Abstract 1441: Association of Statin-Induced Musculoskeletal Side Effects with Sex and a Hepatic Uptake Transporter Reduced Function Allele, SLCO1B1*5
Statin-induced musculoskeletal side effects are common and can interfere with reaching target LDL goals. Observations of these side effects suggest that increased systemic exposure to statins or their metabolites may be responsible. Carriers of the SLCO1B1*5 allele and females have higher levels of statin metabolites. The STRENGTH (Statin Response Examined by Genetic Haplotype Markers) study is a pharmacogenetics study of statin efficacy and safety. Subjects (n = 509, 47% male, 84% white) were randomized to atorvastatin 10mg, simvastatin 20mg, or pravastatin 10mg followed by 80mg, 80mg, and 40mg, respectively. At biweekly intervals, patients reported side effects and creatine kinase (CK) was measured. We analyzed a composite adverse event (AE) of: discontinuation for any side effect (majority musculoskeletal), myalgia, or CK>3x baseline. We sequenced 5 genes (CYP2D6, CYP2C8, CYP2C9, CYP3A4, and SLCO1B1) involved in statin metabolism and tested reduced function alleles (n = 8) with a minor allele frequency (MAF) > 10% for association with AE using chi-square or logistic regression and accounted for multiple comparisons using false discovery rate (FDR). 99 subjects had AE (54 discontinued drug, 39 myalgias, and 7 CK elevations). Of baseline characteristics, gender was associated with AE (% female in AE vs. no AE groups, 66% vs. 50%, p < 0.01). Of genetic variants, SLCO1B1*5 (Val174Ala, MAF in STRENGTH = 0.14) had the best association with AE (% with at least 1 allele in AE vs. no AE groups, 37% vs. 25%, p = 0.03, FDR =0.24). Furthermore, there was evidence for a gene-dose effect (% with AE in those with 0, 1, or 2 alleles: 19%, 27%, and 50%, trend p = 0.01). In multivariate analyses, female sex and SLCO1B1*5 genotype were independently associated with AE (odds ratio, [95% confidence intervals], p-value; 2.2, [1.4–3.7], 0.001 and 1.8, [1.1–2.9], 0.02, respectively). When analysis was limited to the low dose phase (number AE = 64), SLCO1B1*5 genotype and gender continued to be associated with AE (p = 0.04 and 0.007, respectively) In this statin challenge study, female sex and SLCO1B1*5 genotype - two characteristics previously shown to raise statin metabolite levels - were correlated with statin-induced musculoskeletal side effects.