Gougeon A, Aribi I, Guernouche S, Lega J C, Wright J M, Verstuyft C, Lajoinie A, Gueyffier F, Grenet G
Laboratoire de Biométrie et Biologie Evolutive UMR CNRS 5558, Université Lyon 1, Université de Lyon, Villeurbanne, France; RCTs, Lyon, France.
Laboratoire de Biométrie et Biologie Evolutive UMR CNRS 5558, Université Lyon 1, Université de Lyon, Villeurbanne, France.
Atherosclerosis. 2025 Jan;400:118624. doi: 10.1016/j.atherosclerosis.2024.118624. Epub 2024 Oct 18.
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.
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) from Robust Bayesian Meta-Analysis (RoBMA). We compared the odds ratios (OR) from meta-analyses before and after correcting for publication bias using trim-and-fill (OR) and RoBMA (OR) methods.
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 = 18). Correcting the estimate for publication bias resulted in loss of the association, from a significant OR (1.31 95%CI [1.13-1.53]) to corrected ORs suggesting no difference: OR (1.07 95%CI [0.89-1.30]) and OR (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.
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.
他汀类药物相关肌肉症状（SAMS）是导致停药的主要原因。临床药物基因组学实施联盟（CPIC）建议根据已知的SLCO1B1基因型调整他汀类药物治疗剂量，以减少SAMS。我们推测，由于发表偏倚，SLCO1B1基因型与SAMS之间的关联被错误估计。
我们检索了已发表的关于SLCO1B1基因型与SAMS之间关联的系统评价。为评估发表偏倚，我们使用漏斗图目视检查、Egger检验以及稳健贝叶斯荟萃分析（RoBMA）的贝叶斯因子（BF）。我们比较了使用修剪填充法（OR）和RoBMA（OR）方法校正发表偏倚前后荟萃分析的比值比（OR）。
我们纳入了8项队列研究和11项病例对照研究，共涉及三种SLCO1B1基因型和六种他汀类药物的62个OR。在初步分析中，漏斗图提示存在发表偏倚，Egger检验（p = 0.001）和RoBMA（BF = 18）证实了这一点。校正发表偏倚的估计值导致关联消失从显著的OR（1.31，95%CI[1.13 - 1.53]）变为校正后的OR提示无差异：OR（1.07，95%CI[0.89 - 1.30]）和OR（1.02，95%CI[1.00 - 1.33]）。这表明发表偏倚分别高估了关联18%和23%。对于基因型rs4149056、辛伐他汀和阿托伐他汀也发现了类似结果。
在已发表的文献中，SLCO1B基因型对发生SAMS风险的影响被高估，尤其是rs4149056。这可能导致处方者错误地降低他汀类药物剂量甚至避免使用他汀类药物，从而失去他汀类药物潜在的心血管益处。
