The effect of SGLT2 inhibition on prostate cancer: Mendelian randomization and observational analysis using electronic healthcare and cohort data
Jie Zheng, Jieli Lu, Jiying Qi, Qian Yang, Huiling Zhao, Haoyu Liu, Zhihe Chen, Lanhui Huang, Youqiong Ye, Min Xu, Yu Xu, Tiange Wang, Mian Li, Zhiyun Zhao, Ruizhi Zheng, Shuangyuan Wang, Hong Lin, Chunyan Hu, Celine Sze Ling Chui, Shiu Lun Au Yeung, Shan Luo, Olympia Dimopoulou, Padraig Dixon, Sean Harrison, Yi Liu, Jamie Robinson, James Yarmolinsky, Philip Haycock, Jinqiu Yuan, Sarah Lewis, Zhongshang Yuan, Tom R. Gaunt, George Davey Smith, Guang Ning, Richard M. Martin, Bin Cui, Weiqing Wang, Yufang Bi
Abstract
We evaluated the effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on prostate cancer by evidence triangulation. Using Mendelian randomization, we found that genetically proxied SGLT2 inhibition reduced the risk of overall (odds ratio = 0.56, 95% confidence interval [CI] = 0.38 to 0.82; 79,148 prostate cancer cases and 61,106 controls), advanced, and early-onset prostate cancer. Using electronic healthcare data ( n SGLT2i = 24,155; n DPP4i = 24,155), we found that the use of SGLT2 inhibitors was associated with a 23% reduced risk of prostate cancer (hazard ratio = 0.77, 95% CI = 0.61 to 0.99) in men with diabetes. Using data from two prospective cohorts ( n 4C = 57,779; n UK_Biobank = 165,430), we found little evidence to support the association of HbA 1c with prostate cancer, implying a non-glycemic effect of SGLT2 inhibition on prostate cancer. In summary, this study provides multiple layers of evidence to support the beneficial effect of SGLT2 inhibition on reducing prostate cancer risk. Future trials are warranted to investigate whether SGLT2 inhibitors can be recommended for prostate cancer prevention. • A causal protective effect of SGLT2 inhibition on the risk of prostate cancer was observed • This is likely to be a non-glycemic effect of SGLT2 inhibition on prostate cancer • The prescription of SGLT2 inhibitors was prioritized for those with prostate cancer risk Zheng et al. combined genetic, real-world, and cohort evidence to show a causal protective effect of SGLT2 inhibition on the risk of prostate cancer and showed that this effect is likely through a non-glycemic pathway. This study prioritized the prescription of SGLT2 inhibitors for those with prostate cancer risk.