The association between the response of lipid-lowering agents and monogenic variants of familiar hypercholesteremia in Taiwan

Background and Aims The presence of familial hypercholesterolemia (FH) variants (LDLR, APOB, or PCSK9) may affect the ability of lipid-lowering drugs to lower low-density lipoprotein cholesterol (LDL-C) levels. The aim of study is to determine the relationship between the response to lipid-lowering drugs and FH variants. Methods This retrospective cohort study included 1864 patients with coronary artery disease (CAD) who underwent DNA microarray genetic analysis. The study aimed to identify pathogenic or likely pathogenic variants of FH using the ClinVar database. The effectiveness of lipid-lowering agents was quantified into anticipated LDL-C reductions, utilizing the 'rule of six'. The main outcome of the study was evaluated using a multivariate linear regression model. Results This study included 22 FH variant carriers, all exhibiting LDLR variants (81.8% male and average age 65.6 years with no significant differences when compared with non-FH carriers). Upon applying the expected LDL-C level reduction model, it was discerned that FH variant carriers were less successful in achieving LDL-C reduction compared to non-carriers. Moreover, FH carriers exhibited a lower rate of achieving the treatment goal of an LDL-C level less than 70 mg/dL (18.2% in FH carriers versus 66.3% in non-FH carriers on atorvastatin, p< 0.001; and 47.8% in non-FH carriers on rosuvastatin, p= 0.001). The study further revealed that FH carriers exhibited a greater propensity for receiving coronary artery bypass graft (CABG) surgery compared to non-carriers. This was evidenced by 18.2% of FH carriers undergoing CABG versus 3.9% of non-FH carriers in the atorvastatin group (odds ratio 5.47, 95% CI: 1.29-17.64, P = 0.011), and 3.2% in the rosuvastatin group (odds ratio 6.63, 95%CI: 1.20-34.05, P = 0.015). Conclusions CAD patients who are carriers of FH variants exhibit a diminished response to lipid-lowering therapies. Higher-intensity lipid-lowering therapy is recommended for FH patients to achieve more favorable therapeutic outcomes.