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Deciphering the Causal Relationship between Sodium-glucose Cotransporter 2 Inhibition and Cancer Risks: A
Liyin Zhang1, Baorui Xue1, Fangyang Yu1
1Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, 39 Lake Road, East Lake Ecological Scenic, Wuhan 430077, Hubei, China.
Abstract:
Background: Controversy persists regarding the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cancer. The underlying causal relationship remains unclear. Method: A two-sample Mendelian randomization (MR) strategy was employed to investigate the causal associations between SGLT2 inhibitors and 26 site-specific malignancies. Instrumental variants strongly associated with SLC5A2 gene expression and glycated hemoglobin A1c levels were identified as the genetic proxy for SGLT2 inhibition. Cancer-related outcome datasets sourced from the OpenGWAS project were separated into discovery and replication datasets. The meta-analysis was conducted to determine the final causality. Results: Genetically proxied SGLT2 inhibition showed a significant association with bronchial and lung cancer (beta: -0.028 [-0.041, -0.015], P < 0.001), bladder cancer (beta: 0.018 [0.008, 0.027], P < 0.001), prostate cancer (beta: 1.168 [0.594, 1.742], P < 0.001), cervical cancer (beta: -0.019 [-0.031, -0.008], P = 0.001), corpus uterine cancer (beta: 0.015 [0.006, 0.025], P = 0.001) and non-melanoma skin cancer (beta: -0.080 [-0.116, -0.044], P < 0.001) in the discovery cohort. The suggestive causal effect of SGLT2 inhibition on the increased risk of cervical cancer (beta: 3.241 [0.855, 5.627], P = 0.008) and lymphoid leukemia (beta: 4.126 [0.383, 7.868], P = 0.031) was found in the replication cohort. The combined causality of the following types of cancer was observed to remain significant after meta-analysis: bronchial and lung cancer, bladder cancer, prostate cancer, corpus uterine cancer, and non-melanoma skin cancer (all P ≤ 0.001). Conclusion: For the first time we discovered that the SGLT2 inhibition may exert protection on bronchial and lung cancer and non-melanoma skin cancer from a genetic perspective. However, suggestive higher cancer risks of bladder, prostate, and corpus uteri were also noted, which warrants real-world data validation in the future.
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