Type 2 Diabetes, Glycemic Traits and Overall Cancer Risk: A Large-Scale Prospective Cohort Study

Evidence concerning the associations of T2D and glycemic traits with overall cancer risk and their combined effect with genetic susceptibility remains inconsistent and unexplored.

This large-scale prospective cohort study included 475,637 eligible participants from the UK Biobank. We identified 25,887 participants with T2D by clinical data, baseline self-report data, and biochemistry data. HbA1c and random blood glucose were measured at baseline. The associations of T2D, HbA1c, and random blood glucose with the risk of overall cancer and 20 site-specific cancers, stratified by gender, were evaluated by the Cox regression models. We calculated the cancer site-specific polygenic risk scores (PRS) to define genetic risk for each cancer and evaluated the joint effects of genetic risk and T2D on cancer risk. Additive and multiplicative interaction models were established to assess the gene-T2D interaction.

During a median follow-up of 10.95 years, 41,650 incident cancer cases were observed, including 21,957 males and 19,693 females. For all cancers combined, a higher risk was found in females with T2D (HR: 1.20, 95% CI: 1.13-1.28) or high HbA1c levels (≥ 48 mmol/mol) (HR: 1.20, 95% CI: 1.10-1.31). Among site-specific cancers, individuals with T2D or high glycemic traits had a higher risk of pancreatic, bladder, kidney, colorectal, gastric, lung and endometrial cancer. In contrast, we observed inverse associations of T2D and glycemic traits with prostate cancer. Additive interactions between high PRS and T2D were observed in pancreatic cancer risk (with relative excess risk of interaction (RERI) of 2.39 (95% CI: 0.34 to 4.72) and 4.41 (95% CI: 1.09 to 8.62), in males and females respectively), and in prostate cancer risk (with RERI of -0.94 (95% CI: -1.51 to -0.37) in males).

Our study suggests that T2D and high glycemic traits are associated with a higher risk of multiple malignant cancers, particularly in females.