Statin Lactone Metabolism is a Determinant of 5-Year Cardiovascular Outcomes

Abstract

Statins are widely prescribed lipid-lowering medicines, however the effect of drug metabolism variability on clinical outcomes is poorly understood. We conducted a multicentre, prospective, observational trial of 1458 cardiology patients across two healthcare systems in Singapore. Statin metabolism phenotypes via LC-MS/MS were optimized to determine pharmacologic, genotypic, and mechanistic predictors of 5-year clinical outcomes. We found increased atorvastatin lactone (ATVLAC) production ≥3.9ng/mL predicted Major Adverse Cardiovascular Events (MACE) (HR=2.45) and all-cause mortality (HR=3.18); independent of LDL and dose. UGT1A, a lactone-producing gene, associated with ATVLAC at GWAS-significance. UGT1A1*80-associated mutations predicted increased ATVLAC and MACE (HR=1.40). Simvastatin Lactone (SMVLAC) similarly associated with MACE and UGT1A. In 51 co-prescribed drugs, omeprazole was the strongest predictor of increased ATVLAC (1.41-fold) and MACE (HR=1.46). These results support low statin lactone production as a determinant of preferential cardiac outcomes in two-thirds of statin takers. Lactone metabolism is strongly influenced by UGT1A variation and omeprazole co-prescription.

Note:

Funding Information: This work was supported by the National Medical Research Council (CSAINV17nov012), ASTAR Strategic Positioning Fund (SPF2014/001), ASTAR Industrial Alignment Fund (IAF-PP) and funding from the Economic Development Board-IPP with Agilent Technologies.

Conflict of Interests: The authors declare no competing interests.

Ethical Approval: After 5 years have passed from sample collection, we sought clearance from the Singapore Ministry of Health (MOH), National Registry of Diseases Office (NRDO) under request number Y21-S0002 to obtain 5-year clinical outcomes (MACE as a composite of Stroke, Acute Myocardial Infarction and All-Cause Mortality) on the subjects of the study. The NRDO is a division within the Singapore Ministry of Health which collects data on major diseases and health conditions in Singapore, and is responsible for managing national registries in cancer, stroke, kidney failure and acute myocardial infarction. Access and use of the data was approved for use in this study by the NHG DSIRB Group D (2014/00856).

Keywords: Statins, Cardiovascular Risk, Drug Metabolism, Genetic Associations in Metabolism, UGT1A, Omeprazole, Drug-Drug Interactions