Effect of Evolocumab on Complex Coronary Disease Requiring Revascularization

Oyama, Kazuma; Furtado, Remo H M; Fagundes, Antônio; Zelniker, Thomas A; Tang, Minao; Kuder, Julia; Murphy, Sabina A.; Hamer, Andrew; Wang, Huei; Keech, Anthony; Giugliano, Robert P.; Sabatine, Marc S.; Bergmark, Brian A

doi:10.1016/j.jacc.2020.11.011

Cited by 24 publications

(11 citation statements)

References 14 publications

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“…In addition, our MR analysis confirmed previous reports indicating that PCSK9 increases risk of cardiovascular disease. This result is consistent with the findings of reduction in cardiovascular events in randomised clinical trials of PCSK9 inhibitors 42 . We also replicated other results from previous MR studies examining the role of circulating proteins in cardiovascular diseases and traits.…”

Section: Causal Inference Using Mendelian Randomisationsupporting

confidence: 92%

“…We therefore examined whether any of the 11 proteins with inferred causal relationships in our MR analysis (Figure 4) were already current targets, using the DrugBank database 52 . In addition to PCSK9, which, as described previously, is a target of existing drugs used successfully in the treatment of hypercholesterolaemia and cardiovascular disease 42,[53][54][55] , we found that 5 other proteins: PlGF, PRSS8, IL2-RA, MMP-9 (Matrix Metallopeptidase 9) and TFPI are also targets for drugs in various stages of development (Supplementary Table 11).…”

Section: Causal Inference Using Mendelian Randomisationsupporting

confidence: 62%

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Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases

Macdonald-Dunlop

Klarić

Folkersen³

et al. 2021

Preprint

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We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis-instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.

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Section: Causal Inference Using Mendelian Randomisationsupporting

confidence: 92%

Section: Causal Inference Using Mendelian Randomisationsupporting

confidence: 62%

Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases

Macdonald-Dunlop

Klarić

Folkersen³

et al. 2021

Preprint

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“…Most studies of PCSK9 focused on hepatocytes, promoting LDLR degradation in lysosomes by binding with LDLR, thus increasing plasma LDL-C level. Many large clinical trials have revealed that PCSK9 inhibitors can decrease LDL-C level significantly and ameliorate the main adverse cardiovascular events and even reverse plaque accumulation (13,32,33). Recent studies have provided more evidence of the PCSK9 on macrophages by promoting cholesterol uptake, inhibiting cholesterol efflux, and activating inflammation or apoptosis (15,34).…”

Section: Discussionmentioning

confidence: 99%

“…It is closely involved in lipid metabolism and atherosclerosis. In recent years, PCSK9 has attracted much attention in the field of lipid-lowering because of the powerful reduction of plasma LDL-C levels, amelioration of main adverse cardiovascular events and effect on stabilizing plaques with its inhibition (12,13). In addition to promoting the lysosomal degradation of LDL receptor LDLR on the surface of hepatocytes (14), PCSK9 can also act directly on blood vessel walls, by disrupting lipid intake and efflux of macrophages, promoting the secretion of inflammatory factors and inducing apoptosis to participate in atherosclerosis and even plaque destabilization (15,16).…”

Section: Introductionmentioning

confidence: 99%

Role of PCSK9 in Homocysteine-Accelerated Lipid Accumulation in Macrophages and Atherosclerosis in ApoE−/− Mice

Park

Gao

Cong

et al. 2021

Front. Cardiovasc. Med.

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Background: Homocysteine (Hcy) has been established as an independent risk factor for atherosclerosis, and the involvement of hyperhomocysteinemia (HHcy) in atherosclerotic lesions is complex. Proprotein convertase subtilisin kexin 9 (PCSK9) has vital importance in lipid metabolism, and its inhibitors have intense lipid-lowering and anti-atherosclerotic effects. However, the underlying effect of PCSK9 on HHcy-accelerated dyslipidemia of macrophages is still uncertain. The purpose of this study was to investigate the potential role of PCSK9 in Hcy-induced lipid accumulation and atherosclerotic lesions.Methods:In vitro, gene and protein expressions were assessed by real-time quantitative PCR and western blot in THP-1 macrophages with Hcy incubation. Lipid accumulation and cholesterol efflux were evaluated with Hcy treatment. SBC-115076 was used to examine the role of PCSK9 in ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1)-dependent cholesterol efflux. In vivo, lesion area, lipid deposition and collagen contents were determined in aortas of ApoE−/− mice under a methionine diet. SBC-115076 was subcutaneously injected to explore the potential effects of PCSK9 inhibition on alleviating the severity of HHcy-related atherosclerotic lesions.Results: In THP-1 macrophages, Hcy dose- and time-dependently promoted PCSK9 gene and protein levels without regulating the translation of Low-density lipoprotein receptor (LDLR). SBC-115076 used to inhibit PCSK9 largely alleviated lipid accumulation and reversed the cholesterol efflux to apolipoprotein-I(apoA-I) and high-density lipoprotein (HDL) mediated by ABCA1 and ABCG1. In ApoE−/− mice, methionine diet induced HHcy caused larger lesion area and more lipid accumulation in aortic roots. SBC-115076 reduced atherosclerotic severity by reducing the lesion area and lipid accumulation and increasing expressions of ABCA1 and ABCG1 in macrophages from atherosclerotic plaque. In addition, SBC-115076 decreased plasma Hcy level and lipid profiles significantly.Conclusion: PCSK9 promoted lipid accumulation via inhibiting cholesterol efflux mediated by ABCA1 and ABCG1 from macrophages and accelerated atherosclerotic lesions under HHcy treatment. Inhibiting PCSK9 may have anti-atherogenic properties in HHcy-accelerated atherosclerosis.

