Abstract 17284: Metabolomic Effects of Statin Therapy, Ezetimibe and PCSK9-Inhibition: Comparison by Genetic Evidence
Aim: LDL cholesterol is the primary target for cardiovascular prevention. Statins are first-line therapy, but also other LDL lowering drugs are approved: ezetimibe and PCSK9-inhibitors. We aimed to compare the metabolomic profiles of these 3 drug targets via genetic proxies in HMGCR, NPC1L1, and PCSK9. We have recently shown that metabolomics of statin therapy provides insights into the drug mechanisms and potential side-effects (J Am Coll Cardiol 2016;67:1200).
Hypothesis: We hypothesized that NPC1L1 and PCSK9 give rise to similar lipoprotein subclass and fatty acid effects as HMGCR for a similar lowering in LDL-C. We also assessed how NPC1L1 and PCSK9 affect VLDL-cholesterol and many novel biomarkers for type 2 diabetes.
Methods: 123 metabolic measures quantified by nuclear magnetic resonance metabolomics were assessed for n~20,000 individuals with genotype data (Nat Commun 2016;7:11122). The effects of genetic variants in HMGCR, NPC1L1, and PCSK9 were compared to statin effects on lipoprotein subclasses, fatty acids and small molecules including amino acids and glycolysis biomarkers.
Results: Ezetimibe mimicking genotypes caused similar lipoprotein subclass effects as statin therapy, including substantial lowering of VLDL and remnant cholesterol. In contrast, the effects of PCSK9 genotypes were more specific to LDL lipids. Substantial differences in the 3 drug targets were observed for omega-3 and omega-6 fatty acid effects. No robust side-effects on amino acids or glycemic precursors were observed. The 3 drugs had similar modest effects on inflammation.
Conclusions: Based on genetic evidence, lowering of LDL cholesterol by ezetimibe and PCSK9-inhibition results in broadly similar metabolic effects as statin therapy; however, PCSK9-inhibition appears to be less efficacious for lowering triglyceride-rich lipoproteins. Metabolomic characterization of genetic proxies for drug targets can inform pharmacological mechanisms and side-effects.
Author Disclosures: P. Wurtz: Employment; Significant; Employee of Brainshake Ltd, a company offering NMR-based metabolomics.. Ownership Interest; Significant; Shareholder of Brainshake Ltd, a company offering NMR-based metabolomics.. Q. Wang: None. E. Sliz: None. J. Kettunen: None. G. Davey Smith: None. M. Ala-Korpela: Ownership Interest; Significant; Shareholder of Brainshake Ltd, a company offering NMR-based metabolomics..
- © 2016 by American Heart Association, Inc.