Dataset Information

Metabolic effects of PCSK9 inhibition with Evolocumab in subjects with elevated Lp(a).

ABSTRACT:

Background

Epidemiological studies substantiated that subjects with elevated lipoprotein(a) [Lp(a)] have a markedly increased cardiovascular risk. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) lowers both LDL cholesterol (LDL-C) as well as Lp(a), albeit modestly. Effects of PCSK9 inhibition on circulating metabolites such as lipoprotein subclasses, amino acids and fatty acids remain to be characterized.

Methods

We performed nuclear magnetic resonance (NMR) metabolomics on plasma samples derived from 30 individuals with elevated Lp(a) (> 150 mg/dL). The 30 participants were randomly assigned into two groups, placebo (N = 14) and evolocumab (N = 16). We assessed the effect of 16 weeks of evolocumab 420 mg Q4W treatment on circulating metabolites by running lognormal regression analyses, and compared this to placebo. Subsequently, we assessed the interrelationship between Lp(a) and 14 lipoprotein subclasses in response to treatment with evolocumab, by running multilevel multivariate regression analyses.

Results

On average, evolocumab treatment for 16 weeks resulted in a 17% (95% credible interval: 8 to 26%, P < 0.001) reduction of circulating Lp(a), coupled with substantial reduction of VLDL, IDL and LDL particles as well as their lipid contents. Interestingly, increasing concentrations of baseline Lp(a) were associated with larger reduction in triglyceride-rich VLDL particles after evolocumab treatment.

Conclusions

Inhibition of PCSK9 with evolocumab markedly reduced VLDL particle concentrations in addition to lowering LDL-C. The extent of reduction in VLDL particles depended on the baseline level of Lp(a). Our findings suggest a marked effect of evolocumab on VLDL metabolism in subjects with elevated Lp(a).

Trial registration

Clinical trial registration information is registered at ClinicalTrials.gov on April 14, 2016 with the registration number NCT02729025.

SUBMITTER: Zhang X

PROVIDER: S-EPMC7216641 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

Metabolic effects of PCSK9 inhibition with Evolocumab in subjects with elevated Lp(a).

Zhang Xiang X Stiekema Lotte C A LCA Stroes Erik S G ESG Groen Albert K AK

Lipids in health and disease 20200511 1

<h4>Background</h4>Epidemiological studies substantiated that subjects with elevated lipoprotein(a) [Lp(a)] have a markedly increased cardiovascular risk. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) lowers both LDL cholesterol (LDL-C) as well as Lp(a), albeit modestly. Effects of PCSK9 inhibition on circulating metabolites such as lipoprotein subclasses, amino acids and fatty acids remain to be characterized.<h4>Methods</h4>We performed nuclear magnetic resonance (NMR) me ...[more]

PMID: 32393252

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Project description:Abstract: BACKGROUND: Mechanistic studies suggest that proprotein convertase subtilisin/kexin type 9 monoclonal antibody inhibitors (PCSK9mAb) not only reduce low density lipoprotein cholesterol (LDL-C) but can also modulate inflammation. OBJECTIVES: This trial was designed to define the impact of evolocumab on circulating immune cell properties in high-risk ASCVD subjects. METHODS: Double-blind, placebo-controlled trial randomized 41 ASCVD subjects with type 2 diabetes with microalbuminuria and LDL-C level of >70 mg/dL on maximum tolerated statin therapy to receive either subcutaneous evolocumab 420 mg every 4 weeks or matching placebo. The primary outcomes were the change in lipoproteins, blood viscosity, and circulating immune cell transcriptional response at 2 weeks and 12 weeks with evolocumab compared with matching placebo. Safety was assessed in all subjects who received at least one dose of assigned treatment and analyses were conducted in the intention-to-treat population. RESULTS: All 41 randomized subjects completed the 2-week visit. Six subjects (4 evolocumab, 2 placebo) did not receive study medication consistently after the 2-week visit due to suspension of research activities during the COVID-19 pandemic. The groups were well-matched with respect to age, comorbidities, baseline LDL-C, white blood cell counts, and markers of systemic inflammation. Evolocumab reduced LDL-C by -68.8% (p<0.0001) and -52.8% (p<0.0001) at 2 and 12 weeks respectively. There were no differences in blood viscosity at baseline nor at 2 and 12 weeks. RNA-seq was performed on peripheral blood mononuclear cells (PBMC) with and without TLR4 stimulation (“Stress” transcriptomics). There were no group differences in transcriptional profiles in unstimulated PBMC; however, “stress” transcriptomics unmasked immune cell phenotypic differences between evolocumab and placebo groups at 2 and 12 weeks. CONCLUSIONS: This trial is the first to demonstrate that PCSK9 mAB with evolocumab can modulate circulating immune cell properties and highlights the importance of “stress” profiling of circulating immune cells that more clearly define immune contributions to ASCVD. (Funded by Amgen Inc.; ClinicalTrials.gov number, NCT03829046).

