3E-02 - SLCO1B1 Functional Variants and Statin Efficacy Biomarkers: Analysis of 68,553 UK Biobank Users

Background: SLCO1B1 is a key pharmacogene in pharmacogenomics implementation, particularly in in statin prescribing because of its well‐documented role in statin-associated muscle adverse events. Yet, its impact on statin efficacy remains controversial.

Objectives: To evaluate the effect of SLCO1B1 functional variations on biomarker-defined treatment failure of statin therapy.

Methods: We analysed data from 68,553 UK Biobank participants who reported regular use of simvastatin or atorvastatin at baseline recruitment with a structured questionnaire. SLCO1B1 phenotypes were predicted using whole genome sequencing data and classified as "poor" "decreased" "normal" or "increased" function based on the CPIC (Clinical Pharmacogenetics Implementation Consortium). Statin treatment failure was defined as failing to achieve any of three clinical targets in 3 key biomarkers after statin therapy: total cholesterol ≤5 mmol/L, LDL cholesterol ≤4 mmol/L, or triglycerides ≤2.3 mmol/L. Logistic regression models were used to estimate odds ratios (ORs), adjusting for age, sex, ethnicity, and potential genetic confounders.

Results: 14,336 atorvastatin and 54,217 simvastatin users (mean age 61.31±6.14 years, 38.5% female) were included. The distribution of SLCO1B1 function was: “poor” (2.16%), “decreased” (24.76%), “normal” (70.10%), and “increased” (2.96%). Overall, 46.74% of users failed to achieve at least one biomarker target, failure rates were 31.20% for total cholesterol, 4.15% for LDL cholesterol, and 31.20% for triglycerides. Compared to “normal” function of SLCO1B1 gene, “poor” function was associated with higher probability of treatment failure: any (OR 1.34, 95% CI 1.21-1.49), total cholesterol (OR: 1.31, 95% CI: 1.17-1.47), triglycerides (OR: 1.23, 95% CI: 1.09-1.38), and LDL cholesterol (OR: 1.15, 95% CI: 0.88-1.47). A significant dose-response trend was observed (p-trend < 0.05; ranking: increased < normal < decreased < poor), and consistent in both atorvastatin and simvastatin users separately.

Conclusions: In the largest population-based study to date, SLCO1B1 functional variants were shown to significantly influence statin treatment response. Our findings reinforce the potential of pharmacogenomics to tailor cardiovascular prevention strategies.