocumab….”In addition, typos of FOURIER and evolocumab were corrected throughout the article.This correction has been made to the current online version of the article, which is available at https://www.ahajournals.org/doi/10.1161/STROKEAHA.120.028567. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesPCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibition and Stroke PreventionMark J. Alberts, et al. Stroke. 2020;51:1361-1362 November 2020Vol 51, Issue 11 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/STR.0000000000000352PMID: 33104492 Originally publishedOctober 26, 2020 PDF download Advertisement

The incidence of diabetes-associated cognitive dysfunction (DACD) is increasing; however, few clinical intervention measures are available for the prevention and treatment of this disease. Research has shown that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, particularly SBC-115076, have a protective effect against various neurodegenerative diseases. However, their role in DACD remains unknown. In this study, we aimed to explore the impact of PCSK9 inhibitors on DACD. Male Sprague-Dawley (SD) rats were used to establish an animal model of type 2 diabetes mellitus (T2DM). The rats were randomly divided into three groups: the Control group (Control, healthy rats, n = 8), the Model group (Model, rats with T2DM, n = 8), and the PCSK9 inhibitor-treated group (Treat, T2DM rats treated with PCSK9 inhibitors, n = 8). To assess the spatial learning and memory of the rats in each group, the Morris water maze (MWM) test was conducted. Hematoxylin-eosin staining and Nissl staining procedures were performed to assess the structural characteristics and functional status of the neurons of rats from each group. Transmission electron microscopy was used to examine the morphology and structure of the hippocampal neurons. Determine serum PCSK9 and lipid metabolism indicators in each group of rats. Use qRT-PCR to detect the expression levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) in the hippocampal tissues of each group of rats. Western blot was used to detect the expression of PCSK9 and low-density lipoprotein receptor (LDLR) in the hippocampal tissues of rats. In addition, a 4D label-free quantitative proteomics approach was used to analyse protein expression in rat hippocampal tissues. The expression of selected proteins in hippocampal tissues was verified by parallel reaction monitoring (PRM) and immunohistochemistry (IHC). The results showed that the PCSK9 inhibitor alleviated cognitive dysfunction in T2DM rats. PCSK9 inhibitors can reduce PCSK9, total cholesterol (TC), and low-density lipoprotein (LDL) levels in the serum of T2DM rats. Meanwhile, it was found that PCSK9 inhibitors can reduce the expression of PCSK9, IL-1β, IL-6, and TNF-α in the hippocampal tissues of T2DM rats, while increasing the expression of LDLR. Thirteen potential target proteins for the action of PCSK9 inhibitors on DACD rats were identified. PRM and IHC revealed that PCSK9 inhibitors effectively counteracted the downregulation of transthyretin in DACD rats. This study uncovered the target proteins and specific mechanisms of PCSK9 inhibitors in DACD, providing an experimental basis for the clinical application of PCSK9 inhibitors for the potential treatment of DACD.

PCSK9 Inhibitors: What Lies Beyond Monoclonal Antibodies?

S-palmitoylation of PCSK9 induces sorafenib resistance in liver cancer by activating the PI3K/AKT pathway.