RT Journal Article
SR Electronic
T1 Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 278861
DO 10.1101/278861
A1 Eeva Sliz
A1 Johannes Kettunen
A1 Michael V Holmes
A1 Clare Oliver-Williams
A1 Charles Boachie
A1 Qin Wang
A1 Minna Männikkö
A1 Sylvain Sebert
A1 Robin Walters
A1 Kuang Lin
A1 Iona Y Millwood
A1 Robert Clarke
A1 Liming Li
A1 Naomi Rankin
A1 Paul Welsh
A1 Christian Delles
A1 J. Wouter Jukema
A1 Stella Trompet
A1 Ian Ford
A1 Markus Perola
A1 Veikko Salomaa
A1 Marjo-Riitta Järvelin
A1 Zhengming Chen
A1 Debbie A Lawlor
A1 Mika Ala-Korpela
A1 John Danesh
A1 George Davey Smith
A1 Naveed Sattar
A1 Adam Butterworth
A1 Peter Würtz
YR 2018
UL http://biorxiv.org/content/early/2018/03/14/278861.abstract
AB Background Both statins and PCSK9 inhibitors lower blood low-density lipoprotein cholesterol (LDL-C) levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these two lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial, and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial.Methods 228 circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5,359 individuals (2,659 on treatment) in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial at 6-months post-randomization. The corresponding metabolic measures were analyzed in eight population cohorts (N=72,185) using PCSK9 rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors.Results Scaled to an equivalent lowering of LDL-C, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R2=0.88). Alterations in lipoprotein lipid composition and fatty acid balance were similar. However, discrepancies were observed for very-low-density lipoprotein (VLDL) lipid measures. For instance, genetic inhibition of PCSK9 showed weaker effects on lowering of VLDL-cholesterol compared with statin therapy (54% vs. 77% reduction, relative to the lowering effect on LDL-C; P=2 × 10−7 for heterogeneity). Genetic inhibition of PCSK9 showed no robust effects on amino acids, ketones, and a marker of inflammation (GlycA); in contrast, statin treatment lowered GlycA levels.Conclusions Genetic inhibition of PCSK9 results in similar metabolic effects as statin therapy across a detailed lipid and metabolite profile. However, for the same lowering of LDL-C, PCSK9 inhibitors are predicted to be less efficacious than statins at lowering VLDL lipids, which could potentially translate into subtle differences in cardiovascular risk reduction.