Publication bias in pharmacogenetics of statin-associated muscle symptoms: A meta-epidemiological study

Abstract

Background and aims: Statin-associated muscle symptoms (SAMS) are a major cause of treatment discontinuation. Clinical Pharmacogenetics Implementation Consortium (CPIC) recommend dose adjustment for statin treatment according to known SLCO1B1 genotype to reduce SAMS. We hypothesized that the association between SLCO1B1 genotype and SAMS is misestimated because of publication bias.

Methods: We searched published systematic reviews on the association between SLCO1B1 genotype and SAMS. To assessed publication bias, we used funnel plot visual inspection, Egger's test, and the Bayes Factor (BF_{Publication-bias}) from Robust Bayesian Meta-Analysis (RoBMA). We compared the odds ratios (OR_Uncorrected) from meta-analyses before and after correcting for publication bias using trim-and-fill (OR_Trim&Fill) and RoBMA (OR_RoBMA) methods.

Results: We included 8 cohort and 11 case-control studies, totaling 62 OR of three SLCO1B1 genotypes and six statin drugs. In the primary analysis, the funnel plot was suggestive of publication bias, confirmed by Egger's test (p=0.001) and RoBMA (BF_{Publication-bias} = 18). Correcting the estimate for publication bias resulted in loss of the association, from a significant OR_Uncorrected (1.31 95%CI [1.13-1.53]) to corrected ORs suggesting no difference: OR_Trim&Fill (1.07 95%CI [0.89-1.30]) and OR_RoBMA (1.02 95%CI [1.00-1.33]). This suggested that publication bias overestimated the association by 18 % and 23 %, respectively. Similar results were found for genotype rs4149056, simvastatin and atorvastatin.

Conclusions: The effect of the SLCO1B1 genotype on the risk of developing SAMS is overestimated in the published literature, especially rs4149056. This could lead prescribers to incorrectly decreasing statin doses or even avoiding statin use, leading to a loss of the potential cardiovascular benefit of statins.

Keywords: Meta epidemiological study; Publication bias; RoBMA; SLCO1B1; Statin; Statin-associated muscle symptoms; Systematic review; rs2306283; rs4149056; rs4363657.