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

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.