Linking biological variation to outcomes of statin treatment in the general population

Abstract

Background and aims Large interindividual variability in achieved low-density lipoprotein cholesterol (LDL-C) concentration is known for statin recipients. Systematic profiling of cellular lipid trafficking pathways was performed to elucidate how biological variation contributes to treatment outcomes of statin therapy. Methods Using a multiplexed imaging platform 26 readouts for cellular lipid trafficking were obtained from leukocyte subpopulations for each person, including LDL uptake (UPT), lipid storage (LiM) and three combined lipid trafficking scores (LT-P, LT-R, LT). With this pipeline 400 subjects of the FINRISK 2012 Study were analysed, including 200 recipients of cholesterol-lowering medication. Results Large interindividual variability of cellular LDL uptake and lipid storage was observed. Both LDL uptake and LT score associated negatively with LDL-C for statin recipients and the associations strengthened with increase in statin intensity, explaining up to 25% of LDL-C variability. Integration of LT score with a polygenic risk score for LDL-C further increased the association strength. High-intensity statin (HIS) recipients in the lowest quintile of LT score displayed a pro-atherogenic lipoprotein profile containing more VLDL, IDL and LDL particles with altered lipid content as compared to subjects in the highest quintile of the score. Subjects in the lowest quintile of the LT-R score had lower odds to be at their target LDL-C level and subjects in the lowest quintile of LiM score had higher odds to experience a cardiovascular event as compared to the rest of the HIS recipients. Conclusions Interindividual variation in cellular lipid trafficking pathways can contribute to the variability of statin therapy outcomes and provide new opportunities for treatment optimization and risk assessment in cardiovascular disease.