Deciphering the interplay between SGLT2 inhibition, CCL4, and angina pectoris: A Mendelian randomization study

Angina pectoris, a key symptom of coronary artery disease, is closely associated with inflammation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown cardiovascular benefits, but their exact mechanisms, particularly regarding inflammation, are not fully understood. This study used Mendelian Randomization (MR) to investigate whether SGLT2 inhibition reduces angina risk by modulating inflammatory cytokines, especially C-C motif chemokine ligand 4 (CCL4). A two-sample MR approach was employed, using genetic instruments derived from SLC5A2-related eQTLs and HbA1c-associated single nucleotide polymorphisms. Genome-wide association study summary statistics for CCL4 and other inflammatory cytokines were utilized. The primary analysis was conducted using the inverse variance weighted method. SGLT2 inhibition was associated with a significantly reduced risk of angina pectoris (odds ratio [OR] = 0.28, 95% confidence interval [CI]: 0.11–0.70, P  = .007). Notably, CCL4 was the only inflammatory cytokine linked to both SGLT2 inhibition and angina. SGLT2 inhibition was positively associated with CCL4 levels (β = 1.14, 95% CI: 0.33–1.95, P  = .006), and CCL4 itself was associated with a higher risk of angina (OR = 1.07, 95% CI: 1.01–1.13, P  = .022). However, the calculated indirect effect of SGLT2 on angina via CCL4 was negative, indicating that the mediation proportion could not be quantified due to biological complexity. Our study indicates that SGLT2 inhibition may offer protective effects in angina pectoris. The observed association between SGLT2 inhibition and CCL4 suggests a potentially complex inflammatory pathway that warrants further investigation.