Despite its widespread use for cardiovascular risk management, rosuvastatin’s long-term effectiveness is often limited by treatment cessation. Genetic differences, particularly in ABCG2 and SLCO1B1, can alter drug transport, efficacy, and side-effect profiles. The ABCG2 rs2231142 variant increases drug exposure, which may enhance lipid-lowering effects but also raises the likelihood of adverse events, especially muscle-related complications. Investigating these genetic influences in a real-world, ethnically diverse population is critical for improving adherence and enabling tailored therapy. This study evaluated the roles of ABCG2 rs2231142 (G>T; Q141K) and SLCO1B1 rs4149056 (T>C; V174A) variants in rosuvastatin discontinuation and LDL cholesterol response in a multiethnic cohort from the United Arab Emirates. A total of 422 adult patients prescribed rosuvastatin were enrolled in this multicenter prospective cohort and monitored over 12 months. Information on therapy discontinuation was collected from clinical records and patient follow-ups. Genotyping was performed using TaqMan SNP assays. Discontinuation risks associated with each genotype were analyzed using Cox regression and Kaplan-Meier survival curves, while changes in LDL cholesterol were evaluated with descriptive statistics and logistic regression models. Individuals carrying the T/T genotype of ABCG2 rs2231142 exhibited the highest likelihood of stopping therapy (HR = 4.40, p < 0.001), followed by heterozygotes (G/T, HR = 1.75). LDL cholesterol changes were markedly different between those who continued treatment (−17.86 percent) and those who discontinued (+21.89 percent, p < 0.001). The ABCG2 variant was significantly more frequent in discontinuers (30.6 percent vs. 17.4 percent, p = 0.0026), whereas the SLCO1B1 rs4149056 variant showed no significant impact on therapy cessation. Carriers of the ABCG2 minor allele are at elevated risk of discontinuing rosuvastatin due to side effects. Incorporating ABCG2 genotyping into clinical practice may support individualized dosing strategies and enhance patient adherence.
