Advantages of Metformin Therapy for the Prevention and Mitigation of Diabetic Foot Ulcer in Patients With Diabetic Kidney Disease: A Real-Word Evidence From Large-Scale Cohort

Background: Diabetic foot ulcer (DFU) and diabetic kidney disease (DKD) are diabetes-related microvascular complications strongly correlated with high morbidity and mortality. While metformin potentially confers a wound-healing advantage, there is no well-established clinical evidence. This study investigates the effect of metformin on DFU from large DKD cohort for the first time.  Methods: This retrospective cohort study enrolled DKD patients from two South Korean tertiary-referral centers between 2001 and 2016. Primary outcomes were all-cause mortality and DFU events; secondary outcomes included hospitalization, amputation, composite of amputation or vascular intervention, and Wagner Grade≥3. Multivariate cox analysis and propensity score matching (PSM) were used to balance baseline intergroup differences between metformin users and metformin non-users.  Findings: Among 10,832 patients (4,748 metformin users; 6,084 metformin non-users), the 117·5±66·9 months follow-up period, all-cause mortality rate and DFU incidence were 37·1%, and 5·2%, respectively. Fully adjusted multivariate Cox analysis showed that metformin users had lower all-cause mortality (adjusted hazard ratio 0·63; 95% confidence interval 0·58–0·68; p<0·001) and DFU events (0·39; 0·31–0·48; p<0·001). After PSM, metformin users showed lower all-cause mortality (0·61; 0·55–0·67; p<0·001), DFU events (0·42; 0·32–0·56; p<0·001), and secondary outcomes.  Interpretation: Metformin therapy in DKD patient can lower all-cause mortality, DFU incidence, and DFU progression.   Funding Information: This work was partly supported by Institute of Information & Communications Technology Planning & Evaluation project funded by Korean government (Ministry of the Interior and Safety; no.2021-0-01177) and public clinical research grant-in-aid from Seoul Metropolitan Government-Seoul National University Boramae Medical Center (no.04-2021-0042). Declaration of Interests: All authors declare that they have no conflict of interest. Ethics Approval Statement: This study protocol was approved by the Institutional Review Board of SNUH (No. J-2010-119-1166) and BRMH (No. 30-2020-128). The requirement for informed consent was waived by the approving authority due to the study design. All clinical investigations were conducted in accordance with the principles of the Declaration of Helsinki and its 2013 amendment.