Metformin Reduces Radiation-Induced Cardiac Toxicity Risk in Patients Having Diabetes and Breast Cancer: Results from the Taiwan National Cohort and Basic Research

Background: To analyze the effects of metformin in reducing radiation-induced cardiac toxicity (RICT) risk during adjuvant radiotherapy (RT) after surgery for early-stage breast cancer among diabetic women. Methods: A retrospective national cohort study was conducted using the Taiwan Cancer Registry of 2004-2014. This study included 6,993 diabetic women with early-stage breast cancer who received adjuvant breast RT. An inverse probability of treatment weighting (IPTW) Cox hazards model was used to estimate metformin effects on the occurrence of major heart events. To investigate the effects of Metformin on the cardio-protective, primary culture of human cardiomyocytes were first used as the radiation induced cardiac toxicity experimental model. We also compared RICT in cardiac tissue specimens obtained from irradiated (10 Gy/shot) C57BL/6 mice with or without metformin administration. Results: Among diabetic women with breast cancer status post-surgery under adjuvant breast RT, 2,062 were prescribed metformin and 4,931 were not prescribed metformin. Cox proportional hazard regression analysis, with adjustment using IPTW, indicated that metformin use during adjuvant breast RT significantly reduces the risk of major heart events (adjusted hazard ratio [aHR], 0.789; 95% confidence interval [CI], 0.645-0.965; p = 0.021). The basic research results demonstrated that RT significantly reduced mitochondria membrane potential; meanwhile, metformin co-treatment significantly rescued the death of mitochondria in Human cardiomyocytes. In vivo, metformin administration attenuated RT-induced fibrosis in cardiac tissues. Conclusion: Our results suggest that metformin use during adjuvant breast RT was associated with reduced RICT risk in diabetic women with early-stage breast cancer. Funding Statement: Taipei Medical University and Wan Fang Hospital Declaration of Interests: The authors have no potential conflicts of interest to declare. Ethics Approval Statement: Our protocols were reviewed and approved by the Institutional Review Board of Taipei Medical University (TMU-JIRB No. 201712019).