Dissanayake Ajith Munasinghe, Wheldon Mark Christopher, Ahmed Jafar, Hood Christopher John
Department of Endocrinology and Diabetes, Middlemore Hospital, Auckland, New Zealand.
Department of Biostatistics and Epidemiology, Auckland University of Technology, Middlemore Clinical Trials, Middlemore Hospital, Auckland, New Zealand.
Kidney Int Rep. 2017 Mar 29;2(4):705-712. doi: 10.1016/j.ekir.2017.03.005. eCollection 2017 Jul.
Metformin use in advanced chronic kidney disease is controversial. This study sought to examine the pharmacokinetics, safety, and efficacy of low-dose metformin in patients with type 2 diabetes and stage 4 chronic kidney disease.
In this open-label, phase I trial, 3 consecutive cohorts (1, 2, and 3) of 6 patients each were recruited to receive 250-, 500-, or 1000-mg once-daily doses of metformin, respectively. All patients underwent a first-dose pharmacokinetic profile and weekly trough metformin concentrations for the duration of 4 weeks of daily therapy. Prespecified clinical and biochemical safety endpoints of serum bicarbonate, venous pH, and serum lactate were assessed weekly. Efficacy was assessed by pre- and post-HbA1c and 72-hour capillary glucose monitoring.
There was no evidence of accumulation of metformin in any cohort. There were no episodes of hyperlactatemia or metabolic acidosis and no significant change in any biochemical safety measures. Median (interquartile range) observed trough concentrations of metformin in cohorts 1, 2, and 3 were 0.083 (0.121) mg/l, 0.239 (0.603) mg/l, and 1.930 (3.110) mg/l, respectively. Average capillary glucose concentrations and mean HbA1c decreased in all cohorts.
In our patient cohorts with diabetes and stage 4 chronic kidney disease, treatment with 4 weeks of low-dose metformin was not associated with adverse safety outcomes and revealed stable pharmacokinetics. Our study supports the liberalization of metformin use in this population and supports the use of metformin assays for more individualized dosing.
在晚期慢性肾脏病中使用二甲双胍存在争议。本研究旨在探讨低剂量二甲双胍在2型糖尿病合并4期慢性肾脏病患者中的药代动力学、安全性及疗效。
在这项开放标签的I期试验中，连续招募了3个队列（队列1、2和3），每个队列6名患者，分别接受每日一次250毫克、500毫克或1000毫克的二甲双胍剂量。所有患者在每日治疗的4周期间进行了首剂药代动力学分析，并每周测定二甲双胍谷浓度。每周评估血清碳酸氢盐、静脉血pH值和血清乳酸等预先设定的临床和生化安全性终点指标。通过糖化血红蛋白（HbA1c）测定前后及72小时毛细血管血糖监测评估疗效。
在任何队列中均未发现二甲双胍蓄积的证据。未发生高乳酸血症或代谢性酸中毒事件，任何生化安全性指标均无显著变化。队列1、2和3中观察到的二甲双胍谷浓度中位数（四分位间距）分别为0.083（0.121）毫克/升、0.239（0.603）毫克/升和1.930（3.110）毫克/升。所有队列的平均毛细血管血糖浓度和平均HbA1c均下降。
在我们的糖尿病合并4期慢性肾脏病患者队列中，4周低剂量二甲双胍治疗未出现不良安全结局，且药代动力学稳定。我们的研究支持在该人群中放宽二甲双胍的使用，并支持使用二甲双胍检测进行更个体化的给药。
