Abstract 11344: Effect of SLCO1B1*5 on Low-Density Lipoprotein Cholesterol Levels and Long-Term Clinical Events in Patients During Statin Therapy Following Cardiac Catheterization
Background: We and others have demonstrated that the reduced function *5 variant (rs4149056, defined by the minor, C allele) in the hepatic transporter SLCO1B1 impairs statin clearance and is associated with myopathy and premature drug discontinuation, effects that may depend on statin type. Because statins are powerful medications that lower low-density lipoprotein cholesterol (LDLc) and prevent cardiovascular (CV) events, we hypothesized that *5 carriers would have higher LDLc and an increased risk of CV events compared to noncarriers, in a statin specific manner.
Methods: We conducted a retrospective study of 3416 Caucasians from the Duke CATHGEN biorepository. Death/myocardial infarction (MI), genotype, and patient-reported statin usage data were available in 2864 patients. Of these, we identified two independent cohorts (C1, n=498; C2, n=907) with available LDLc at baseline and at 1, 2, and 3 years after cardiac catheterization. Linear mixed models tested the association between *5 and LDLc over a 3-year period in C1 followed by verification in C2. The effect of *5 on death/MI over a median duration of 6 years was assessed using an extended Cox model where statin usage was modeled as a time-dependent covariate.
Results: Over a 3-year period, carriers of *5 in C1 had a 7.1 ± 2.9 mg/dL higher LDLc per copy of the C allele (p=0.01), independent of statin usage. This finding was validated in C2, where carriers had a 5.8 ± 2.1 mg/dL higher LDLc per C allele (p=0.006). Combined cohort analyses showed a 5.6 ± 1.7 mg/dL higher LDLc per C allele (p=0.0008) after adjusting for known predictors of statin-mediated LDLc lowering. In multivariable analysis, *5 was not associated with death/MI (hazard ratio=0.98 [0.83-1.16], p=0.8). We found no evidence for an interaction between *5 and statin type in all analyses (p>0.4).
Conclusions: In two large, independent cohorts representative of patients with complex CV disease, we observed that carrying the SLCO1B1*5 allele was associated with a significant ~5% higher LDLc per C allele over a 3-year period. This difference may be due to either a direct effect of *5 on statin efficacy or an indirect effect on statin utilization. No difference was observed in CV events between carriers and noncarriers over a median follow-up of 6 years.
- © 2013 by American Heart Association, Inc.