University of California, San Diego, La Jolla, CA, United States of America.
National Research Institute, Los Angeles, CA, United States of America.
PLoS One. 2018 Sep 25;13(9):e0203946. doi: 10.1371/journal.pone.0203946. eCollection 2018.
Metformin use is restricted in patients with renal impairment due to potential excess systemic accumulation. This study evaluated the glycemic effects and safety of metformin delayed-release (Metformin DR), which targets metformin delivery to the ileum to leverage its gut-based mechanisms of action while minimizing systemic exposure.
Participants (T2DM [HbA1c 7-10.5%], eGFR ≥60 mL/min/1.73m2, not taking metformin for ≥2 months) were randomized to QD placebo (PBO); QD Metformin DR 600, 900, 1200, or 1500 mg; or to single-blind BID Metformin immediate-release (IR) 1000 mg. The primary endpoint was change in HbA1c for Metformin DR vs. PBO at 16 weeks in the modified intent-to-treat (mITT) population (≥ 1 post-baseline HbA1c while on study drug), using a mixed-effects repeated measures model.
571 subjects were randomized (56 years, 53% male, 80% white; BMI 32.2±5.5 kg/m2; HbA1c 8.6±0.9%; 51% metformin naive); 542 were in the mITT population. Metformin DR 1200 and 1500 mg significantly reduced HbA1c (-0.49±0.13% and -0.62±0.12%, respectively, vs. PBO -0.06±0.13%; p<0.05) and FPG (Caverage Weeks 4-16: -22.3±4.2 mg/dL and -25.1±4.1 mg/dL, respectively vs. -2.5±4.2 mg/dL p<0.05). Metformin IR elicited greater HbA1c improvement (-1.10±0.13%; p<0.01 vs. Placebo and all doses of Metformin DR) but with ~3-fold greater plasma metformin exposure. Normalizing efficacy to systemic exposure, glycemic improvements with Metformin DR were 1.5-fold (HbA1c) and 2.1-fold (FPG) greater than Metformin IR. Adverse events were primarily gastrointestinal but these were less frequent with Metformin DR (<16% incidence) vs. Metformin IR (28%), particularly nausea (1-3% vs 10%).
Metformin DR exhibited greater efficacy per unit plasma exposure than Metformin IR. Future studies will evaluate the effects of Metformin DR in patients with type 2 diabetes and advanced renal disease.
Clinicaltrials.gov NCT02526524.
由于潜在的全身性蓄积过多，二甲双胍在肾功能受损的患者中受到限制。本研究评估了二甲双胍延迟释放（Metformin DR）的血糖作用和安全性，该药物靶向将二甲双胍递送到回肠，以利用其基于肠道的作用机制，同时最大限度地减少全身暴露。
参与者（T2DM [HbA1c 7-10.5%]，eGFR≥60 mL/min/1.73m2，至少 2 个月未服用二甲双胍）被随机分配至 QD 安慰剂（PBO）；QD Metformin DR 600、900、1200 或 1500mg；或单盲 BID 二甲双胍即刻释放（IR）1000mg。主要终点是在修改后的意向治疗（mITT）人群中（≥ 1 个研究药物时的基线后 HbA1c），与 PBO 相比，Metformin DR 治疗 16 周时的 HbA1c 变化，使用混合效应重复测量模型。
571 名受试者被随机分配（56 岁，53%男性，80%白人；BMI 32.2±5.5kg/m2；HbA1c 8.6±0.9%；51%为二甲双胍初治）；542 名受试者纳入 mITT 人群。Metformin DR 1200 和 1500mg 显著降低了 HbA1c（-0.49±0.13%和-0.62±0.12%，分别与 PBO-0.06±0.13%相比；p<0.05）和 FPG（平均第 4-16 周：-22.3±4.2mg/dL 和-25.1±4.1mg/dL，分别与-2.5±4.2mg/dL 相比；p<0.05）。二甲双胍 IR 产生了更大的 HbA1c 改善（-1.10±0.13%；p<0.01 与安慰剂和所有剂量的 Metformin DR 相比），但全身暴露的血浆二甲双胍浓度更高。将疗效归一化为全身暴露，Metformin DR 的血糖改善是二甲双胍 IR 的 1.5 倍（HbA1c）和 2.1 倍（FPG）。不良事件主要是胃肠道，但 Metformin DR（<16%的发生率）比二甲双胍 IR（28%）的发生率较低，特别是恶心（1-3%比 10%）。
与二甲双胍 IR 相比，Metformin DR 表现出更高的单位血浆暴露疗效。未来的研究将评估 Metformin DR 在 2 型糖尿病和晚期肾病患者中的疗效。
Clinicaltrials.gov NCT02526524。
