Cytochrome p450 variation and response to statin therapy following acute coronary syndrome

Background - Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy . . Methods and Results - The Secondary Prevention of Acute Coronary Events - Reduction of Cholesterol to Key European Targets (SPACE ROCKET) Trial was a rnulticentre, randomized, controlled trial assessing the proportion of patients, at 3 months, achieving European Society of Cardiology 2003 (ESC-03) lipid targets. Of 1263 patients randornized, 77.6% simvastatin versus 79.9% rosuvastatin achieved ESC- 03 targets [OR: 1.16; 95% Cl: 0.88-1.53; P = 0.29]. A post-hoc analysis showed higher achievement of the new ESC, American Heart Association and American College of Cardiology optimal lipid target of LDLc less than 1.81 mmo1/1 (70 mg/dl with rosuvastatin (45.0%) compared with simvastatin (37.8%; OR: 1.37; 95% Cl: 1.09-1.72; p=0.007). We genotyped 601 patients for functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (l075A~C), CYP2C19*2 (681G>A), CYP3AS*1 (6986A>G), and hepatic influx and efflux transporters SLCOIBl (S21T>C) and BCRP (421C>A). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (p=O.006) or BCRP (p=O.OlO). Multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the ESC/AHAJACC LDL cholesterol target (OR: 2.29; 95% Cl: 1.16-4.53; P=0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). Gene variants of CYP2C9, CYP2C19, or SLC01Bl did not affect lipid-lowering response, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; OR: 1.21' 95% Cl: 0.77-1.90: p=0.415). Conclusion - Rosuvastatin lOmg lowered mean cholesterol more effectively than simvastatin 40mgand achieved better results for the latest, more stringent, ESC targets. This difference is more apparent in patients with CYP3A5 and/or BCRP variant genotypes.EThOS - Electronic Theses Online ServiceGBUnited Kingdo