Pharmacogenetic Associations with Statin Regimen Modification, Intolerance, and Adverse Outcomes in Coronary Artery...

Background: Statins are central to primary and secondary prevention of atherosclerotic cardiovascular disease but are often underutilized due to myopathy and intolerance. While individual pharmacogenetic (PGx) variants, particularly in SLCO1B1, are linked to statin-associated muscle symptoms, the real-world impact of both clinical and cumulative PGx burden on regimen modification and adverse outcomes remains unclear. We aimed to evaluate the existing uncertainty regarding whether combined PGx scores can effectively guide statin dose titration and regimen modification, thereby filling a key clinical gap. Methods: A retrospective cohort study of 911 statin-treated patients with coronary artery disease was conducted from the Qatar Cardiovascular Biorepository with available whole-genome sequencing data. Variants in SLCO1B1, ABCG2, and CYP2C9 were combined into a functional PGx burden score, and their associations with statin regimen modification, intolerance, myopathy, liver injury, adherence, and composite adverse events were evaluated. The composite adverse events were defined as the occurrence of any statin-related adverse event, including statin-associated myopathy, liver injury, or poor medication adherence, during the follow-up period. Patients were classified as having experienced the composite outcome if at least one of these events occurred. Results: Over 12 months following statin initiation, 10.2% of patients underwent dose escalation, 11.4% de-escalation, and 78.4% remained on the same regimen. PGx burden is not statistically significantly associated with statin intolerance (OR 1.14; 95% CI: 0.73-1.76), composite adverse outcome (OR 1.08; 95% CI 0.82-1.42), or time to regimen change (HR 1.02; 95% CI 0.77-1.35). However, higher PGx burden showed a directional tendency toward dose de-escalation (RRR 1.18, 95% CI 0.76-1.84) and lower likelihood of escalation (RRR 0.93, 95% CI 0.56-1.54). Conclusions: Clinical factors, particularly statin intensity and myopathy, were the primary determinants of regimen modification. The PGx burden contributes to vulnerability to statin-related adverse effects in a context-dependent manner but does not independently drive statin regimen modification in routine clinical practice. Prospective studies are warranted to assess the clinical utility of PGx-guided workflows in statin therapy.