Synergistic associations of metformin and <scp>GLP</scp> ‐1 receptor agonist use with adiposity‐related cancer incidence in people living with type 2 diabetes

BACKGROUND: Metformin and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may reduce the risk of adiposity-related cancers in patients with type 2 diabetes (T2D). The potential synergistic effects of these treatments on cancer incidence remain unclear, considering their distinct biological mechanisms and their associated effects on body weight. METHODS: A retrospective cohort analysis was conducted using a large global database (TriNetX) of patients with T2D. Three cohorts: single agent use with metformin or GLP-1 RAs, and dual/combination metformin/GLP-1 RA use, were compared with a reference group treated with DPP4 inhibitors (DPP4i). Propensity score matching (1:1) was applied to control for confounders. Cancer incidence and all cause mortality were assessed over 5 years of follow up. RESULTS: After matching, metformin and GLP-1 RA treatment were both associated with a lower risk of all adiposity-related cancers and all-cause mortality; the latter was associated with greater reductions in both. Cancer rates were (hazard ratio) 0.96 [95% CI 0.92, 0.99] and 0.86 [0.82, 0.89], while mortality rates were 0.78 [0.76, 0.80] and 0.61 [0.59, 0.63] for metformin and GLP-1 RA, respectively. Dual therapy showed the strongest association with lower cancer incidence (0.61 [0.57, 0.65]) and mortality (0.33 [0.32, 0.35]). Results were more significant in younger, male patients with obesity. CONCLUSION: In patients with T2D, dual metformin and GLP-1 RA treatment was associated with a 39% lower incidence of adiposity-related cancers and a 67% lower mortality, with a striking impact on cancer-related outcomes.