Implementation of a Pharmacogenetic Strategy for Statin Therapy in the Spanish National Health System: A Systematic Review and Regulatory Framework Analysis

Background/Objectives: Statins are the first-line lipid-lowering therapy, but their use is limited by interindividual variability in efficacy and safety, particularly statin-associated muscle symptoms. This systematic review aimed to identify pharmacogenetic biomarkers related to statin response, compare them with regulatory recommendations, and propose a candidate pharmacogenetic panel for future clinical validation and implementation studies. Methods: A PRISMA-based systematic review identified 78 eligible studies. A novel composite consistency index integrated the frequency and direction of reported associations across studies, weighted by the methodological quality of the evidence. Identified pharmacogenetic biomarkers were compared with international pharmacogenetic guidelines and Spanish regulatory recommendations to support prioritization. Results:SLCO1B1 showed the strongest and most consistent evidence, particularly for simvastatin-induced myotoxicity, whereas ABCG2 demonstrated the most consistent evidence for rosuvastatin. Evidence linking genetic biomarkers to atorvastatin-related adverse reactions was heterogeneous, while CYP2C9 was associated with fluvastatin response. Other biomarkers were positively associated with statin-related adverse reactions; however, the available evidence remains limited. Conclusions: International guidelines and Spanish regulatory resources revealed substantial concordance despite differences in biomarker inclusion and therapeutic recommendations. Based on the available evidence, a candidate pharmacogenetic biomarker panel is proposed for future implementation studies in personalized statin therapy. SLCO1B1 and ABCG2 emerged as the biomarkers with the strongest and most consistent support across published evidence, regulatory recommendations, and established statin transport pathways. CYP2C9 was also identified as a potentially relevant implementation biomarker; however, the supporting evidence was more limited. Additional biomarkers showed positive associations with statin-related adverse reactions; however, further validation is required.