Impact of Metformin and Diabetes on Tumor Response to Total Neoadjuvant Therapy in Advanced Rectal Cancer: A Multicenter Retrospective Cohort Study

AIM: Diabetes mellitus (DM) is associated with impaired response to neoadjuvant chemoradiotherapy in rectal cancer. Metformin may enhance treatment response by improving tumor oxygenation and inhibiting cell growth and proliferation through activation of AMP-activated protein kinase and downstream inhibition of mTOR and HIF-1α pathways. However, the impact of DM and metformin use in patients receiving total neoadjuvant therapy (TNT) for advanced rectal cancer remains unknown. OBJECTIVE: This study evaluates the effect of DM and metformin use on overall complete response (oCR) after TNT. METHODS: This multicenter, retrospective cohort study included consecutive rectal cancer patients treated with TNT with curative intent at three South Australian hospitals between 2019 and 2025. Patients were grouped by diabetes status and metformin use. The primary outcome was the oCR rate, encompassing both clinical complete response (cCR) and pathological complete response (pCR) rates. The main secondary outcome was response at distant sites (complete M1 response). RESULTS: Among 244 patients who completed TNT, 44 (18.0%) were diabetic and 31 (12.7%) patients used metformin. No significant differences in response rates were observed between diabetic and nondiabetic groups: oCR (47.7%vs. 41.5%, p = 0.450), cCR (40.9% vs. 37.5%, p = 0.673), pCR (12.5% vs. 8.3%, p = 0.457), and M1 complete response (50% vs. 36.2%, p = 0.873). Similarly, no significant differences in oCR, cCR, pCR, or complete M1 response were observed between metformin users and non-users. However, subgroup analysis of diabetic patients demonstrated that those taking metformin had a significantly higher oCR rate than those not taking metformin (58.1% vs. 23.1%, p = 0.049). CONCLUSION: Diabetes and metformin use did not significantly affect tumor response rates in the overall cohort of patients with advanced rectal cancer treated with TNT. However, among diabetic patients, metformin use was associated with improved response to TNT. Given the retrospective design and limited sample size, large-scale prospective studies are required to validate these findings.