Target trial emulation of impact of SGLT2 inhibitors of distant metastasis risk in patients with breast cancer and type 2 diabetes

SGLT2 inhibitors exert pleiotropic effects beyond glucose lowering, including potential anticancer properties. A target trial emulation study using the TriNetS Globa Collaborative Network (194 million patients; data covering 2017 – 2025) investigated whether SGLT2 inhibitor use is associated with reduced distant metastasis risk in patients with breast cancer and type 2 diabetes (T2D). Adult women with breast cancer, mastectomy, and T2D who initiated SGLT2 inhibitors (exposure) or other antidiabetic medications (comparator) post-mastectomy were identified. After 1:1 propensity score matching (3569 patients per group), the authors assessed composite distant metastasis and organ-specific metastasis using 90-day landmark analysis (after mastectomy) over five-year follow-up. SGLT2 inhibitor use was associated with a reduction in composite distant metastasis (HR 0.676; p=0.001). Organ-specific analyses showed the strongest protection for liver metastasis (HR 0.461; p<0.001), followed by lung (0.550; pxtagstartz0.001) and bone (0.576; p<0.001) metastasis, while brain metastasis showed no significant association (0.837; p=0.481). Results remained significant in per-protocol and US-only sensitivity analyses. Negative control outcomes confirmed absence of systematic bias. The authors conclude that SGLT2 inhibitor use was associated with significantly reduced distant metastasis risk among patients with breast cancer and T2D.