We read with great interest the recent paper by Liang et al. who conclude that their meta-analysis indicated an association between metformin (MET) use prior to admission and lower mortality in septic adult patients with diabetes mellitus [
1]. We would like to make some comments. Nearly half of critically ill patients, especially those with septic shock, have or develop acute kidney injury (AKI), and 20–25% need renal replacement therapy (RRT) within the first week of their admission [
2]. Because of its low molecular weight and minimal protein binding, metformin is equally (highly) eliminated by ultrafiltration (convection) and dialysis (diffusion). Furthermore, its large volume of distribution within a two-compartment pharmacokinetic model implies that metformin may be more effectively cleared by prolonged RRT. This was corroborated by Keller et al., who showed a dramatic reduction of metabolic acidosis and metformin plasma concentrations within the first 24 h after initiating CRRT in patients with MET-induced lactic acidosis, followed by normalization on the second day in all subjects [
3]. Although we do not know the exact rate of CRRT in both arms [
1], it may well be that one group had more CRRT than the other, particularly the metformin group. For instance, in the study of Doenyas-Barak et al., which had a huge impact on the conclusions of this meta-analysis, the use of RRT was higher in the MET-treated population (38.6 vs. 21.2%,
p = 0.13) [
1,
4]. Accordingly, we suspect that the observed difference in mortality rate may be due to the more frequent use of RRT in the MET-treated population. A protective effect of RRT has already been suggested by Peters et al., who found that despite higher illness severity, the mortality rate in patients with MET-associated lactic acidosis treated with intermittent hemodialysis (IHD) was no different to that of non-dialyzed subjects [
5].
Acknowledgements
We would like to thank Dr. Melissa Jackson for critical review of the manuscript.
Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit
http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.