Metabolomic Consequences of Genetic Inhibition of PCSK9 Compared With Statin Treatment

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Sliz , E , Kettunen , J , Holmes , M V , Williams , C O , Boachie , C , Wang , Q , Maennikkoe , M , Sebert , S , Walters , R , Lin , K , Millwood , I Y , Clarke , R , Li , L , Rankin , N , Welsh , P , Delles , C , Jukema , J W , Trompet , S , Ford , I , Perola , M , Salomaa , V , Jaervelin , M-R , Chen , Z , Lawlor , D A , Ala-Korpela , M , Danesh , J , Davey Smith , G , Sattar , N , Butterworth , A & Würtz , P 2018 , ' Metabolomic Consequences of Genetic Inhibition of PCSK9 Compared With Statin Treatment ' , Circulation , vol. 138 , no. 22 , pp. 2499-2512 . https://doi.org/10.1161/CIRCULATIONAHA.118.034942

Title: Metabolomic Consequences of Genetic Inhibition of PCSK9 Compared With Statin Treatment
Author: Sliz, Eeva; Kettunen, Johannes; Holmes, Michael V.; Williams, Clare Oliver; Boachie, Charles; Wang, Qin; Maennikkoe, Minna; Sebert, Sylvain; Walters, Robin; Lin, Kuang; Millwood, Iona Y.; Clarke, Robert; Li, Liming; Rankin, Naomi; Welsh, Paul; Delles, Christian; Jukema, J. Wouter; Trompet, Stella; Ford, Ian; Perola, Markus; Salomaa, Veikko; Jaervelin, Marjo-Riitta; Chen, Zhengming; Lawlor, Debbie A.; Ala-Korpela, Mika; Danesh, John; Davey Smith, George; Sattar, Naveed; Butterworth, Adam; Würtz, Peter
Contributor: University of Helsinki, National Institute for Health and Welfare (THL)
University of Helsinki, Diabetes and Obesity Research Program
Date: 2018-11-27
Language: eng
Number of pages: 14
Belongs to series: Circulation
ISSN: 0009-7322
URI: http://hdl.handle.net/10138/276972
Abstract: Background: Both statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower blood low-density lipoprotein cholesterol levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these 2 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: Two hundred twenty-eight circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5359 individuals (2659 on treatment) in the PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial at 6 months postrandomization. The corresponding metabolic measures were analyzed in 8 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 low-density lipoprotein cholesterol, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R-2=0.88). Alterations in lipoprotein lipid composition and fatty acid distribution were similar. However, discrepancies were observed for very-low-density lipoprotein lipid measures. For instance, genetic inhibition of PCSK9 had weaker effects on lowering of very-low-density lipoprotein cholesterol compared with statin therapy (54% versus 77% reduction, relative to the lowering effect on low-density lipoprotein cholesterol; P=2x10(-7) for heterogeneity). Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation (GlycA), whereas statin treatment weakly lowered GlycA levels. Conclusions: Genetic inhibition of PCSK9 had similar metabolic effects to statin therapy on detailed lipid and metabolite profiles. However, PCSK9 inhibitors are predicted to have weaker effects on very-low-density lipoprotein lipids compared with statins for an equivalent lowering of low-density lipoprotein cholesterol, which potentially translate into smaller reductions in cardiovascular disease risk.
Subject: lipoproteins
Mendelian randomization analysis
metabolomics
statins
MAGNETIC-RESONANCE METABOLOMICS
GENOME-WIDE ASSOCIATION
LOW-DENSITY-LIPOPROTEIN
PHYSICAL-ACTIVITY
LDL CHOLESTEROL
REDUCING LIPIDS
HEART-DISEASE
RISK
EPIDEMIOLOGY
SAFETY
3121 General medicine, internal medicine and other clinical medicine
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