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“…Complex coronary revascularization was defined as coronary artery bypass graft surgery (CABG) or complex PCI, as previously reported. 8 Complex PCI was defined according to the GLOBAL LEADERS (A Clinical Study Comparing Two Forms of Anti-Platelet Therapy After Stent Implantation) criteria: multivessel PCI, ≥3 stents implanted, ≥3 lesions treated, bifurcation PCI with ≥2 stents, or total stent length >60 mm. 9 A revascularization was considered to be ischemia-driven if it was prompted by symptoms of angina pectoris, objective signs of ischemia at rest or during exercise (or equivalent) by ECG or noninvasive imaging, or abnormal results of invasive functional testing.…”

Section: Methodsmentioning

confidence: 99%

Effect of Evolocumab in Patients With Prior Percutaneous Coronary Intervention

Furtado

Fagundes

Oyama

et al. 2022

Circ: Cardiovascular Interventions

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Background: Patients with prior percutaneous coronary intervention (PCI) are at high residual risk for multiple types of coronary events within and beyond the stented lesion. This risk might be mitigated by more intensive LDL-C (low-density lipoprotein cholesterol)-lowering beyond just with statin therapy. Methods: FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27 564 patients with stable atherosclerotic disease on statin to the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab or placebo with a median follow-up of 2.2 years. The end points of interest were major adverse cardiovascular events (MACE; a composite of cardiovascular death, myocardial infarction, stroke, unstable angina or coronary revascularization), and major coronary events (a composite of coronary heart death, myocardial infarction, or coronary revascularization). We compared the risk of MACE and the magnitude of relative and absolute risk reductions with evolocumab in patients with and without prior PCI. Results: Seventeen thousand seventy-three patients had prior PCI. In the placebo arm, those with prior PCI had higher rates of MACE (13.2% versus 8.3%; hazard ratio [HR] adj 1.61 [95% CI, 1.42–1.84]; P <0.0001) and major coronary events (11.5% versus 6.0%; HR adj , 1.72 [95% CI, 1.49–1.99]; P <0.0001). Relative risk reductions with evolocumab were similar in patients with and without prior PCI (MACE: HR, 0.84 [0.77–0.91] versus HR, 0.88 [0.77–1.01]; P interaction 0.51; major coronary events: HR, 0.82 [0.75–0.90] versus HR, 0.88 [0.75–1.04]; P interaction 0.42). Absolute risk reductions for MACE were 2.0% versus 0.9% ( P interaction 0.14) and for major coronary events 2.0% versus 0.7% ( P interaction 0.045). In those with prior PCI, the effect of evolocumab on coronary revascularization (HR, 0.76 [0.69–0.85]) was directionally consistent across types of revascularization procedures: coronary artery bypass grafting (HR, 0.71 [0.54–0.94]); any PCI (HR, 0.77 [0.69–0.86]); PCI for de novo lesions (HR, 0.76 [0.66–0.88]); and PCI for stent failure or graft lesions (HR, 0.76 [0.63–0.91]). Conclusions: Evolocumab reduces the risk of MACE in patients with prior PCI including the risk of coronary revascularization, with directionally consistent effects across several types of revascularization procedures, including coronary artery bypass grafting and PCI for stent or graft failure. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01764633.

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Effect of Evolocumab on Complex Coronary Disease Requiring Revascularization

Cited by 24 publications

References 14 publications

Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases

Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases

Role of PCSK9 in Homocysteine-Accelerated Lipid Accumulation in Macrophages and Atherosclerosis in ApoE−/− Mice

Effect of Evolocumab in Patients With Prior Percutaneous Coronary Intervention

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