Metformin Use and Long-term Clinical Outcomes in Kidney Transplant Recipients

Rationale & Objective: Metformin has been recommended for some patients with advanced chronic kidney disease. However, the value of metformin in kidney transplant recipients (KTRs) with pretransplant diabetes mellitus (DM) or posttransplant DM is uncertain. We investigated the clinical effects of metformin in KTRs. Study Design: Retrospective cohort study. Setting & Participants: A total of 1,995 KTRs with diabetes from 6 tertiary referral centers in the Republic of Korea. Exposure: Metformin usage was defined as the use of metformin for >90 days after kidney transplantation; 1,193 KTRs were metformin users, and 802 KTRs did not use metformin. Changing usage of metformin among those exposed for >90 days was also characterized. Outcome: Primary outcomes were all-cause mortality and death-censored graft failure (DCGF). Secondary outcomes were biopsy-proven acute rejection (BPAR) and lactic acidosis events. Analytical Approach: Survival analyses were conducted using multivariable Cox regression and competing risk analyses using Fine and Gray models. Changes in metformin use over time were modeled using a time-varying covariate. Metformin usage, mean daily dose, and hemoglobin A_1c (HbA_1c) changes were considered in the landmark analysis to address time-varying confounding. Results: Metformin use was associated with a lower risk of DCGF (adjusted hazard ratio [AHR], 0.47 [95% CI, 0.23-0.96], P = 0.038); there was no significant association with all-cause mortality (AHR, 0.94 [95% CI, 0.32-2.76], P = 0.915) or BPAR (AHR 0.98 [95% CI, 0.62-1.54], P = 0.942). In the subgroup analysis, metformin usage was associated with a reduced risk of all-cause mortality and a lower risk of DCGF for both pretransplantation DM and posttransplant DM groups. Metformin usage was associated with a lower risk of BPAR in the posttransplant DM group, although it was less effective in the pretransplantation DM group. There was no confirmed case of metformin-associated lactic acidosis (MALA) in the present cohort. A higher dose of metformin was correlated with lower risks of DCGF and BPAR. Limitations: Data on newer antidiabetic drugs such as SGLT2 inhibitors are limited, and there is potential limited generalizability to other populations. Conclusions: Metformin usage may benefit KTRs, as evidenced by its association with a reduced risk of DCGF and the absence of MALA events. Randomized controlled trials are needed to validate these observational findings.