DOI: 10.1161/circ.148.suppl_1.18108 ISSN: 0009-7322

Abstract 18108: Statin Biotransformation and 5-Year Cardiovascular Outcomes in the SAPhIRE Multicentre Observational Trial

Eugene C goh, Lik Hang Wu, Leroy sivappiragasam Pakkiri, Mei Li Ng, Jielin Yang, Maya George, Folefac Aminkeng, Jianjun Liu, E Shyong Tai, Jack W Tan, Chester L Drum
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Importance: Individual variation in statin biotransformation may explain differences in clinical outcomes but remains poorly understood.

Objectives: To quantify statin biotransformation phenotypes in cardiology patients and validate predictors of 5-year clinical outcomes in two independent cohorts.

Design: SAPhIRE is a multicentre, prospective, observational trial of 1363 general cardiology patients taking atorvastatin or simvastatin. The study was initiated in 2014. Sample collection was completed in 2016, and outcomes of participants were followed-up to June 2020 via the Singapore National Registry of Diseases Office (NRDO).

Setting: Participants were enrolled across the National University Hospital of Singapore (NUH) and Singapore General Hospital (SGH). Pharmacologic, genotypic, and mechanistic predictors of 5-year clinical outcomes were determined using clinical data, quantitative mass spectrometry and GWAS.

Main Outcome(s): Major Adverse Cardiovascular Events (MACE) via linkage with NRDO. Risk analysis (multivariable Cox hazards modelling, univariable Kaplan Meier) was used to assess association of metabolism, genomics, and co-prescriptions on 5-year outcomes.

Results: In both independent cohorts, increased statin lactone production of the upper tertile (ATVLAC≥3.9ng/ml) predicted MACE (HR=2.45, CI=1.60-3.44, P<0.001) and all-cause mortality (HR=3.18, CI=1.96-5.16, P<0.001), independently of LDL and drug dose. UGT1A, a lactone-producing gene, associated with ATVLAC at genome-wide significance. In a candidate gene analysis of UGT1A, UGT1A1*80-associated GOF mutations (rs887829, rs11891311, rs6742078, rs4148324, rs4148325 and rs10929302) predicted 1.34-fold higher ATVLAC compared to major allele homozygotes, and after controlling for clinical variables, exhibited higher rates of MACE (average HR=1.40, p<0.05). Among 51 co-prescriptions, omeprazole was the strongest predictor of increased ATVLAC (1.41-fold, P<10-8) and MACE (HR=1.46, CI=1.06-2.00, P=0.020).

Conclusion: A phenotype of low statin lactone production predicts preferential cardiac outcomes in two-thirds of statin takers and is influenced by both UGT1A variation and omeprazole co-prescription.

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