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Association between metformin use prior to admission and lower mortality in septic adult patients with diabetes mellitus: beware of potential confounders

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].

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Abbreviations

MET:

Metformin

AKI:

Acute kidney injury

RRT:

Renal replacement therapy

IHD:

Intermittent hemodialysis

CRRT:

Continuous renal replacement therapy

References

  1. 1.

    Liang H, Ding X, Li L, Wang T, Kan Q, Wang L, Sun T. Association of preadmission metformin use and mortality in patients with sepsis and diabetes mellitus: a systematic review and meta-analysis of cohort studies. Crit Care. 2019;23(1):50. https://doi.org/10.1186/s13054-019-2346-4.

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  2. 2.

    Peters E, Antonelli M, Wittebole X, Nanchal R, François B, Sakr Y, et al. A worldwide multicentre evaluation of the influence of deterioration or improvement of acute kidney injury on clinical outcome in critically ill patients with and without sepsis at ICU admission: results from The Intensive Care Over Nations audit. Crit Care. 2018;22(1):188. https://doi.org/10.1186/s13054-018-2112-z..

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  3. 3.

    Keller G, Cour M, Hernu R, Illinger J, Robert D, Argaud L. Management of metformin-associated lactic acidosis by continuous renal replacement therapy. PLoS One. 2011;6:e23200.

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    Doenyas-Barak K, Beberashvili I, Marcus R, Efrati S. Lactic acidosis and severe septic shock in metformin users: a cohort study. Crit Care. 2016;20:10.

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    Peters N, Jay N, Barraud D, Cravoisy A, Nace L, Bollaert PE, et al. Metformin-associated lactic acidosis in an intensive care unit. Crit Care. 2008;12:R149.

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Acknowledgements

We would like to thank Dr. Melissa Jackson for critical review of the manuscript.

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PMH, SR, and DDB designed the paper. All authors participated in drafting and reviewing. The authors read and approved the final version of the manuscript.

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Correspondence to Patrick M. Honore.

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Honore, P.M., Mugisha, A., Kugener, L. et al. Association between metformin use prior to admission and lower mortality in septic adult patients with diabetes mellitus: beware of potential confounders. Crit Care 24, 183 (2020). https://doi.org/10.1186/s13054-020-02909-3

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