Effect of metformin on arginine and dimethylarginines in patients with advanced type 2 diabetes: A post hoc analysis of a randomized trial

Wiebe M.C. Top, Philippe Lehert, Casper G. Schalkwijk, Coen D.A. Stehouwer, Adriaan Kooy*

*Corresponding author for this work

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    Aim: To study the effect of metformin on plasma levels of arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), indicators of the nitric oxide pathway.

    Materials and Methods: 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.

    Results: 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).

    Conclusions: 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.

    Original languageEnglish
    Pages (from-to)1983-1988
    Number of pages6
    JournalDiabetes, Obesity and Metabolism
    Issue number10
    Early online date15-Jun-2022
    Publication statusPublished - 2022


    • cardiovascular disease
    • metformin
    • randomized trial
    • type 2 diabetes

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