Association between glucose-lowering treatment and cancer metastasis among patients with preexisting type 2 diabetes and incident malignancy.

Preclinical data suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors may promote metastatic progression of preexisting cancer via nuclear factor erythroid 2-related factor 2 (NRF2) activation. We aimed to investigate the association between different glucose-lowering treatments, including DPP-4 inhibitors and metformin, both with potential NRF2 modulating effects, and new-onset metastatic cancer among type 2 diabetes patients with comorbid incident cancer. This population-based cohort study included 223,530 diabetic patients newly diagnosed with primary cancer during 2009-2011 in Korea. The patients were categorized into five study cohorts in accordance with treatment modalities during the follow-up until the end of 2016: no-antidiabetic drugs (no-AD), metformin, DPP-4 inhibitors, metformin+DPP-4 inhibitors, and insulin treatment. After propensity score (PS) matching in a 1:1 ratio against the no-AD group, 18,805 patients in metformin, 1,865 in DPP-4 inhibitors, 31,074 in metformin+DPP-4 inhibitors, and 1,895 patients in insulin groups were identified for cohort entry and analyzed against the corresponding number of no-AD patients in each PS-matched comparison pair. Metastatic risk was lower with metformin plus or minus DPP-4 inhibitors (HR 0.84, 95% CI 0.79-0.90 and 0.87, 0.80-0.95, respectively), not significantly associated with DPP-4 inhibitors (0.99, 0.77-1.29) except after thyroid cancer (3.89, 1.01-9.64), and higher with insulin therapy (1.81, 1.46-2.24) compared to no-AD use for all cancers combined. In conclusion, DPP-4 inhibitor therapy was not associated with significant risk of cancer metastasis relative to no-AD therapy, irrespective of patient age and sex, except after thyroid cancer, while metastatic risk was decreased with metformin treatment among type 2 diabetes patients with preexisting cancer.