Top Wiebe M C, Lehert Philippe, Schalkwijk Casper G, Stehouwer Coen D A, Kooy Adriaan
Department of Internal Medicine, Treant Care Group, Hoogeveen, The Netherlands.
Bethesda Diabetes Research Center, Hoogeveen, The Netherlands.
Diabetes Obes Metab. 2022 Oct;24(10):1983-1988. doi: 10.1111/dom.14784. Epub 2022 Jul 4.
To study the effect of metformin on plasma levels of arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), indicators of the nitric oxide pathway.
In this post hoc analysis of the HOME trial, we analysed plasma levels of arginine, ADMA and SDMA during the 4.3-year follow-up (comparing the effects of metformin versus placebo on top of insulin therapy). Statistical analysis was performed with a mixed model approach, in which simultaneously constant treatment effects were estimated, as well as time-dependent treatment effects.
We found that metformin compared with placebo did not affect ADMA or SDMA plasma levels but rapidly decreased arginine plasma levels and hence the arginine to ADMA ratio. The constant treatment effect on ADMA was 0.99 (95% CI 0.97, 1.00) relative to placebo and the time-dependent treatment effect was 1.00 (95% CI 1.00, 1.01). By contrast, the constant treatment effect on arginine was 0.86 (95% CI 0.84, 0.88), with only a minimal time-dependent change of 1.01 (95% CI 1.00, 1.01).
The potential benefits of metformin on endothelial function cannot be explained by a decrease in ADMA or by improved global arginine availability. The clinical significance of the decreased arginine plasma levels is not clear and can be harmful or beneficial, depending on the mechanism involved. However, a potential effect of metformin on the nitric oxide pathway is not restricted to the studied metabolites.
研究二甲双胍对血浆中精氨酸、不对称二甲基精氨酸（ADMA）和对称二甲基精氨酸（SDMA）水平的影响，这些是一氧化氮途径的指标。
在这项对HOME试验的事后分析中，我们分析了4.3年随访期间精氨酸、ADMA和SDMA的血浆水平（比较二甲双胍与安慰剂在胰岛素治疗基础上的效果）。采用混合模型方法进行统计分析，同时估计固定治疗效果以及时间依赖性治疗效果。
我们发现，与安慰剂相比，二甲双胍不影响ADMA或SDMA的血浆水平，但能迅速降低精氨酸的血浆水平，从而降低精氨酸与ADMA的比值。相对于安慰剂，对ADMA的固定治疗效果为0.99（95%可信区间0.97，1.00），时间依赖性治疗效果为1.00（95%可信区间1.00，1.01）。相比之下，对精氨酸的固定治疗效果为0.86（95%可信区间0.84，0.88），时间依赖性变化极小，为1.01（95%可信区间1.00，1.01）。
二甲双胍对内皮功能的潜在益处不能通过ADMA的降低或整体精氨酸可用性的改善来解释。精氨酸血浆水平降低的临床意义尚不清楚，根据所涉及的机制，可能有害或有益。然而，二甲双胍对一氧化氮途径的潜在影响并不局限于所研究的代谢物。
