二甲双胍治疗 2 型糖尿病和甲基丙二酸：一项随机对照 4.3 年试验的事后分析。

Long-term treatment with metformin in type 2 diabetes and methylmalonic acid: Post hoc analysis of a randomized controlled 4.3year trial.

机构信息

Department of Internal Medicine, Care Group Treant, Location Bethesda Hoogeveen, 7909AA 1 Hoogeveen, Netherlands; Bethesda Diabetes Research Center, 7909AA 1 Hoogeveen, Netherlands.

Department of Internal Medicine, Care Group Treant, Location Bethesda Hoogeveen, 7909AA 1 Hoogeveen, Netherlands; Bethesda Diabetes Research Center, 7909AA 1 Hoogeveen, Netherlands; Department of Internal Medicine, University Medical Center Groningen, Post Office 30.001, 9700 RB Groningen, Netherlands.

出版信息

J Diabetes Complications. 2018 Feb;32(2):171-178. doi: 10.1016/j.jdiacomp.2017.11.001. Epub 2017 Nov 8.

DOI:10.1016/j.jdiacomp.2017.11.001

PMID:29174300

Abstract

AIMS

Metformin treatment is associated with a decrease of serum vitamin B12, but whether this reflects tissue B12 deficiency is controversial. We studied the effects of metformin on serum levels of methylmalonic acid (MMA), a biomarker for tissue B12 deficiency, and on onset or progression of neuropathy.

METHODS

In the HOME trial, 390 insulin-treated patients with type 2 diabetes were treated with metformin or placebo for 52months. In a post hoc analysis, we analyzed the association between metformin, MMA and a validated Neuropathy Score (NPS).

RESULTS

Metformin vs placebo increased MMA at the end of the study (95%CI: 0.019 to 0.055, p=0.001). Mediation analysis showed that the effect of metformin on the NPS consisted of a beneficial effect through lowering HbA1c (-0.020 per gram year) and an adverse effect through increasing MMA (0.042 per gram year), resulting in a non-significant net effect (0.032 per gram year, 95% CI: -0.121 to 0.182, p=0.34).

CONCLUSION

Metformin not only reduces serum levels of B12, but also progressively increases serum MMA. The increase of MMA in metformin users was associated with significant worsening of the NPS. These results provide further support that metformin-related B12 deficiency is clinically relevant. Monitoring of B12 in users of metformin should be considered.

摘要

目的

二甲双胍治疗与血清维生素 B12 水平下降有关，但这是否反映组织 B12 缺乏仍存在争议。我们研究了二甲双胍对血清甲基丙二酸（MMA）水平的影响，MMA 是组织 B12 缺乏的生物标志物，以及对神经病变的发生或进展的影响。

方法

在 HOME 试验中，390 名接受胰岛素治疗的 2 型糖尿病患者接受二甲双胍或安慰剂治疗 52 个月。在事后分析中，我们分析了二甲双胍、MMA 与经过验证的神经病变评分（NPS）之间的关系。

结果

与安慰剂相比，二甲双胍在研究结束时增加了 MMA（95%CI：0.019 至 0.055，p=0.001）。中介分析表明，二甲双胍对 NPS 的影响包括通过降低 HbA1c（每年每克降低 0.020）产生有益作用，以及通过增加 MMA（每年每克增加 0.042）产生不利作用，导致无显著净效应（每年每克 0.032，95%CI：-0.121 至 0.182，p=0.34）。