Journal Article

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

Stiekema, Lotte C. A., Groen, Albert K., Zhang, Xiang, Stroes, Erik S. G.

2020

Overview

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 .

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Aged / Amino acids / Analysis / Antibodies, Monoclonal, Humanized - therapeutic use / Apolipoproteins / Biomedical and Life Sciences / Cardiovascular diseases / Cholesterol / Cholesterol, HDL - blood / Cholesterol, LDL - antagonists & inhibitors / Cholesterol, LDL - blood / Cholesterol, VLDL - antagonists & inhibitors / Cholesterol, VLDL - blood / Clinical Nutrition / Clinical trials / Drug dosages / Epidemiology / Evolocumab / Fasting / Fatty acids / Female / Gene Expression / Heart surgery / Humans / Hyperlipidemias - blood / Hyperlipidemias - diagnosis / Hyperlipidemias - drug therapy / Hyperlipidemias - genetics / Hypolipidemic Agents - therapeutic use / Kexin / Life Sciences / Lipid Metabolism - drug effects / Lipidology / Lipids / Lipoprotein A / Lipoprotein(a) - antagonists & inhibitors / Lipoprotein(a) - blood / Lipoproteins / Lipoproteins (very low density) / Low density lipoprotein / Low density lipoproteins / Magnetic Resonance Spectroscopy / Male / Medical Biochemistry / Metabolism / Metabolites / Metabolome / Metabolomics / Middle Aged / Monoclonal antibodies / Multivariate Analysis / NMR / Nonsteroidal anti-inflammatory drugs / Nuclear magnetic resonance / Patients / PCSK9 antibodies / PCSK9 Inhibitors / Proprotein Convertase 9 - blood / Proprotein Convertase 9 - genetics / Proprotein convertases / Substance abuse treatment / Subtilisin / Trans fatty acids / Triglycerides / Triglycerides - antagonists & inhibitors / Triglycerides - blood / Variables / VLDL