Statin Lactone Metabolism is a Determinant of 5-year Cardiovascular Outcomes Independent of Serum Cholesterol

Statin Lactone Metabolism is a Determinant of 5-year Cardiovascular Outcomes Independent of Serum Cholesterol | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Statin Lactone Metabolism is a Determinant of 5-year Cardiovascular Outcomes Independent of Serum Cholesterol Chester Drum, Eugene Goh, Lik Hang Wu, Leroy Sivappiragasam Pakkiri, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4023614/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Statins are a first line treatment for reducing cardiovascular risk, however the individual clinical benefit of statins remains highly variable. To understand the clinical impact of individual statin metabolites on long-term clinical outcomes, we conducted a 5-year, multicentre, prospective, observational trial of 1362 cardiology patients across two independent healthcare systems in Singapore. In addition to genotyping, subjects were also phenotyped based on mass spectrometry quantification of all known plasma statin metabolites, sampled at two time points in late elimination phase. The atorvastatin lactone metabolite (ATVLAC) ≥3.9ng/mL 13 hours post-dose predicted Major Adverse Cardiovascular Events (MACE) (HR=2.45) and all-cause mortality (HR=3.18), independently of drug dose and achieved LDL. UGT1A , a lactone-producing gene, associated with ATVLAC at genome-wide significance, independently predicted MACE (HR=1.40). Simvastatin Lactone (SMVLAC) also associated with MACE and UGT1A , suggesting a class effect. Among 51 co-prescribed non-statin drugs, omeprazole (a UGT inducer) was the strongest predictor of plasma ATVLAC (1.41-fold) and MACE (HR=1.46). These results suggest the statin lactone metabolite is a determinant of differential outcomes in statin takers and omeprazole co-prescription is a novel, potential risk factor. Genotyping the enzymatic source of statin lactone, UGT1A , may play a role in pharmacogenetic risk prediction. Health sciences/Diseases/Cardiovascular diseases/Dyslipidaemias Health sciences/Health care/Therapeutics/Adverse effects Health sciences/Medical research/Outcomes research Biological sciences/Genetics/Genetic association study/Genome-wide association studies Health sciences/Health care/Therapeutics/Drug therapy/Pharmacogenetics Statins Cardiovascular Risk Drug Metabolism Genetic Associations in Metabolism UGT1A Omeprazole Drug-Drug Interactions Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryNote.pdf Supplementary Note SupplementaryFigandTables.pdf Supplemental Figures and Tables Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4023614","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":279505466,"identity":"f9b1248f-6350-4d36-87d8-b023c61f00db","order_by":0,"name":"Chester 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