Project description:ImportanceThe PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER randomized clinical trial. Patients with metabolic syndrome (MetS) are at increased cardiovascular risk.ObjectiveTo investigate outcomes with evolocumab in patients with and without MetS.Design, setting, and participantsThe FOURIER trial randomized patients worldwide with stable atherosclerotic cardiovascular disease receiving statin to evolocumab vs placebo with follow-up for a median of 2.2 years. Data were collected February 2013 to November 2016. For this prespecified analysis, patients with the requisite data were stratified based on the National Cholesterol Education Program Adult Treatment Panel III MetS criteria; in secondary analyses, patients were further substratified by diabetes at baseline. Analysis was intention to treat. Analysis began March 2018 and ended April 2020.InterventionsPatients were randomized to evolocumab or placebo.Main outcomes and measuresThe primary end point was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary end point was cardiovascular death, myocardial infarction, or stroke.ResultsOf 27 342 patients (mean [SD] age, 63 [9] years; 20 623 men [75.4%]) included in this analysis, 16 361 (59.8%) with baseline MetS were, when compared with patients without MetS, at higher risk of cardiovascular events (adjusted hazard ratio [95% CI], 1.31 [1.18-1.46]; P < .001 for the primary and 1.38 [1.20-1.57]; P < .001 for the key secondary end point). Evolocumab reduced low-density lipoprotein cholesterol similarly in patients with MetS (median [interquartile range], 92 [79-109] mg/dL vs 30 [19-48] mg/dL; P < .001) and without MetS (median [interquartile range], 92 [81-108] mg/dL vs 29 [18-44] mg/dl; P < .001). For the primary end point, the hazard ratios (95% CI) with evolocumab vs placebo were 0.83 (0.76-0.91) and 0.89 (0.79-1.01) in patients with and without MetS (P for interaction = .39). For the key secondary end point, the corresponding hazard ratios (95% CIs) were 0.76 (0.68-0.86) and 0.86 (0.74-1.01) (P for interaction = .23), respectively. Evolocumab did not increase the risk of new-onset diabetes or other major safety outcomes including worsening glycemic control, compared with placebo in patients with MetS.Conclusions and relevancePatients with atherosclerotic cardiovascular disease and MetS have substantial residual risk of cardiovascular events despite statin therapy. Evolocumab significantly reduced low-density lipoprotein cholesterol and cardiovascular risk in patients with MetS without increasing new-onset diabetes, worsening glycemic control, or other major safety events. These data suggest the addition of evolocumab to statin therapy in patients with atherosclerotic cardiovascular disease and MetS is safe and efficacious to reduce residual cardiovascular risk.Trial registrationClinicalTrials.gov Identifier: NCT01764633.

Dataset Information

Metabolic effects of PCSK9 inhibition with Evolocumab in subjects with elevated Lp(a).

Background

Methods

Results

Conclusions

Trial registration

Publications

Metabolic effects of PCSK9 inhibition with Evolocumab in subjects with elevated Lp(a).

Similar Datasets

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