SGLT2 inhibitors and risk of distant metastasis in patients with breast cancer and type 2 diabetes: a target trial emulation with biological plausibility analysis

Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert pleiotropic effects beyond glucose lowering, including potential anticancer properties. Whether SGLT2 inhibitor use is associated with reduced distant metastasis risk in patients with breast cancer and type 2 diabetes remains unknown. Methods We conducted a target trial emulation study using the TriNetX Global Collaborative Network (194 million patients; data covering Jan 1, 2017 to Dec 31, 2025). Adult women with breast cancer, mastectomy, and type 2 diabetes who initiated SGLT2 inhibitors (exposure) or other antidiabetic medications (comparator) post-mastectomy were identified using a new-user design. After 1:1 propensity score matching (3569 per group), we assessed composite distant metastasis (ICD-10: C78 + C79) and organ-specific metastasis using 90-day landmark analysis over five-year follow-up. An exploratory transcriptomic analysis using paired primary–metastasis RNA-sequencing data (GSE110590) assessed biological plausibility. Findings SGLT2 inhibitor use was associated with a reduction in composite distant metastasis (HR 0·676; 95% CI 0·532–0·859; p=0·001). Organ-specific analyses showed the strongest protection for liver metastasis (HR 0·461; 95% CI 0·278–0·765; p < 0·001), followed by lung (HR 0·550; 95% CI 0·351–0·863; p < 0·001) and bone metastasis (HR 0·576; 95% CI 0·394–0·843; p < 0·001), while brain metastasis showed no significant association (HR 0·837; 95% CI 0·460–1·523; p=0·481). Results remained significant in per-protocol and US-only sensitivity analyses. Negative control outcomes confirmed absence of systematic bias. Liver metastases exhibited the broadest metabolic hyperactivity (eight of 15 pathways at FDR<0·05), directionally consistent with organ-specific clinical protection. Interpretation SGLT2 inhibitor use was associated with significantly reduced distant metastasis risk, with an organ-specific gradient that was directionally consistent with exploratory transcriptomic findings. These hypothesis-generating observations should be interpreted with caution. Prospective randomised controlled trials with pre-specified organ-specific distant metastasis endpoints and a dedicated post-mastectomy SGLT2 inhibitor initiation protocol are needed to establish whether the observed associations reflect a causal protective effect before any change in clinical practice. Funding This study was supported by the Tri-Service General Hospital and by a collaborative research grant between Cheng Hsin General Hospital and National Defense Medical University. The funders had no role in study design, data collection, data analyses, data interpretation, or the writing of the report.