The Effects of GLUT9 and URAT1 Inhibitors on Cardiovascular Diseases: A Drug-Targeted Mendelian Randomization Study

Objective The strong association between hyperuricemia and cardiovascular diseases prompts this study to investigate the effects of uric acid-lowering drugs, GLUT9 and URAT1 inhibitors (GLUT9i and URAT1i), on cardiovascular diseases using Mendelian randomization (MR) analyses. Methods In GWAS data, SNPs strongly associated with blood uric acid within 100kb regions around the GLUT9 and URAT1 genes are identified, serving as proxies for the targeted effects of genes on uric acid. Subsequently, these SNPs were utilized for MR analyses with gout, common cardiovascular diseases (heart failure, myocardial infarction, ischemic stroke, venous thromboembolism), and their risk factors (blood glucose, lipid levels, blood pressure). MR-Egger was employed for pleiotropy testing, and Cochran's Q test was utilized for heterogeneity testing to ensure the robustness of the MR analysis. Results Both URAT1i and GLUT9i are effective drugs for gout. URAT1i is associated with a reduced risk of heart failure (OR = 0.76, 95% CI 0.63, 0.92, P = 0.004), decreased diastolic blood pressure (β=-0.07, 95% CI -0.13, 0.00, P = 0.048), reduced high-density lipoprotein levels (β=-0.05, 95% CI -0.10, -0.01, P = 0.016), and increased fasting blood glucose levels (β = 0.07, 95% CI 0.02, 0.13, P = 0.006). Conversely, GLUT9i leads to reductions in fasting blood glucose (β =-0.03, 95% CI -0.05, -0.01, P = 0.013) and diastolic blood pressure (β =-0.03, 95% CI -0.05, -0.01, P = 0.005), and increases in high-density lipoprotein (β = 0.02, 95% CI 0.00, 0.03, P = 0.011) Conclusion For patients suffering from gout in conjunction with conditions like hyperglycemia, dyslipidemia, and hypertension, GLUT9i may represent a more promising therapeutic approach.