Relationships of SGLT2 inhibition, circulating metabolites, and cancer: A Mendelian randomization study

The effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on cancer remains controversial. This study aimed to investigate the causal relationship between SGLT2 inhibition, circulating metabolites and cancer through Mendelian randomization. Genetic instruments for SGLT2 inhibition were identified as genetic variants. A two-sample, two-step Mendelian randomization approach was adopted to determine the causal relationship between SGLT2 inhibition and cancer, as well as the mediating role of circulating metabolites that link SGLT2 inhibition to cancer. SGLT2 inhibition was associated with an increased risk of lung cancer, colorectal cancer, skin cancer, and basal cell carcinoma, and a decreased risk of brain cancer. The mediation proportions of SGLT2 inhibition through polyunsaturated fatty acids and omega-6 fatty acids concerning colorectal cancer were 2.388% and 2.131% of the total effect, respectively. The mediation proportion of SGLT2 inhibition through acetone concerning skin cancer was 5.127%. For brain cancer, the mediation proportions of SGLT2 inhibition through medium-high-density lipoprotein triglycerides, high-density lipoprotein triglycerides, and very-low-density lipoprotein triglycerides were 2.648%, 2.131%, and 2.095%, respectively. Our study established the causal effects of SGLT2 inhibition on circulating metabolites. SGLT2 inhibition can influence cancer through various metabolites.