Metformin is associated with reduced rejection and improved graft survival in kidney transplant recipients with post-transplant diabetes mellitus

Abstract

Abstract Metformin is widely used as an initial therapy for type 2 diabetes mellitus and often adopted for glycemic control in kidney transplant recipients (KTRs) with post-transplantation diabetes mellitus (PTDM). Despite its increasing use, evidence regarding how metformin interacts with immunosuppressive agents, particularly calcineurin inhibitors, and whether it modifies the risk of allograft rejection, remains limited. We conducted a multicenter retrospective cohort study of 555 KTRs diagnosed with PTDM between 2000 and 2018. Patients were grouped according to calcineurin inhibitor (CNI), tacrolimus, or cyclosporine use and further stratified according to metformin use. Propensity score matching was performed to minimize confounding factors. Among tacrolimus-treated recipients, metformin use was associated with a significantly reduced risk of acute T cell-mediated rejection (TCMR) (HR 0.40, 95% CI 0.18–0.90) and graft failure (HR 0.32, 95% CI 0.14–0.72). A longer duration of metformin use (> 3.8 years) was associated with greater protective effects. Although these associations did not reach statistical significance in cyclosporine-treated recipients, the direction of the effect was similar across both CNI groups. Furthermore, interaction analysis demonstrated no significant interaction between metformin use and CNI type with respect to acute TCMR risk. In KTRs with PTDM, metformin use was associated with a reduced rejection risk and improved graft outcomes. This association appeared consistent across CNI groups, although statistical significance was observed only among tacrolimus-treated recipients. These findings support a potential immunomodulatory role of metformin in KTRs and warrant further investigation.