Department of Internal Medicine, Heukseok Hospital, Chung-Ang University, Seoul, Korea; Department of Clinical Medical Sciences, College of Medicine.
Department of Internal Medicine, Seoul National University Hospital Seoul, Korea.
Am J Kidney Dis. 2023 Sep;82(3):290-299.e1. doi: 10.1053/j.ajkd.2023.01.446. Epub 2023 Mar 23.
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.
Retrospective cohort study.
SETTING & PARTICIPANTS: A total of 1,995 KTRs with diabetes from 6 tertiary referral centers in the Republic of Korea.
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.
Primary outcomes were all-cause mortality and death-censored graft failure (DCGF). Secondary outcomes were biopsy-proven acute rejection (BPAR) and lactic acidosis events.
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 (HbA) changes were considered in the landmark analysis to address time-varying confounding.
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.
Data on newer antidiabetic drugs such as SGLT2 inhibitors are limited, and there is potential limited generalizability to other populations.
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.
二甲双胍已被推荐用于一些患有晚期慢性肾脏病的患者。然而，对于移植前糖尿病（DM）或移植后 DM 的肾移植受者（KTR），二甲双胍的价值尚不确定。我们研究了二甲双胍在 KTR 中的临床效果。
回顾性队列研究。
来自韩国 6 家三级转诊中心的共 1995 名患有糖尿病的 KTR。
二甲双胍的使用定义为肾移植后使用>90 天的二甲双胍；1193 名 KTR 使用二甲双胍，802 名 KTR 未使用二甲双胍。还描述了暴露>90 天的患者中二甲双胍使用的变化情况。
全因死亡率和死亡校正移植物失败（DCGF）。次要结局为活检证实的急性排斥反应（BPAR）和乳酸性酸中毒事件。
使用多变量 Cox 回归和 Fine 和 Gray 模型进行生存分析，使用时变协变量对时间变化的二甲双胍使用进行建模。在 landmark 分析中考虑了二甲双胍的使用、平均日剂量和血红蛋白 A（HbA）的变化，以解决时变混杂问题。
二甲双胍的使用与较低的 DCGF 风险相关（调整后的危险比[AHR]，0.47[95%CI，0.23-0.96]，P=0.038）；与全因死亡率（AHR，0.94[95%CI，0.32-2.76]，P=0.915）或 BPAR（AHR 0.98[95%CI，0.62-1.54]，P=0.942）无显著关联。在亚组分析中，对于移植前 DM 和移植后 DM 组，二甲双胍的使用均与全因死亡率降低和 DCGF 风险降低相关。对于移植后 DM 组，二甲双胍的使用与较低的 BPAR 风险相关，尽管在移植前 DM 组中效果较差。在本队列中未发现确认的二甲双胍相关乳酸性酸中毒（MALA）病例。较高剂量的二甲双胍与较低的 DCGF 和 BPAR 风险相关。
关于新型抗糖尿病药物（如 SGLT2 抑制剂）的数据有限，且其在其他人群中的适用性可能存在局限性。
二甲双胍的使用可能使 KTR 受益，这一点可从其与降低 DCGF 风险和无 MALA 事件相关联得到证明。需要进行随机对照试验来验证这些观察结果。
