Publication bias in pharmacogenetics of statin-associated muscle symptoms, an umbrella review with a meta-epidemiological study

Abstract

AbstractBackgroundStatin-associated muscle symptoms (SAMS) are a major cause of treatment discontinuation. Adjusting statin dosages for solute carrier organic anion transporter family member 1B1 (SLCO1B1) genotype has been proposed to reduce SAMS. We hypothesized that the association between SLCO1B1 genotype and SAMS is misestimated because of publication bias.MethodsWe searched for published systematic reviews evaluating the association between SLCO1B1 genotype and SAMS. We collected the odds ratio (OR) of this association in each clinical study. We assessed the presence of publication bias using the visual inspection of a funnel plot and Egger’s test and used the Bayes Factor (BFPublication-bias) of the Robust Bayesian Meta-Analysis (RoBMA) as a sensitivity analysis. We evaluated the effect of publication bias by comparing qualitatively and quantitatively (ratio of OR [ROR]) OR of the meta-analysis i) uncorrected for potential publication bias (ORUncorrected) and ii) corrected using the trim-and-fill (ORTrim&Fill). We also used the RoBMA (ORRoBMA) for corrected OR as a sensitivity analysis. Our primary analysis covered the associations between any SLCO1B1 genotype and any statin drug. Secondary analysis focused on SLCO1B1 genotypes and statin drug subgroups.ResultsWe included 8 cohort and 11 case-control studies, totaling 62 OR of three SLCO1B1 genotypes and five statin drugs plus one ‘mixed’ statin treatment. All controls were statin-tolerant patients. In the primary analysis, the funnel plot was suggestive of publication bias, confirmed by Egger’s test (p=0.001) and RoBMA (BFPublication-bias=18). Correcting the estimate for publication bias resulted in loss of the association, from a significant ORUncorrected(1.31 95% CI [1.13– 1.53]) to corrected ORs suggesting no difference: i) ORTrim&Fill(1.07 95% CI [0.89–1.30]) and ii) ORRoBMA(1.02 95% CI [1.00–1.33]). The RORTrim&Filland the RORRoBMAsuggested that publication bias overestimated the association by 18% and 23%, respectively. The results were similar for the most studied SLCO1B1 genotype, as for simvastatin and atorvastatin.ConclusionThe effect of the SLCO1B1 genotype on the risk of developing SAMS is overestimated in the published literature. 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.Clinical perspectiveWhat is new?There is significant publication bias in the available literature regarding the association between SLCO1B1 genotype and statin-associated muscle symptoms.The available literature overestimates the importance of the SLCO1B1 genotype on statin-associated muscle symptoms.What are the clinical implications?The cardiovascular benefit of statins might be wrongly lost when adjusting statin therapy with the SLCO1B1 genotype.The effect of publication bias should be considered when writing guidelines.